Mitigation of aging-related plasticity decline through taurine supplementation and environmental enrichment

Mitigation of aging-related plasticity decline through taurine supplementation and environmental enrichment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Mitigation of aging-related plasticity decline through taurine supplementation and environmental enrichment Aleksandra Gawryluk, Anita Cybulska-Klosowicz, Agata Charzynska, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4372981/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Aug, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Aging-related biochemical changes in nerve cells lead to dysfunctional synapses and disrupted neuronal circuits, ultimately affecting vital processes such as brain plasticity, learning, and memory. The imbalance between excitation and inhibition in synaptic function during aging contributes to cognitive impairment, emphasizing the importance of compensatory mechanisms. Fear conditioning-related plasticity of somatosensory barrel cortex, relying on the proper functioning and extensive upregulation of GABAergic system, in particular interneurons containing somatostatin, is compromised in aging (one-year-old) mice. The present research explores two potential interventions, taurine supplementation and environmental enrichment, revealing their effectiveness in supporting learning-induced plasticity in the aging mouse brain. They do not act through a mechanism normalizing the Glutamate/GABA balance that is disrupted in aging, but they do allow for increase in somatostatin levels, an effect observed in young animals after learning. These findings highlight the potential of lifestyle interventions and diet supplementation to mitigate age-related cognitive decline by promoting experience-dependent plasticity. Biological sciences/Neuroscience/Learning and memory Biological sciences/Neuroscience/Neural ageing Biological sciences/Neuroscience/Somatosensory system Biological sciences/Neuroscience/Synaptic plasticity Biological sciences/Neuroscience Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Aging-related biochemical alterations in nerve cells lead to malfunctioning synapses and, consequently, entire neuronal circuits, adversely affecting their functioning, including such vital processes as brain plasticity, learning, and memory. Along with the reduced release of neurotransmitters and decreased neuronal reactivity observed in aging, a decrease in the number of neurons and their synaptic contacts can cause a loss of balance between excitation and inhibition (E/I), leading to impaired plasticity. If compensatory mechanisms are ineffective, this can cause cognitive impairment and even activate biochemical pathways, leading to various pathological conditions. E/I imbalance is, however, also observed in physiological aging of the nervous system, when it is associated with impaired plasticity and reduced cognitive potential. The direction of E/I changes may vary depending on the brain area studied. In the prefrontal cortex, available experimental data support an increase in inhibition with age, correlating with memory deficits (Potier et al., 2006 ; Stanley et al., 2012 ; Bories et al., 2013 ; Bañuelos et al., 2014 ; Cox et al., 2023 ), while evidence of decreased inhibition was found in the sensory systems and hippocampus (Yu, Wang et al., 2006 ). In the rat parietal cortex, an imbalance of arousal/inhibition in favor of inhibition correlated with cognitive impairment (Wong et al., 2006 ). These data indicate that in aging, cognitive performance is affected by changes in the E/I balance at the synapse. We have confirmed this hypothesis, showing a reduction in the Glutamate/GABA ratio in the somatosensory cortex of aging mice, which was associated with impaired learning-dependent neuroplasticity (Liguz-Lecznar et al., 2015 ). Plasticity of cortical maps induced by fear-conditioning, in which a tactile stimulus applied to the vibrissae is paired with a mild electric aversive stimulus to the tail, requires a strong response from the GABAergic system (Siucinska 2006 ; Liguz-Lecznar et al., 2011 ; Cybulska-Klosowicz et al., 2013 ; Posluszny et al., 2015 ). The same conditioning pattern that leads to an expansion of the functional cortical representation of stimulated vibrissae in young mice becomes ineffective in aging animals (Liguz-Lecznar et al., 2015 ). Extension of the conditioning procedure from 3 to 7 days allowed to induce plastic change, which went hand in hand with an increase in GABA levels. This means that the decrease in plasticity in aging animals is due to the failure of the mechanisms that control plasticity, in this case, an insufficient, ineffective response of the GABAergic system to the increased demand for inhibition (Liguz-Lecznar et al., 2015 ). Maintaining a high plastic potential of the brain and engaging experience-dependent plasticity can offset the adverse effects of aging. This has been confirmed by several experiments demonstrating the beneficial effects of a stimulating environment, physical and cognitive training on memory (Schmidt et al. 2022 ; Kaushik et al., 2023 ; for review: Sale et al., 2014 , Sahini et al., 2024), Aβ accumulation (Li et al. 2013 ), neurogenesis in the hippocampus, or increased glutamate and GABA levels in old animals (Segovia et al., 2006 ). The observed effects can be attributed to an interference with age-related compensatory/adaptive changes, which, unlike degenerative changes, are modifiable with various supporting strategies. The results of translational research have shown that certain lifestyle elements, so-called healthy habits, including physical activity, cognitive engagement, and an adequate diet, can promote successful aging (Moore et al., 2018 ; Krivanek et al., 2021 ; Weuve et al., 2004 ). In this paper, two approaches were chosen that could potentially help preserve plastic potential and consequently improve cognitive abilities: taurine supplementation (TS) and enrichment of the animals' habitat environment (EE). Taurine is a sulfur-containing non-essential amino acid that plays many functions in the nervous system, including, among others, a role as a neurotransmitter, neurotrophic factor, neuromodulator, and neuroprotectant (Wu and Prentice, 2010 ). Taurine content declines with age, which in the brain was shown for the 27-month-old mouse hippocampus (Zhu et al., 2019 ) and cerebellum of 2-year-old rats (Suarez et al., 2016), and this has been correlated with cognitive deficits and age-associated diseases (Singh et al., 2023 ). Taurine supplementation, on the other hand, ameliorates age-related cognitive deficits like time orientation or judgment and abstract thinking (Bae et al., 2017 ), the performance of passive avoidance tasks, and cross-shaped water maze (El Idrissi et al., 2013). Because taurine is a modulator of the GABAergic system (Idrissi and Trenkner 2004 ; Chen et al., 2029), whose function is impaired in the aging brain, contributing to E/I imbalance, we tested its ability to support plasticity. The second strategy - enriched environment - was selected due to its solidly documented proplastic effects, including neuroplasticity in old age (Gelfo et al., 2018 ; Sale et al., 2014 ; Mora, 2013 for review). We demonstrated the effectiveness of both - TS and EE - strategies in supporting plasticity in the aging mouse brain. Each strategy affected the process of plastic change progression in a slightly different way, and in neither case did the effect rely on restoring the balance between glutamate and GABA to the value observed in young animals. Materials and Methods Animals The experiments used 60 female C57BL/6 mice. In the majority of experiments two age groups: young (Y, 3-month-old, n Y = 12), and aged (A, 12-14-month-old, n A = 42) were used. Only in an experiment investigating age-dependent taurine levels an additional group of old animals (O, 22-24-month-old, n O = 6) was included. All animals were housed in cages with nesting material, five per cage, unless otherwise declared, in a temperature- and humidity-controlled room (20–22°C, 40–50% humidity), on a 12-hour light/dark cycle (lights on at 7 am), with ad libitum access to food and water. All procedures were done following the European Community Council Directive (2010/63/EU) and were approved and carried out by the relevant guidelines and regulations of the First Local Ethical Committee for Animal Experiments in Warsaw, Poland. Every effort was made to minimize the number of animals used and their suffering. Experimental arrangement and training scheme Fear conditioning procedure Before the conditioning procedure, the animals were accustomed to being immobilized, 10 minutes a day for 3 weeks, in a restraining apparatus covering the neck of the mouse and allowing free head movements. After the adaptation period, the vibrissae in row B on one side of the muzzle were stimulated manually with a soft brush for 9 s with three uniform movements (conditioned stimulus, CS), and in the last second of the third movement, the mice received a moderately strong electrical pulse in the tail (unconditioned stimulus, UCS, 0.5 mA, 0.5 s). The paired stimuli were repeated four times per minute for 10 minutes. The procedure was conducted for 3 days with one session per day, as described by Siucinska and Kossut 1996 . This conditioning procedure results in plastic changes in the extent of the functional cortical representation of the “trained” row of vibrissae, which do not occur in pseudo conditioned animals and which are eliminated by an extinction procedure (Siucinska and Kossut 1996 ). All conditioning sessions were video recorded to register a conditioned response. Conditioned response (CR) analysis Behavioral verification of associative learning was performed as described previously (Cybulska-Klosowicz et al., 2009 ). The natural response of a mouse to the touch of vibrissae is to turn its head toward the stimulus, and during conditioning, this response is suppressed (minifreezing), which is considered a marker of acquiring a predictive value by the stimulus. We have shown previously that this CR was present 24 hrs after the training when CS only was presented in the same schedule as during the training (Cybulska-Klosowicz et al., 2009 ). The number of CSs accompanied by head movement was counted for each minute of the training (from 0 to 4 stimuli per minute), and then the counts were averaged for each session. A measure of the acquisition of a CR was a significant decrease in the number of CSs associated with head movement in session three, compared to session one. The head movements associated with CS were presented as a % of all CSs applied during the whole session. Plastic change detection To visualize conditioning-induced plastic changes in the barrel cortex, we used [14C]-2-deoxyglucose autoradiography, a method that allows studying brain metabolic activity in vivo (Sokoloff, et al. 1977). The cortical representation of the vibrissae row B stimulated during conditioning and the control row B on the other side of the muzzle were labeled with 2-DG autoradiography 24 h after the last conditioning session (Siucinska and Kossut, 1996 ). Each mouse was placed in a restraining device, and all vibrissae, except the B rows to be imaged, were removed. A single dose (10 µCi per animal) of [14]C2-deoxyglucose (American Radiolabeled Chemicals Inc., specific activity 53 mCi/mmol) was injected intramuscularly, and row B of vibrissae on both sides of the snout was stimulated manually for 30 minutes at 2 Hz. Immediately after stimulation, mice were perfused with 4% PFA in PBS, the cortex was isolated and flattened between two microscopic slides separated by 2 mm separators to obtain tangential sections and then frozen at -80°C. Next, the cortex was cut using a cryostat into 30–35 µm thick slices. Subsequent slices were collected on coverslips and immediately dried on a heating plate. The slides were then exposed for two weeks against mammographic film (Kodak) in the presence of [14]C radioactivity standards. The films were developed and fixed using Kodak X-ray photography reagents, then rinsed and dried. To quantify the extent of the plastic change, the width of labeling of the functional representation of row B was measured using a previously established criterion (Kossut et al. 1988 ), considering as activated regions in which the labeling, measured by the degree of [14]C incorporation, was 15% greater than in adjacent areas of the cortex. We have established previously that the 15% difference corresponds to two standard deviations above the mean value of labeling in the surrounding cortex (Kossut et al. 1988 ). The barrel cortex of the contralateral hemisphere is used as an internal control in studying plastic changes. The possibility of treating the somatosensory cortex contralateral to the experimental one as an internal control for young and aging animals was confirmed by the following experiments, and also by our previous studies. For plasticity studies: (i) the width of labeling of the representation of row B of vibrissae in the control hemisphere in conditioned animals was not significantly different from that in naive animals of the same age group; (ii) there was also no change in the width of labeling in the control hemisphere between young (572 ± 51 µm, n = 3, but see also Kossut et al., 1988 , Jablonska et al., 1999 ) and aged animals (562 ± 45 µm, n = 3, see also Liguz-Lecznar, et al. 2011 ); (iii) there were no differences in the width of labeling in the control hemisphere of animals subjected to TS (553.3 ± 41 µm, n = 4) or EE (554.1 ± 8.5 µm, n = 4), when compared to the age-matched naive animals. Strategies supporting plasticity Enriched environment (EE) exploration in aged mice Selected groups of aged mice were placed in an enriched environment (A_EE). It consisted of a larger-than-standard cage, measuring 60 x 40 x 30 cm, inside which houses (shelter), small objects of different textures, small mazes, swings, and nesting material were placed. All accessories were changed weekly to further stimulate the mice to explore their new environment. The mice spent 6 weeks in EE and then they were used in further experiments. Taurine supplementation (TS) in aged mice Selected groups of aged mice for 6 weeks received 5% aqueous taurine solution (Sigma; T0625) ad libitum instead of water (A_TS). Animals were housed in home cages, 5 animals per cage. The water requirement of an adult mouse is approximately 7 ml per day. The animals were not restricted in any way in their access to the taurine solution during the experiment. The water was changed once a week, and the volume of the remaining solution was checked. During the experiment no significant changes were observed in the amount of taurine solution consumed, nor were there differences in the consumption of taurine solution compared to water. Studies of the potential long-term toxicity of taurine in Wistar rats showed that a diet of 0.5 or 5% taurine for 18 months did not cause any clinical, behavioral, or hematological effects. No adverse histological effects were observed in the brain, cerebellum, myocardium, spleen, pancreas, gastrointestinal tract walls, or testes (Consultancy 2015 ). After this time, the animals were used in subsequent procedures. The dose of taurine administered to the animals was determined according to the “GRAS Exemption Claim for Taurine for Use in Enhanced Water Beverages – 2015” (Consultancy 2015 ) and based on a study by Hwang and colleagues (Hwang, Hour, and Cheng 2000 ). Biochemical analyses Tissue samples collection for HPLC and ELISA analyses To collect tissue samples, animals were sacrificed by severing the spinal cord to avoid the possible effects of anesthetics on the measurements taken. For analyses of aging-related changes, tissue fragments from both hemispheres were combined, while for analyses of changes after induced plasticity, tissue fragments from each hemisphere – control and experimental - were analyzed separately. The brains were removed from the skull and the cerebral cortex was separated on ice, gently flattened, and then somatosensory cortex fragments containing the barrel cortex were taken. The somatosensory cortex was dissected using a 2 mm diameter template according to the method described by Strominger and Woolsey (Strominger and Woolsey 1987 ). Estimation of amino acid levels using the HPLC method To determine the amino acid content, tissue samples were homogenized in ten volumes of ice-cold 2% perchloric acid, and the supernatants were collected and filtered through a 0.45 µm filter (Millipore) after centrifugation. HPLC analysis of amino acids was performed using a Luna C18 (250 × 5 mm) 5-µm reverse phase column. Compounds were eluted isocratically with the mobile phase delivered at 0.7 ml/min using a Shimadzu Class LC-10ADvp pump. An electrochemical detector with a flow-through cell (Intro-Antec Leyden) linked to the Shimadzu Class VP Integrator SCL-10 Avp was used. A high-density glassy carbon-working electrode (Antec) was operated at + 0.85 V. Samples were injected through a Rheodyne 7725i dispensing valve with a 20 µl loop. Preparation of the mobile phase and the derivatizing agents was based on the method of Rowley et al. ( 1995 ), with some modifications. The mobile phase consisted of 45 mM disodium phosphate and 0.15 mM EDTA with 24% methanol (v/v) water, adjusted to pH 3.9 with 0.2 M citric acid. It was then filtered through 0.45-µm filters and degassed for 15 min. Stock solutions (0.01 M) of amino acid standards were prepared in double deionised water and maintained at 4°C for 5 days. To prevent adhesion to glass, amino acid (especially GABA) standards were prepared in polyethylene vials. Working solutions were prepared daily by dilution of the stock solutions. Derivatization was performed at room temperature for 8 min. The derivatization reagent was obtained by dissolving 22 mg of OPA (phthalaldehyde) in: 0.5 ml of 1M sodium sulfite, 0.5 ml of methanol, 0.9 ml of 0.1 M tetraborate buffer, brought to pH 10.4 with 5M NaOH. Shimadzu's Class-VP computer program was used to record the chromatograms and process them. The concentration of amino acids in the sample was calculated from a standard curve prepared in the concentration range: 0.05-8 µM, then calculated as µM/g tissue. Somatostatin (SOM) level analysis with enzyme-linked immunosorbent assay ELISA Somatosensory cortex tissue for ELISA analysis was collected 24 hours after the last conditioning session. Tissue was dissected, and samples were homogenized in sterile PBS containing a protease inhibitor mixture (87786, Thermo Scientific) and centrifuged at 11,000 rpm for 20 min at 4°C. The supernatant was then collected, and protein concentrations were measured using a BCA protein assay kit. Protein levels were analyzed using the MBS701139 Mouse somatostatin ELISA Kit, MyBioSource Inc., according to the manufacturer's instructions. Statistical analyses Statistical analyses were performed using GraphPad Prism 5 software (GraphPad Software). A paired Student's t-test (significance level p < 0.05) was used to compare the results from the experimental and control hemispheres, while a one-way analysis of variance (ANOVA) with Dunett’s test as post hoc was used for the analysis between age groups. Spearman’s rank correlation was used to examine the age-related changes in taurine. For CR analysis the number of head movements, in response to the CS, was expressed as a percentage for each minute of conditioning on each of the 3 days. The results from a given day were then averaged and differences between consecutive days were analyzed using one-way ANOVA and Tukey's post hoc test. The significance of the glutamate/GABA ratio after TS and EE was determined using an unpaired Student's t-test. Results Taurine level in the mice somatosensory cortex decreases with age. With the HPLC technique, we examined how aging affects taurine levels in the somatosensory cortex. Spearman's rho analysis revealed that taurine levels were negatively correlated with age (rs = -0.76, p < 0.001). However, a statistically significant decrease was only seen in old (O; 2-year-old mice), despite the downward trend already visible between young (Y) and aged animals (A) (one-way ANOVA: F (15,2) = 19.25, p < 0.001; Tukey's post hoc test: Y vs. O: p < 0.001; A vs. O p < 0.01) (Fig. 1 ). Both TS and EE are effective in supporting experience-dependent plasticity in aged animals. Analysis of autoradiograms showed, that both TS and exposure of aged animals to EE enabled the induction of plastic change as a result of the short (3-days lasting) conditioning regimen, which, as we have shown earlier, was not possible in aged mice. In both strategies we confirmed a significant enlargement of trained row representation in the aged group following TS and EE when compared to control hemisphere (one-way ANOVA, F (2,14) = 47.05, p < 0.0001, Dunett’s post hoc test, p < 0.0001 for TS and F (2,14) = 168.3, p < 0.0001, Dunett’s post hoc test p < 0.0001 for EE) (Fig. 2 a, 2 b, 2 c). The between-group analysis showed also that the labeling width of row B of vibrissae representation in the control hemisphere was not significantly different from that measured in the control age-matched mice, which were not subjected to the conditioning procedure (549.0 ± 14.6 µm vs. 544.3 ± 16.68 µm for TS, one-way ANOVA, F (2,14) = 47.05, p < 0.0001, Dunett’s post hoc test p = 0.9; and 523.0 ± 18.7 µm vs. 551.3 ± 15.6 µm for EE; one-way ANOVA, F (2,14) = 168.3, p < 0.0001, Dunett’s post hoc test p = 0.3). Following TS, the width of trained row of vibrissae representation labeling was on average 18.2% greater than the width of the representation of control row of vibrissae (contralateral control hemisphere) (671.0 ± 34.9 µm, trained row representation vs. 549.0 ± 14.6 µm control row representation ; paired Student's t-test, p < 0.005). As for the EE strategy, the width of the labeling of the trained row of vibrissae representation in layer IV of the barrel cortex of aged mice was on average 24.79% larger than the control row representation (696.5 ± 17.4 µm vs. 523.0 ± 18.7 µm; paired Student's t-test, p < 0.005) (Fig. 2 d, 2 e, 2 f). The course and dynamics of the CR development is different for TS and EE Similarly to young animals (repeated measures ANOVA; F (5,45) = 19.98; Tukey's post hoc, day 1 vs. day 2; p < 0.001) (Fig. 3 a), aged mice present a CR in the course of 3-day conditioning paradigm (repeated measures ANOVA with; F (6,72) = 7.9; Tukey's post hoc, day 1 vs. day 2; p < 0.05 and day 2 vs. day 3 p < 0.001) (Fig. 3 b), even though they do not develop the plastic change in the form of broadening the trained row of vibrissae representation. These results have already been described in our previous publications (see Cybulska-Klosowicz et al. 2013 , Liguz-Lecznar et al., 2011 , Posluszny et al., 2015 ). In the current publication, we have replicated and included them in this section for comparative purposes. Analysis of the CR acquired by the aged animals during fear conditioning (minifreezing) following TS and EE showed, that in both groups, the number of head movements toward the CS decreased in the course of the 3-day conditioning. In the case of TS, the average percentage of CSs associated with head movement was 47.73 ± 4.43% on the first day of conditioning and significantly decreased to 32.73 ± 4.11% on day 2 (repeated measures ANOVA; F (10,90) = 26.85; Tukey's post hoc, day 1 vs. day 2; p < 0.01), and on day three to 18.86 ± 2.91% (repeated measures ANOVA; F (10,90) = 26.85;Tukey's post hoc, day 2 vs. day 3; p < 0.01). Thus, a 28.86% reduction in the number of head movements was observed throughout conditioning (repeated measures ANOVA; F (10,90) = 26.85; Tukey's post hoc, day 1 vs. day 3; p < 0.001). Aged mice after TS presented specific course of the acquisition of the CR, different from young (Fig. 3 a) or aged mice housed in the standard conditions (Fig. 3 b). No significant differences were observed in successive minutes during a single session, while on each successive day of conditioning, the level of head movements in the first minute of the session was similar to the number of head movements from the last minute of the previous day's session (Fig. 3 c). Aged mice housed in EE also developed a normal CR during the 3-day conditioning session. The reduction in the number of CSs (expressed as %) followed by head movement ranged from 64.62 ± 5.31% on the first day, to 27.88 ± 4.41% on the second day (repeated measures ANOVA; F (12,108) = 97.43; Tukey's post hoc, day 1 vs. day 2; p < 0.001) to 25.38 ± 4.43% on day 3 (repeated measures ANOVA; F (12,108) = 97.43, Tukey's post hoc, day 2 vs. day 3; p = ns). A 39.24% reduction in the number of head movements was recorded throughout conditioning (repeated measures ANOVA; F (12,108) = 97.43;Tukey's post hoc ; p < 0.001). In this group of animals, a different course of acquisition of the CR was observed than in the TS, young, or aged group. It was found that during the first two sessions, mice significantly reduced the number of head movements (one-way ANOVA, 1 min vs. 10 min - day 1; p < 0.001, 1 min vs. 10 min - day 2; p < 0.005). In addition, it was noted that in the first minute of subsequent conditioning sessions, animals reacted to more CSs with head movement than in the last minute of the previous session (Fig. 3 d). Neither TS nor EE restores Glutamate/GABA ratio values to those observed in young animals. Our previous studies have shown an imbalance between the levels of two primary neurotransmitters glutamate and GABA in the somatosensory cortex of aging mice as measured by the glutamate/GABA ratio (5.11 ± 0.13 in young and 4.38 ± 0.05 in aged animals, see Liguz-Lecznar et al., 2015 ). Here, HPLC analysis showed, that in aged animals following TS, the glutamate/GABA ratio in the somatosensory cortex remained significantly lower (4.93 ± 0.04) than in young (5.75 ± 0.13) animals (p < 0.001). A similar situation was observed following EE in aged mice. It did not lead to a restoration of the balance between the two major cortical neurotransmitters with a glutamate/GABA ratio of 5.23 ± 0.06 in aged animals p < 0.01) (Fig. 4 ). TS and EE differently influence conditioning-induced levels of SOM. As we have shown previously, the subclass of GABAergic interneurons involved in conditioning-induced plasticity in young animals are somatostatin-containing cells (SOM INs). A significant increase of SOM level can be seen in the somatosensory cortex of the experimental hemisphere in comparison to the control hemisphere with the experimental/control hemisphere ratio of 1.34 ± 0.1 (paired Student's t-test, p = 0.002). It was significantly higher than in the aged group (one-way ANOVA, F (3,20) = 5.42, p = 0.04), which did not present the upregulation of SOM in the experimental hemisphere. Both, TS and EE induced significant SOM levels increase in aged somatosensory cortex after training [experimentalcontrol hemisphere ratios: 1.186 ± 0.04 (paired Student's t-test, p = 0.003) and 1.44 ± 0.13 (paired Student's t-test, p = 0.002), respectively]. However, in comparison to the aged conditioned animals ratio, only EE induced a significantly higher increase (one-way ANOVA, F (3,20) = 5.42, p = 0.006; Tukey’s post hoc; p < 0.05, p < 0.01) (Fig. 5 ). Discussion Several studies have shown an association between lifestyle factors and the structure and function of the aging brain, mainly cognitive functions (Krivanek et al. 2021 ). Dietary approaches like caloric restriction and intermittent fasting or pharmacological interventions involving antioxidants, telomerase, and probiotics seem to have the potential to decelerate or reverse aging-related processes. The plasticity of somatosensory cortical representations induced by classical conditioning, involving unilateral tactile stimulation of vibrissae as a conditioned stimulus and an aversive stimulus administered to the tail, is compromised in aging but can be stimulated with an extended conditioning paradigm (Liguz-Lecznar et al., 2011 ). The prerequisite for this type of plastic change is the proper functioning of the GABAergic system (Posluszny, et al. 2015). Furthermore, it is accompanied by an extensive mobilization of the GABAergic system, as indicated by an increase in the level and expression of several GABAergic markers including GAD mRNA and protein level, mRNA for α1 subunit of the GABAA receptor, GABA level, density of GABA-immunoreactive cells in layer IV cortical representation of trained row of vibrissae, number of inhibitory synapses on dendritic spines, increase in tonic inhibition ( Siucinska, Kossut, and Stewart 1999 , Gierdalski, et al. 2001, Siucinska 2006 ; Jasinska et al. 2010 , Urban-Ciecko et al. 2010 , Liguz-Lecznar et al., 2015 ; Liguz-Lecznar et al., 2011 ). Here, we have shown the effectiveness of two approaches supporting plasticity in aging animals' somatosensory cortex. The first one was taurine supplementation. Taurine is a biogenic amino acid found in various organs, including the brain, heart, and kidneys (Aerts and Van Assche 2002 ). It has been shown to decline with age in the hippocampus, striatum, and cerebellum (Dawson et al., 1999 ; Suarez et al., 2016). We confirmed a decrease of taurine levels in the somatosensory cortex, but only in 2-year-old animals. This means that at the time of plasticity investigation (1-year-old mice), the taurine level in the somatosensory cortex was not significantly altered. Among other effects, taurine affects the function of the GABAergic system. It has been shown to act as a GABAA receptor agonist being a structural analog of glycine and GABA (El Idrissi and Trenkner 2004 ; El Idrissi et al. 2003 ). Thus, taurine supplementation might positively modulate the GABAergic system, offering hope that it can effectively counteract the changes observed in aging and stimulate the neuroplastic potential. Indeed, six weeks of TS (5% aqueous solution) enabled the initiation of the plastic change in the somatosensory cortex of aged mice with a plasticity extent similar to the young animals. Chronic supplementation with low doses of taurine was shown to improve learning in old mice and performance on a spatial task in a water pool (Trenkner et al. 1998 ) and in the Y maze test (Singh et al., 2023 ). It also allowed restoration of plasticity damaged after alcohol administration and in a mouse model of Alzheimer's disease, in addition to improving visual discrimination impaired in old mice (Kim and Cha 2014 ; Paulucio et al., 2018 ). The present paper shows, for the first time, the positive influence of TS on experience-dependent learning-associated plasticity in the somatosensory cortex. Thus, taurine appears to support neuroplasticity potential in various brain areas significantly. In addition to its direct action on the GABAergic system, the beneficial effects of taurine in the aging nervous system may be related to its multiple actions in various cellular processes, including the maintenance of calcium homeostasis (El Idrissi 2008 ; Wu et al. 2005 ; Foos and Wu 2002 ), protection against glutamate excitotoxicity, apoptosis (Foos and Wu 2002 ; Galindo-Leon et al., 2009 ), inflammation (Kim and Cha 2014 ), telomerase deficiency, DNA damage, mitochondrial dysfunction (Singh et al., 2023 ) and oxidative stress (Menzie et al., 2013 ). These processes play an essential role in aging and may also affect plasticity induction. The second strategy was an exposition of aged animals to the environmental enrichment, whose positive effects on the phenomenon of neuronal plasticity have been widely verified. Several experimental studies have demonstrated that EE mitigates age-related alterations in the brain, including cortical thickness, dendritic branching, spine density, neurogenesis, and gliogenesis. These effects consistently correlate with enhanced performance in diverse learning tasks among older animals (Mora et al., 2007 ; Kolb et al., 2003 ; Mora 2022). Environmental enrichment has also been shown to reduce cognitive deficits and Aβ levels in animal models of AD (Lazarov et al., 2005 ). In animal studies, EE that provides cognitive stimulation was associated with improved cognitive functioning across the lifespan (Sampedro-Piquero and Begega 2017 ), as well as increased neurogenesis, positive regulation of neuronal growth factors, and increased synapse density and synaptic plasticity (van Praag et al., 2000 , Pham et al., 2002 , Cotman and Berchtold 2002 ). One of the critical parameters for synaptic plasticity and cognitive functions such as learning and memory is the balance between excitation and inhibition, and we have shown that it was disturbed in the somatosensory cortex of aging animals (Liguz-Lecznar et al., 2011 ). The link between the reduced ability to induce plastic change in the somatosensory cortex and the glutamate/GABA imbalance in aged animals, coupled with the lack of GABAergic system mobilization following conditioning, allowed us to speculate that one of the reasons for the reduced plastic potential in aging somatosensory cortex may be dysregulation of neurotransmission. Both TS and EE, by affecting elements of the GABAergic system, glutamatergic system, or both, can potentially affect the balance between them. Chronic supplementation of taurine in mice resulted in increased levels of GABA and glutamate (El Idrissi and Trenkner 2004 ) and upregulation of GAD levels in the cortex and hippocampus (El Idrissi et al. 2005 ). After EE, increased levels of glutamate and GABA were observed in the hippocampus of old rats (Segovia et al., 2006 ). Still, there were also reports of reduced GABA release and reduced inhibition in the visual system of mice and humans after EE, which was associated with improved plasticity (Sale et al., 2007 ; Begenisic et al., 2011 ). This indicates that this strategy may work differently depending on the area studied. Nevertheless, in our experiments, neither TS nor EE restored the glutamate/GABA balance in the aged somatosensory cortex as their ratio remained reduced compared to young animals due to a decrease in glutamate level. This result does not allow us to conclude unquestionably that there is no effect of the applied strategies on the homeostasis between excitation and inhibition since it is determined not only by the neurotransmitter levels but also by receptors functioning and activation of relevant signaling pathways. The aforementioned parameters can be influenced by both of the strategies we used. Taurine is an agonist of GABAA and glycine receptors and a weak agonist of presynaptic NMDA receptors, which alters their affinity for glycine (Suárez and Solís 2006 ). EE resulted in increased expression of the GLUR1 subunit gene of the AMPA receptor in the hippocampus (Mlynarik, Johansson, and Jezova 2004 ). Glutamate metabotropic receptor levels in the prefrontal cortex, striatum (Melendez et al. 2004 ), and hippocampus (Cortese et al., 2018 ) in rats were also altered. Still, the direction of the changes depended on the subunit and area studied. Our previous research showed that a specific subclass of GABAergic neurons containing the somatostatin peptide plays a pivotal role in forming the conditioning-induced plastic change in the mice's somatosensory cortex. There was a significant increase in the number of SOM-containing GABAergic interneurons in the representation of the conditioned vibrissae (Cybulska-Klosowicz et al., 2013 ). Moreover, chemogenetic silencing of somatostatin interneurons in the barrel cortex prevented fear conditioning-induced plasticity in this area (Dobrzanski et al., 2020). Here, we demonstrated an increase in the level of SOM in the somatosensory cortex of the experimental barrel cortex of young mice, which could not be seen in aged conditioned animals. It was, however, observed in the experimental barrel cortex of aged animals subjected to both TS and EE. Long-term administration of low doses of taurine increased the level of SOM in the brain (El Idrissi et al., 2005 ), and the number of SOM neurons in the cortex and hippocampus (El Idrissi et al., 2013), which, given the involvement of a subset of somatostatin-containing interneurons in the plasticity we studied, could have induced the desired effects of enabling the plastic change of cortical representation. This is most likely related to the involvement of SOM INs, particularly those located in cortical layer IV, in the disinhibitory loop on excitatory neurons. One of the functions of SOM INs is to regulate the activity of parvalbumin-containing neurons (PV INs), which are activated by tactile stimuli and, in turn, exert a strong inhibitory effect on excitatory cells (O'Connor et al., 2013 ; Scala et al., 2019 ). This effect can be weakened by the inhibitory action of SOM INs on the PV INs in layer IV of SI. In this way, SOM INs boost the information from the thalamus, leading to plastic change induced by associative learning (Letzkus et al., 2015 ; Liguz-Lecznar et al., 2016 ). An essential aspect of conditioning is acquiring a conditioned response (CR), indicating the association between CS and UCS. During the fear conditioning, we observe so-called “minifreezing”, understood as refraining from the animal's natural reflex of turning its head toward a tactile stimulus (CS). In young conditioned animals, the course of CR acquisition is quite repetitive. It is characterized by a significant reduction in the number of CS-associated head movements in the first 2–3 minutes of the first conditioning session. This effect persists for subsequent sessions (Cybulska-Klosowicz et al., 2013 ). Aged mice, even though they did not develop the plastic change, presented correct CR at the end of the conditioning. However, it developed with different dynamics than in the young group. That means that they developed an association between CS and UCS, but this did not translate into a plastic change expressed as a broadening of the cortical representation of the trained row of vibrissae. Interestingly, the dynamics of the CR development in the aged animals following TS or EE differed from each other and other groups investigated. The described differences in the behavioral response of animals to conditioning suggest that there may be differences in the mechanisms of the learning process in each particular group. These differences do not seem to be linked to the SOM level in the cortex, which was augmented every time the plasticity was present. Perhaps other types of interneurons may also be involved here. In preliminary studies, in the somatosensory cortex of the experimental hemisphere, we found a decrease in Neuropeptide Y mRNA in young animals (data not shown). Neuropeptide Y in the cerebral cortex often co-occurs with SOM and lowers the excitability of neuronal circuits. It can have both stimulatory and impairing effects on memory, depending on the type of memory, the brain area studied, and the receptor subtypes activated (Beck and Pourié 2013 ). Intrathecal administration of NPY before fear conditioning induces an anti-anxiety effect and is associated with impaired memory acquisition (Karlsson et al., 2005 ); (Gøtzsche and Woldbye 2016 ). On the other hand, deleting the Npy gene or its Y1 receptor results in enhanced fear response acquisition (Verma et al., 2012 ). Thus, the downregulation of Npy we observed in the experimental barrel cortex in young animals may enhance the UCS effect and support conditioning. Obviously, this hypothesis, requires further investigations. Our findings demonstrated that promoting brain plasticity through specific dietary patterns or environmental reinforcement can effectively offset the negative effects of aging on learning-induced experience-dependent plasticity. This plasticity is crucial in the aging brain, enabling individuals to continually adapt to new information and environments and fostering cognitive resilience. Its effective stimulation by forming and strengthening neural connections can counteract age-related decline and promote cognitive flexibility, contributing to overall well-being in aging. Declarations Competing interests: The author(s) declare no competing interests. Author Contribution AG, RZ, AS, AC carried out the experiments and analyzed the results; ACK and MK contributed to the interpretation of the results; ACK, MK and MLL wrote the manuscript with input from all authors; MLL supervised the project, designed the figures and took the lead in writing the manuscript. Acknowledgement The work was supported by a National Science Centre Grant (2013/09/B/NZ3/00540) to MLL. Some of the results presented in this publication were obtained using equipment supported by a project financed by the Polish Ministry of Science and Higher Education: Polish Euro-BioImaging Node “Advanced Light Microscopy Node Poland, No 2022/WK/05. Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. References Aerts, L. & Van Assche, F. A. Taurine and taurine-deficiency in the perinatal period. J. Perinat. Med. 30, 281–6 (2002). Almási, Z., Dávid, C., Witte, & M. Staiger, J. F. Distribution patterns of three molecularly defined classes of GABAergic neurons across columnar compartments in mouse barrel cortex. Front Neuroanat 13: 45 (2019). Bae, M. A., Gao, R., Kim, S. H. & Chang, K. J. Past taurine intake has a positive effect on present cognitive function in the elderly. Adv. Exp. Med. Biol. 975 Pt 1, 67–77 (2017). Bañuelos, C., et al . Prefrontal cortical Gabaergic dysfunction contributes to age-related working memory impairment. J. Neurosci. 34, 3457–66 (2014). Beck, B., & Pourié, G. Ghrelin, neuropeptide Y, and other feeding-regulatory peptides active in the hippocampus: role in learning and memory. Nutr. Rev. 71, 541–61 (2013). Begenisic, T. et al . Environmental enrichment decreases GABAergic inhibition and improves cognitive abilities, synaptic plasticity, and visual functions in a mouse model of Down Syndrome. Front. Cell Neurosci. 5: 29 (2011). Bories, C., Husson, Z., Guitton, M. J. & De Koninck, Y. Differential balance of prefrontal synaptic activity in successful versus unsuccessful cognitive aging. J. Neurosci. 33, 1344–56 (2013). Chen, C. et al . Roles of taurine in cognitive function of physiology, pathologies and toxication. Life Sci. 231, 116584 (2019). Consultancy, lntertek Scientific & Regulatory. Office of Food Additive Safety (HFS-200), Center for Food Safety and Applied Nutrition (CFSAN), and Food and Drug Administration (FDA). 2015. Gras Exemption Claim for Taurine for Use in Enhanced Water Beverages. Cortese, G. P., Olin, A., O'Riordan, K., Hullinger, R. & Burger, C. Environmental enrichment improves hippocampal function in aged rats by enhancing learning and memory, LTP, and mGluR5-Homer1c activity. Neurobiol. Aging 63, 1–11 (2018). Cotman, C. W. & Berchtold, N. C. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 25, 295–301 (2002). Cox, L.A., Puppala, S., Chan, J., Zimmerman, K.D., Hamid, Z., Ampong, I., Huber, H.F., Li, G., Jadhav, A.Y.L., Wang, B., Li, C., Baxter, M.G., Shively, C., Clarke, G.D., Register, T.C., Nathanielsz, P.W., Olivier, M. Integrated multi-omics analysis of brain aging in female nonhuman primates reveals altered signaling pathways relevant to age-related disorders. Neurobiol. Neurobiol Aging. 132, 109–119 (2023). Cybulska-Klosowicz, A. et al . Interneurons containing somatostatin are affected by learning-induced cortical plasticity. Neuroscience 254, 18–25 (2013). Cybulska-Klosowicz, A., Zakrzewska, R. & Kossut, M. Brain activation patterns during classical conditioning with appetitive or aversive UCS. Behav. Brain Res. 204, 102–11 (2009). Dawson, Jr R., Pelleymounter, M. A., Cullen, M. J., Gollub, M. & Liu, S. An age-related decline in striatal taurine is correlated with a loss of dopaminergic markers. Brain Res Bull 48, 319–24 (1999). Dobrzanski, G. et al . Learning-induced plasticity in the barrel cortex is disrupted by inhibition of layer 4 somatostatin-containing interneurons. Biochim. Biophys. Acta Mol. Cell. Res. 1869, 119146 (2022). El Idrissi, A. & Trenkner, E. Taurine as a modulator of excitatory and inhibitory neurotransmission. Neurochem. Res. 29, 189–97 (2004). El Idrissi, A. et al . Decreased GABA(a) receptor expression in the seizure-prone fragile X mouse." Neurosci. Lett. 377, 141–6 (2005). El Idrissi, A. Taurine improves learning and retention in aged mice. Neurosci. Lett. 436, 19–22 (2008). El Idrissi, A., Messing, J., Scalia, J. & Trenkner E. Prevention of epileptic seizures by taurine. Adv. Exp. Med. Biol. 526: 515–25 (2003). El Idrissi, A., Shen, C. H. & L'amoreaux, W. J. Neuroprotective role of taurine during aging. Amino Acids 45, 735–50 (2013). El Idrissi, A., Shen, C. H. & L'amoreaux, W. J.. Neuroprotective role of taurine during aging. Amino Acids 45, 735–50 (2013). Foos, T. M. & Wu, J. Y. The Role of taurine in the central nervous system and the modulation of intracellular calcium homeostasis. Neurochem Res. 27, 21–6 (2002). Fu, Y., Kaneko, M., Tang, Y., Alvarez-Buylla, A. & Stryker, M. P. A. Cortical disinhibitory circuit for enhancing adult plasticity. Elife 4, e05558 (2015). Galindo-Leon, E. E., Lin, F. G. & Liu, R. C. Inhibitory plasticity in a lateral band improves cortical detection of natural vocalizations. Neuron 62, 705–16 (2009). Gelfo, F., Mandolesi, L., Serra, L., Sorrentino, G., & Caltagirone, C. The neuroprotective effects of experience on cognitive functions: evidence from animal studies on the neurobiological bases of brain reserve. Neuroscience, 370, 218–235 (2018). Gierdalski, M. et al . Rapid regulation of Gad67 mRNA and protein level in cortical neurons after sensory learning. Cereb. Cortex 11, 806–15 (2001). Gøtzsche, C. R. & Woldbye, D. P. The role of Npy in learning and memory. Neuropeptides 55, 79–89 (2016). Hwang, D. F., Hour, J. L. & Cheng, H. M. Effect of taurine on toxicity of oxidized fish oil in rats. Food Chem. Toxicol. 38, 585–91 (2000). Jablonska, B., Gierdalski, M., Kossut, M. & Skangiel-Kramska, J. Partial blocking of NMDA receptors reduces plastic changes induced by short-lasting classical conditioning in the SI barrel cortex of adult mice. Cereb. Cortex 9, 222–31 (1999). Jasinska, M. et al . Rapid, Learning-induced inhibitory synaptogenesis in murine barrel field. J. Neurosci. 30, 1176–84 (2010). Karlsson, R. M., Holmes, A., Heilig, M. & Crawley, J. N. Anxiolytic-like actions of centrally-administered neuropeptide Y, but not galanin, in C57bl/6j Mice. Pharmacol. Biochem. Behav. 80, 427–36 (2005). Kaushik, M., Kaushik, P., Panwar, S., Joshi, S.D., Parvez, S. Environment enrichment facilitates long-term memory consolidation through behavioral tagging. eNeuro . 10, ENEURO.0365-22.2023 (2023). Kim, C. & Cha, Y. N. Taurine chloramine produced from taurine under inflammation provides anti-inflammatory and cytoprotective effects. Amino Acids 46, 89–100 (2014). Kolb, B., Gibb, R. & Gorny, G. Experience-dependent changes in dendritic arbour and spine density in neocortex vary qualitatively with age and sex. Neurobiol Learn Mem. 79, 1–10 (2003). Kossut, M., Hand, P. J., Greenberg, J. & Hand C. L. Single vibrissal cortical column in SI cortex of rat and its alterations in neonatal and adult vibrissa-deafferented animals: a quantitative 2DG study. J. Neurophysiol. 60, 829 – 52 (1988). Krivanek, T. J., Gale, S. A., McFeeley, B. M., Nicastri, C. M. & Daffner, K. R. Promoting successful cognitive aging: a ten-year update. J. Alzheimers Dis. 81, 871–920 (2021). Lazarov, O. et al . Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 120, 701 – 13 (2005). Letzkus, J. J., Wolff, S. B. & Lüthi, A. Disinhibition, a circuit mechanism for associative learning and memory. Neuron 88, 264 – 76 (2015). Li, S. et al . Environmental novelty activates Β2-adrenergic signaling to prevent the impairment of hippocampal Ltp by Aβ oligomers. Neuron 77, 929 – 41 (2013). Liguz-Lecznar, M. et al . Altered Glutamate/Gaba equilibrium in aged mice cortex influences cortical plasticity. Brain Struct. Funct. 220, 1681–93 (2015). Liguz-Lecznar, M. et al . Altered Glutamate/Gaba equilibrium in aged mice cortex influences cortical plasticity. Brain Struct. Funct. 220, 1681–93 (2015). Liguz-Lecznar, M., Siucinska, E., Zakrzewska, R. & Kossut, M. Impairment of experience-dependent cortical plasticity in aged mice. Neurobiol Aging 32, 1896–905 (2011). Liguz-Lecznar, M., Urban-Ciecko, J. & Kossut, M. Somatostatin and somatostatin-containing neurons in shaping neuronal activity and plasticity. Front. Neural Circuits 10: 48 (2016). Melendez, R. I., Gregory, M. L., Bardo, M. T. & Kalivas, P. W. Impoverished rearing environment alters metabotropic glutamate receptor expression and function in the prefrontal cortex. Neuropsychopharmacology 29, 1980–7 (2004). Menzie, J., Prentice, H. & Wu, J. Y. Neuroprotective mechanisms of taurine against ischemic stroke. Brain Sci. 3, 877–907 (2013). Mlynarik, M., Johansson, B. B. & Jezova, D. Enriched environment influences adrenocortical response to immune challenge and glutamate receptor gene expression in rat hippocampus. Ann. N Y Acad. Sci. 1018, 273–80 (2004). Mohd Sahini, S.N., Mohd Nor Hazalin, N.A., Srikumar, B.N., Jayasingh, Chellammal, H.S., Surindar Singh, G.K. Environmental enrichment improves cognitive function, learning, memory and anxiety-related behaviours in rodent models of dementia: Implications for future study. Neurobiol Learn Mem. 208, 10788 (2024). Moore, K., Hughes, C. F., Ward, M., Hoey, L. & McNulty, H. Diet, Nutrition and the ageing brain: current evidence and new directions. Proc. Nutr. Soc. 77, 152–163 (2018). Mora, F. Successful brain aging: plasticity, environmental enrichment, and lifestyle. Dialogues Clin. Neurosci. 15, 45–52 (2013). Mora, F., Segovia, G. & del Arco, A. Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain Res. Rev. 55, 78–88 (2007). Mora, F., Segovia, G. & del Arco, A. Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain Res Rev. 55, 78–88 (2007). O'Connor, D. H. et al . Neural coding during active somatosensation revealed using illusory touch. Nat. Neurosci. 16, 958–65 (2013). Paulucio, D. et al . Acute effect of ethanol and taurine on frontal cortex absolute beta power before and after exercise. PLoS One 13, e0194264 (2018). Pham, T. M., Winblad, B., Granholm, A. C. & Mohammed, A. H. Environmental influences on brain neurotrophins in rats. Pharmacol. Biochem. Behav. 73, 167–75 (2002). Posluszny, A. et al . Learning-dependent plasticity of the barrel cortex is impaired by restricting Gaba-ergic transmission. PLoS One 10, e0144415 (2015). Potier, B., Jouvenceau, A., Epelbaum, J. & Dutar P. Age-related alterations of Gabaergic input to Ca1 pyramidal neurons and its control by nicotinic acetylcholine receptors in rat hippocampus. Neuroscience 142, 187–201 (2006). Reed, H. E. et al . Effects of vasoactive intestinal polypeptide on neurones of the rat suprachiasmatic nuclei in vitro. J. Neuroendocrinol. 14, 639–46 (2002). Rowley, H. L., Martin, K. F. & Marsden, C. A. Determination of in vivo amino acid neurotransmitters by high-performance liquid chromatography with O-phthalaldehyde-sulphite derivatisation. J. Neurosci. Methods 57, 93–9 (1995). Sale, A. et al . Environmental enrichment in adulthood promotes amblyopia recovery through a reduction of intracortical inhibition. Nat. Neurosci. 10, 679–81 (2007). Sale, A., Berardi, N. & Maffei, L. Environment and brain plasticity: towards an endogenous pharmacotherapy. Physiol. Rev. 94, 189–234 (2014). Sampedro-Piquero, P. & Begega, A. Environmental enrichment as a positive behavioral intervention across the lifespan. Curr. Neuropharmacol. 15, 459–470 (2017). Scala, F. et al . Layer 4 of mouse neocortex differs in cell types and circuit organization between sensory areas. Nat. Commun. 10, 4174 (2019). Schmidt, S., Haase, M., Best, L., Groth, M., Lindner, J., Witte, O.W., Kaleta, C., Frahm, C. Restoring age-related cognitive decline through environmental enrichment: a transcriptomic approach. Cells, 11, 3864 (2022). Segovia, G., Yague, A. G., Garcia-Verdugo, J. M. & Mora, F. Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats. Brain Res Bull. 70, 8–14 (2006). Segovia, G., Yagüe, A. G., García-Verdugo, J. M. & Mora, F. Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and Gaba in the hippocampus of aged rats. Brain Res. Bull. 70, 8–14 (2006). Singh, P. et al . Taurine deficiency as a driver of aging. Science, 380(6649), eabn9257 (2023). Siucinska, E. & Kossut, M. Short-lasting classical conditioning induces reversible changes of representational maps of vibrissae in mouse SI cortex - a 2DG study. Cereb. Cortex 6, 506–13 (1996). Siucinska, E. Gad67-positive puncta: contributors to learning-dependent plasticity in the barrel cortex of adult mice. Brain Res. 1106, 52–62 (2006). Siucinska, E., Kossut M. & Stewart, M. G. Gaba immunoreactivity in mouse barrel field after aversive and appetitive classical conditioning training involving facial vibrissae. Brain Res. 843, 62–70 (1999). Sokoloff, L. et al . The [14C]Deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J. Neurochem. 28, 897–916 (1977). Stanley, E. M., Fadel, J. R. & Mott, D. D. Interneuron loss reduces dendritic inhibition and Gaba release in hippocampus of aged rats. Neurobiol. Aging 33, 431.e1-13 (2012). Strominger, R. N. & Woolsey, T. A. Templates for locating the whisker area in fresh flattened mouse and rat cortex. J. Neurosci. Methods 22, 113–8 (1987). Suárez, L. M. & Solís, J. M. Taurine potentiates presynaptic NMDA receptors in hippocampal schaffer collateral axons. Eur. J. Neurosci. 24, 405–18 (2006). Suárez, L. M., Muñoz, M. D., del Río, R. M. & Solís, J. M. Taurine content in different brain structures during ageing: effect on hippocampal synaptic plasticity. Amino Acids 48, 1199–1208 (2016). Trenkner, E., El Idrissi, A., Dumas, R. & A. Rabe, A. Functional consequences of calcium uptake modulation by taurine in vivo and in vitro. Adv. Exp. Med. Biol. 442: 277–84 (1998). Urban-Ciecko, J., Kossut, M. & Mozrzymas, J. W. Sensory learning differentially affects GABAergic tonic currents in excitatory neurons and fast spiking interneurons in layer 4 of mouse barrel cortex. J. Neurophysiol. 104, 746–54 (2010). van Praag, H., Kempermann, G. & Gage, F. H. Neural consequences of environmental enrichment. Nat. Rev. Neurosci. 1, 191–8 (2000). Verma, D., Tasan, R. O., Herzog, H. & Sperk, G. Npy controls fear conditioning and fear extinction by combined action on Y₁ and Y₂ receptors. Br. J. Pharmacol. 166, 461–73 (2012). Wang, H. L., Li, A. & T. Wu, T. Vasoactive intestinal polypeptide enhances the GABAergic synaptic transmission in cultured hippocampal neurons. Brain Res. 746, 294–300 (1997). Weuve, J. et al . Physical activity, including walking, and cognitive function in older women. JAMA 292, 1454–61 (2004). Wong, T. P. et al . Imbalance towards inhibition as a substrate of aging-associated cognitive impairment. Neurosci. Lett. 397, 64–8 (2006). Woolsey, T. A. & Van der Loos, H. The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The Description of a Cortical Field Composed of Discrete Cytoarchitectonic Units. Brain Res. 17, 205 – 42 (1970). Wu, H. et al . Mode of action of taurine as a neuroprotector. Brain Res. 1038, 123–31 (2005). Wu, J. Y. & Prentice H. Role of taurine in the central nervous system. J. Biomed. Sci. 17(Suppl 1), S1 (2010). Yu Z-Y, Wang W, Fritschy J-M, Witte OW, Redecker C. Changes in neocortical and hippocampal GABAA receptor subunit distribution during brain maturation and aging. Brain Res. 1099, 73–81 (2006). Zhu, M., Akimana, C., Wang, E. & Ng, C. K. 1 H-MRS quantitation of age-dependent taurine changes in mouse brain. Mol. Imaging Biol. 21, 812–817 (2019). Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4372981","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":301362953,"identity":"07429686-0be1-4425-828a-4ac5ef9ee159","order_by":0,"name":"Aleksandra Gawryluk","email":"","orcid":"","institution":"Nencki Institute of experimental Biology, Polish Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Aleksandra","middleName":"","lastName":"Gawryluk","suffix":""},{"id":301362955,"identity":"1dde4364-4274-495f-b495-8c3ef8ff9498","order_by":1,"name":"Anita Cybulska-Klosowicz","email":"","orcid":"","institution":"Nencki Institute of experimental Biology, Polish Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Anita","middleName":"","lastName":"Cybulska-Klosowicz","suffix":""},{"id":301362957,"identity":"4845de80-b90b-4abf-8256-092e99e90d4d","order_by":2,"name":"Agata Charzynska","email":"","orcid":"","institution":"Nencki Institute of experimental Biology, Polish Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Agata","middleName":"","lastName":"Charzynska","suffix":""},{"id":301362960,"identity":"1afb2a17-ebe6-4a52-8246-e72df38d40ce","order_by":3,"name":"Renata Zakrzewska","email":"","orcid":"","institution":"Nencki Institute of experimental Biology, Polish Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Renata","middleName":"","lastName":"Zakrzewska","suffix":""},{"id":301362963,"identity":"9c96e16c-6dec-4e8f-ad31-9d4544bdc3ab","order_by":4,"name":"Alicja Sobolewska","email":"","orcid":"","institution":"Institute of Psychiatry and Neurology","correspondingAuthor":false,"prefix":"","firstName":"Alicja","middleName":"","lastName":"Sobolewska","suffix":""},{"id":301362964,"identity":"e25a351c-f48e-49b3-bcd8-5177c51bf5ca","order_by":5,"name":"Malgorzata Kossut","email":"","orcid":"","institution":"Nencki Institute of experimental Biology, Polish Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Malgorzata","middleName":"","lastName":"Kossut","suffix":""},{"id":301362965,"identity":"a1a31ffd-6c05-4992-b528-e70b3ff71a09","order_by":6,"name":"Monika Liguz-Lecznar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYFAC5oYDQFIOxGRsMACSIO4DvFoYwVqMUbUkENACIhMb4ExCWnQbGBsPfm2rS9/O3nvw44wCBjm+GwlsD/BpMTvA2HBYto0td2fPuWTJDQYMxpI3EtgNCGqRbOPJ3XAjx4zxgQFD4gagLRJEaJFIN7j/BqylnigtBz+2GSQY3OAxYwQ6DMggpOUw0BaGcwmGG87kGEvOMJAwnHnmYTt+vxxvPvzxR1mdvMHxM4Yfe/7YyPMdTz724AMeLQzMQMSD4EoAMWMbPg1gwPgDTYCNoJZRMApGwSgYUQAAbq9TGobZeRkAAAAASUVORK5CYII=","orcid":"","institution":"Nencki Institute of experimental Biology, Polish Academy of Sciences","correspondingAuthor":true,"prefix":"","firstName":"Monika","middleName":"","lastName":"Liguz-Lecznar","suffix":""}],"badges":[],"createdAt":"2024-05-05 20:23:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4372981/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4372981/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-70261-5","type":"published","date":"2024-08-22T15:58:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56484138,"identity":"ba510a62-b110-44e1-9a46-e72bc0f2ea5f","added_by":"auto","created_at":"2024-05-14 19:34:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":8144,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in taurine levels induced by aging in the somatosensory cortex. One-way ANOVA, Tukey's post hoc, **p \u0026lt; 0.01, ***p \u0026lt; 0.001; mean ± s.d. Y - young (3-month-old), A - aged (1-year-old), O - old (2-year-old), n\u003csub\u003eY\u003c/sub\u003e = 6, n\u003csub\u003eA \u003c/sub\u003e= 6, n\u003csub\u003eO\u003c/sub\u003e = 6\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4372981/v1/2123e5c588e7bf84bab55e96.png"},{"id":56484142,"identity":"bcb018e3-47c4-47fe-892b-455059eef391","added_by":"auto","created_at":"2024-05-14 19:34:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":102690,"visible":true,"origin":"","legend":"\u003cp\u003ePlastic change analysis in aged mice barrel cortex after TS (\u003cstrong\u003ea, b, c\u003c/strong\u003e) and EE (\u003cstrong\u003ed, e, f\u003c/strong\u003e). \u003cstrong\u003ea,d\u003c/strong\u003e – Examples of autoradiograms of layer IV barrel cortex tangential sections, shown in pseudocolors, presenting the pattern of 2-DG incorporation during conditioning. The most active areas are shown in red, the least active in blue. Arrows indicate representations of row B vibrissae (control and trained). \u003cstrong\u003eb, e \u003c/strong\u003e- labeling intensity profiles of the regions indicated by the black rectangle. Black line – control row of vibrissae, red line – trained row of vibrissae. \u003cstrong\u003ec, f\u003c/strong\u003e - the width of labeling of row B representation of aged naïve mice (A), control row of vibrissae representation of aged conditioned mice (A_TS_C and A_EE_C), and trained row representation of aged conditioned mice (A_TS_T and A_EE_T). One-way ANOVA, Dunett’s post hoc test; data represent mean ± s.d.; ***p \u0026lt; 0.001; n\u003csub\u003eA\u003c/sub\u003e = 5, n\u003csub\u003eA _TS \u003c/sub\u003e= 6\u003csub\u003e\u0026nbsp; \u003c/sub\u003eand n\u003csub\u003eA_EE \u003c/sub\u003e= 6.\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4372981/v1/40cdd2190a0d1dd488ef9c82.png"},{"id":56484139,"identity":"8208accd-b730-49f7-aec2-65d16594ba2d","added_by":"auto","created_at":"2024-05-14 19:34:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":41504,"visible":true,"origin":"","legend":"\u003cp\u003eDynamics of the acquisition of the conditioned response (CR) in young (\u003cstrong\u003ea\u003c/strong\u003e) and aged mice (\u003cstrong\u003eb, c, d\u003c/strong\u003e) after classical conditioning (\u003cstrong\u003eb\u003c/strong\u003e); classical conditioning in aged mice, following taurine supplementation (TS) (\u003cstrong\u003ec\u003c/strong\u003e) or environmental enrichment (EE) (\u003cstrong\u003ed\u003c/strong\u003e). The graphs show the percentage of trials in successive minutes of conditioning involving the head turn toward the CS. \u003cstrong\u003ea\u003c/strong\u003e – Young mice develop the CR very dynamically. A significant change is evident as early as the first minutes of the first session and persists until the end of training (from 14.6 ± 2.8 % during the first session to 5.4 ± 3.9 % during the last one). \u003cstrong\u003eb\u003c/strong\u003e - In aged mice, a significant decrease in CS stimuli associated with head movement is seen only on the second day of conditioning. During the third session, further development of the CR (decrease in head movements in response to CS) is observed. \u003cstrong\u003ec\u003c/strong\u003e - In aged mice CR following TS develops slowly but gradually. There is no significant decrease in CS stimuli associated with head movement within any sessions, but the differences occur between averaged values from individual sessions. \u003cstrong\u003ed \u003c/strong\u003e– Following EE conditioned aged mice developed the CR more slowly than young animals, but with similar dynamics. A significant decrease in head movement-associated CS stimuli is evident in the course of the first (red) and second (blue) sessions and remains low during session 3 (black). Repeated measures ANOVA, mean ± s.e.m.; *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001; young mice, n\u003csub\u003eY\u003c/sub\u003e = 6; aged mice, n\u003csub\u003eA\u003c/sub\u003e = 9; aged mice, TS, n\u003csub\u003eA_TS\u003c/sub\u003e = 11; aged mice, EE, n\u003csub\u003eA_EE \u003c/sub\u003e= 13. Differences between successive days of conditioning are shown below the graphs.\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4372981/v1/90945bb4cee57db90d6cdebb.png"},{"id":56484140,"identity":"90ae9d26-1512-4ceb-82c5-266660c7c7c9","added_by":"auto","created_at":"2024-05-14 19:34:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":17643,"visible":true,"origin":"","legend":"\u003cp\u003eNeither taurine supplementation (A_TS), nor environmental enrichment (A_EE) restores the glutamate/GABA balance in the somatosensory cortex of aged animals. It remains significantly lower than in young animals (Y). Unpaired Student's t-test, mean ± s.d., n\u003csub\u003eY\u003c/sub\u003e = 6, n\u003csub\u003eA\u003c/sub\u003e_\u003csub\u003eTS\u003c/sub\u003e = 6; n\u003csub\u003eA\u003c/sub\u003e_\u003csub\u003eEE\u003c/sub\u003e = 6.\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4372981/v1/91c6b67c7e10c95c0210b2c4.png"},{"id":56484141,"identity":"ba4c3c74-960d-4622-bda0-e7f776e9d5de","added_by":"auto","created_at":"2024-05-14 19:34:57","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":34287,"visible":true,"origin":"","legend":"\u003cp\u003eDifferences in somatostatin (SOM) levels in the somatosensory cortex induced by fear conditioning, shown as the ratio of SOM levels in the experimental hemisphere relative to the control hemisphere. # - significant increase of SOM levels in experimental hemispheres (paired Student's t-test; \u003csup\u003e##\u003c/sup\u003ep \u0026lt; 0.01). * - significant differences between different experimental groups (one-way ANOVA, *p \u0026lt; 0.05, **p \u0026lt; 0.01). Mean ± s.d., n = 6 for each group; Y – young animals, A – aged animals, A_TS – taurine supplementation, aged animals, A_EE – enriched environment, aged animals.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4372981/v1/3c4f9e9f2b7badf3c54073e8.png"},{"id":63300584,"identity":"a53da183-5f78-48c9-8d61-383fe7ca101c","added_by":"auto","created_at":"2024-08-26 16:15:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":873887,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4372981/v1/6ebbf73b-6289-42d1-8578-390831c8576c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mitigation of aging-related plasticity decline through taurine supplementation and environmental enrichment","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAging-related biochemical alterations in nerve cells lead to malfunctioning synapses and, consequently, entire neuronal circuits, adversely affecting their functioning, including such vital processes as brain plasticity, learning, and memory. Along with the reduced release of neurotransmitters and decreased neuronal reactivity observed in aging, a decrease in the number of neurons and their synaptic contacts can cause a loss of balance between excitation and inhibition (E/I), leading to impaired plasticity. If compensatory mechanisms are ineffective, this can cause cognitive impairment and even activate biochemical pathways, leading to various pathological conditions. E/I imbalance is, however, also observed in physiological aging of the nervous system, when it is associated with impaired plasticity and reduced cognitive potential. The direction of E/I changes may vary depending on the brain area studied. In the prefrontal cortex, available experimental data support an increase in inhibition with age, correlating with memory deficits (Potier et al., \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Stanley et al., \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Bories et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Ba\u0026ntilde;uelos et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Cox et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), while evidence of decreased inhibition was found in the sensory systems and hippocampus (Yu, Wang et al., \u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). In the rat parietal cortex, an imbalance of arousal/inhibition in favor of inhibition correlated with cognitive impairment (Wong et al., \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). These data indicate that in aging, cognitive performance is affected by changes in the E/I balance at the synapse.\u003c/p\u003e \u003cp\u003eWe have confirmed this hypothesis, showing a reduction in the Glutamate/GABA ratio in the somatosensory cortex of aging mice, which was associated with impaired learning-dependent neuroplasticity (Liguz-Lecznar et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Plasticity of cortical maps induced by fear-conditioning, in which a tactile stimulus applied to the vibrissae is paired with a mild electric aversive stimulus to the tail, requires a strong response from the GABAergic system (Siucinska \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Liguz-Lecznar et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Cybulska-Klosowicz et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Posluszny et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). The same conditioning pattern that leads to an expansion of the functional cortical representation of stimulated vibrissae in young mice becomes ineffective in aging animals (Liguz-Lecznar et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Extension of the conditioning procedure from 3 to 7 days allowed to induce plastic change, which went hand in hand with an increase in GABA levels. This means that the decrease in plasticity in aging animals is due to the failure of the mechanisms that control plasticity, in this case, an insufficient, ineffective response of the GABAergic system to the increased demand for inhibition (Liguz-Lecznar et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMaintaining a high plastic potential of the brain and engaging experience-dependent plasticity can offset the adverse effects of aging. This has been confirmed by several experiments demonstrating the beneficial effects of a stimulating environment, physical and cognitive training on memory (Schmidt et al. \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Kaushik et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; for review: Sale et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2014\u003c/span\u003e, Sahini et al., 2024), Aβ accumulation (Li et al. \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2013\u003c/span\u003e), neurogenesis in the hippocampus, or increased glutamate and GABA levels in old animals (Segovia et al., \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). The observed effects can be attributed to an interference with age-related compensatory/adaptive changes, which, unlike degenerative changes, are modifiable with various supporting strategies. The results of translational research have shown that certain lifestyle elements, so-called healthy habits, including physical activity, cognitive engagement, and an adequate diet, can promote successful aging (Moore et al., \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Krivanek et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Weuve et al., \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e2004\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this paper, two approaches were chosen that could potentially help preserve plastic potential and consequently improve cognitive abilities: taurine supplementation (TS) and enrichment of the animals' habitat environment (EE). Taurine is a sulfur-containing non-essential amino acid that plays many functions in the nervous system, including, among others, a role as a neurotransmitter, neurotrophic factor, neuromodulator, and neuroprotectant (Wu and Prentice, \u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Taurine content declines with age, which in the brain was shown for the 27-month-old mouse hippocampus (Zhu et al., \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) and cerebellum of 2-year-old rats (Suarez et al., 2016), and this has been correlated with cognitive deficits and age-associated diseases (Singh et al., \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Taurine supplementation, on the other hand, ameliorates age-related cognitive deficits like time orientation or judgment and abstract thinking (Bae et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2017\u003c/span\u003e), the performance of passive avoidance tasks, and cross-shaped water maze (El Idrissi et al., 2013). Because taurine is a modulator of the GABAergic system (Idrissi and Trenkner \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Chen et al., 2029), whose function is impaired in the aging brain, contributing to E/I imbalance, we tested its ability to support plasticity.\u003c/p\u003e \u003cp\u003eThe second strategy - enriched environment - was selected due to its solidly documented proplastic effects, including neuroplasticity in old age (Gelfo et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Sale et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Mora, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2013\u003c/span\u003e for review).\u003c/p\u003e \u003cp\u003eWe demonstrated the effectiveness of both - TS and EE - strategies in supporting plasticity in the aging mouse brain. Each strategy affected the process of plastic change progression in a slightly different way, and in neither case did the effect rely on restoring the balance between glutamate and GABA to the value observed in young animals.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAnimals\u003c/h2\u003e \u003cp\u003eThe experiments used 60 female C57BL/6 mice. In the majority of experiments two age groups: young (Y, 3-month-old, n\u003csub\u003eY\u003c/sub\u003e = 12), and aged (A, 12-14-month-old, n\u003csub\u003eA\u003c/sub\u003e = 42) were used. Only in an experiment investigating age-dependent taurine levels an additional group of old animals (O, 22-24-month-old, n\u003csub\u003eO\u003c/sub\u003e = 6) was included. All animals were housed in cages with nesting material, five per cage, unless otherwise declared, in a temperature- and humidity-controlled room (20\u0026ndash;22\u0026deg;C, 40\u0026ndash;50% humidity), on a 12-hour light/dark cycle (lights on at 7 am), with ad libitum access to food and water. All procedures were done following the European Community Council Directive (2010/63/EU) and were approved and carried out by the relevant guidelines and regulations of the First Local Ethical Committee for Animal Experiments in Warsaw, Poland. Every effort was made to minimize the number of animals used and their suffering.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eExperimental arrangement and training scheme\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eFear conditioning procedure\u003c/h2\u003e \u003cp\u003eBefore the conditioning procedure, the animals were accustomed to being immobilized, 10 minutes a day for 3 weeks, in a restraining apparatus covering the neck of the mouse and allowing free head movements. After the adaptation period, the vibrissae in row B on one side of the muzzle were stimulated manually with a soft brush for 9 s with three uniform movements (conditioned stimulus, CS), and in the last second of the third movement, the mice received a moderately strong electrical pulse in the tail (unconditioned stimulus, UCS, 0.5 mA, 0.5 s). The paired stimuli were repeated four times per minute for 10 minutes. The procedure was conducted for 3 days with one session per day, as described by Siucinska and Kossut \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e1996\u003c/span\u003e. This conditioning procedure results in plastic changes in the extent of the functional cortical representation of the \u0026ldquo;trained\u0026rdquo; row of vibrissae, which do not occur in pseudo conditioned animals and which are eliminated by an extinction procedure (Siucinska and Kossut \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e1996\u003c/span\u003e). All conditioning sessions were video recorded to register a conditioned response.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eConditioned response (CR) analysis\u003c/h2\u003e \u003cp\u003eBehavioral verification of associative learning was performed as described previously (Cybulska-Klosowicz et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). The natural response of a mouse to the touch of vibrissae is to turn its head toward the stimulus, and during conditioning, this response is suppressed (minifreezing), which is considered a marker of acquiring a predictive value by the stimulus. We have shown previously that this CR was present 24 hrs after the training when CS only was presented in the same schedule as during the training (Cybulska-Klosowicz et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). The number of CSs accompanied by head movement was counted for each minute of the training (from 0 to 4 stimuli per minute), and then the counts were averaged for each session. A measure of the acquisition of a CR was a significant decrease in the number of CSs associated with head movement in session three, compared to session one. The head movements associated with CS were presented as a % of all CSs applied during the whole session.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePlastic change detection\u003c/h2\u003e \u003cp\u003eTo visualize conditioning-induced plastic changes in the barrel cortex, we used [14C]-2-deoxyglucose autoradiography, a method that allows studying brain metabolic activity in vivo (Sokoloff, et al. 1977). The cortical representation of the vibrissae row B stimulated during conditioning and the control row B on the other side of the muzzle were labeled with 2-DG autoradiography 24 h after the last conditioning session (Siucinska and Kossut, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e1996\u003c/span\u003e). Each mouse was placed in a restraining device, and all vibrissae, except the B rows to be imaged, were removed. A single dose (10 \u0026micro;Ci per animal) of [14]C2-deoxyglucose (American Radiolabeled Chemicals Inc., specific activity 53 mCi/mmol) was injected intramuscularly, and row B of vibrissae on both sides of the snout was stimulated manually for 30 minutes at 2 Hz. Immediately after stimulation, mice were perfused with 4% PFA in PBS, the cortex was isolated and flattened between two microscopic slides separated by 2 mm separators to obtain tangential sections and then frozen at -80\u0026deg;C.\u003c/p\u003e \u003cp\u003eNext, the cortex was cut using a cryostat into 30\u0026ndash;35 \u0026micro;m thick slices. Subsequent slices were collected on coverslips and immediately dried on a heating plate. The slides were then exposed for two weeks against mammographic film (Kodak) in the presence of [14]C radioactivity standards. The films were developed and fixed using Kodak X-ray photography reagents, then rinsed and dried. To quantify the extent of the plastic change, the width of labeling of the functional representation of row B was measured using a previously established criterion (Kossut et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1988\u003c/span\u003e), considering as activated regions in which the labeling, measured by the degree of [14]C incorporation, was 15% greater than in adjacent areas of the cortex. We have established previously that the 15% difference corresponds to two standard deviations above the mean value of labeling in the surrounding cortex (Kossut et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1988\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eThe barrel cortex of the contralateral hemisphere is used as an internal control in studying plastic changes.\u003c/span\u003e \u003c/p\u003e \u003cp\u003eThe possibility of treating the somatosensory cortex contralateral to the experimental one as an internal control for young and aging animals was confirmed by the following experiments, and also by our previous studies. For plasticity studies: (i) the width of labeling of the representation of row B of vibrissae in the control hemisphere in conditioned animals was not significantly different from that in naive animals of the same age group; (ii) there was also no change in the width of labeling in the control hemisphere between young (572\u0026thinsp;\u0026plusmn;\u0026thinsp;51 \u0026micro;m, n\u0026thinsp;=\u0026thinsp;3, but see also Kossut et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1988\u003c/span\u003e, Jablonska et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e1999\u003c/span\u003e) and aged animals (562\u0026thinsp;\u0026plusmn;\u0026thinsp;45 \u0026micro;m, n\u0026thinsp;=\u0026thinsp;3, see also Liguz-Lecznar, et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e); (iii) there were no differences in the width of labeling in the control hemisphere of animals subjected to TS (553.3\u0026thinsp;\u0026plusmn;\u0026thinsp;41 \u0026micro;m, n\u0026thinsp;=\u0026thinsp;4) or EE (554.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5 \u0026micro;m, n\u0026thinsp;=\u0026thinsp;4), when compared to the age-matched naive animals.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStrategies supporting plasticity\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eEnriched environment (EE) exploration in aged mice\u003c/h2\u003e \u003cp\u003eSelected groups of aged mice were placed in an enriched environment (A_EE). It consisted of a larger-than-standard cage, measuring 60 x 40 x 30 cm, inside which houses (shelter), small objects of different textures, small mazes, swings, and nesting material were placed. All accessories were changed weekly to further stimulate the mice to explore their new environment. The mice spent 6 weeks in EE and then they were used in further experiments.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eTaurine supplementation (TS) in aged mice\u003c/h2\u003e \u003cp\u003eSelected groups of aged mice for 6 weeks received 5% aqueous taurine solution (Sigma; T0625) ad libitum instead of water (A_TS). Animals were housed in home cages, 5 animals per cage. The water requirement of an adult mouse is approximately 7 ml per day. The animals were not restricted in any way in their access to the taurine solution during the experiment. The water was changed once a week, and the volume of the remaining solution was checked. During the experiment no significant changes were observed in the amount of taurine solution consumed, nor were there differences in the consumption of taurine solution compared to water. Studies of the potential long-term toxicity of taurine in Wistar rats showed that a diet of 0.5 or 5% taurine for 18 months did not cause any clinical, behavioral, or hematological effects. No adverse histological effects were observed in the brain, cerebellum, myocardium, spleen, pancreas, gastrointestinal tract walls, or testes (Consultancy \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAfter this time, the animals were used in subsequent procedures. The dose of taurine administered to the animals was determined according to the \u0026ldquo;GRAS Exemption Claim for Taurine for Use in Enhanced Water Beverages \u0026ndash; 2015\u0026rdquo; (Consultancy \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) and based on a study by Hwang and colleagues (Hwang, Hour, and Cheng \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2000\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eBiochemical analyses\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eTissue samples collection for HPLC and ELISA analyses\u003c/h2\u003e \u003cp\u003eTo collect tissue samples, animals were sacrificed by severing the spinal cord to avoid the possible effects of anesthetics on the measurements taken. For analyses of aging-related changes, tissue fragments from both hemispheres were combined, while for analyses of changes after induced plasticity, tissue fragments from each hemisphere \u0026ndash; control and experimental - were analyzed separately.\u003c/p\u003e \u003cp\u003eThe brains were removed from the skull and the cerebral cortex was separated on ice, gently flattened, and then somatosensory cortex fragments containing the barrel cortex were taken. The somatosensory cortex was dissected using a 2 mm diameter template according to the method described by Strominger and Woolsey (Strominger and Woolsey \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e1987\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eEstimation of amino acid levels using the\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHPLC method\u003c/span\u003e\u003c/p\u003e \u003cp\u003eTo determine the amino acid content, tissue samples were homogenized in ten volumes of ice-cold 2% perchloric acid, and the supernatants were collected and filtered through a 0.45 \u0026micro;m filter (Millipore) after centrifugation. HPLC analysis of amino acids was performed using a Luna C18 (250 \u0026times; 5 mm) 5-\u0026micro;m reverse phase column. Compounds were eluted isocratically with the mobile phase delivered at 0.7 ml/min using a Shimadzu Class LC-10ADvp pump. An electrochemical detector with a flow-through cell (Intro-Antec Leyden) linked to the Shimadzu Class VP Integrator SCL-10 Avp was used. A high-density glassy carbon-working electrode (Antec) was operated at +\u0026thinsp;0.85 V. Samples were injected through a Rheodyne 7725i dispensing valve with a 20 \u0026micro;l loop. Preparation of the mobile phase and the derivatizing agents was based on the method of Rowley et al. (\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e1995\u003c/span\u003e), with some modifications. The mobile phase consisted of 45 mM disodium phosphate and 0.15 mM EDTA with 24% methanol (v/v) water, adjusted to pH 3.9 with 0.2 M citric acid. It was then filtered through 0.45-\u0026micro;m filters and degassed for 15 min. Stock solutions (0.01 M) of amino acid standards were prepared in double deionised water and maintained at 4\u0026deg;C for 5 days. To prevent adhesion to glass, amino acid (especially GABA) standards were prepared in polyethylene vials. Working solutions were prepared daily by dilution of the stock solutions. Derivatization was performed at room temperature for 8 min. The derivatization reagent was obtained by dissolving 22 mg of OPA (phthalaldehyde) in: 0.5 ml of 1M sodium sulfite, 0.5 ml of methanol, 0.9 ml of 0.1 M tetraborate buffer, brought to pH 10.4 with 5M NaOH. Shimadzu's Class-VP computer program was used to record the chromatograms and process them. The concentration of amino acids in the sample was calculated from a standard curve prepared in the concentration range: 0.05-8 \u0026micro;M, then calculated as \u0026micro;M/g tissue.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSomatostatin (SOM) level analysis with enzyme-linked immunosorbent assay ELISA\u003c/h2\u003e \u003cp\u003eSomatosensory cortex tissue for ELISA analysis was collected 24 hours after the last conditioning session. Tissue was dissected, and samples were homogenized in sterile PBS containing a protease inhibitor mixture (87786, Thermo Scientific) and centrifuged at 11,000 rpm for 20 min at 4\u0026deg;C. The supernatant was then collected, and protein concentrations were measured using a BCA protein assay kit. Protein levels were analyzed using the MBS701139 Mouse somatostatin ELISA Kit, MyBioSource Inc., according to the manufacturer's instructions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using GraphPad Prism 5 software (GraphPad Software).\u003c/p\u003e \u003cp\u003eA paired Student's t-test (significance level p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) was used to compare the results from the experimental and control hemispheres, while a one-way analysis of variance (ANOVA) with Dunett\u0026rsquo;s test as post hoc was used for the analysis between age groups. Spearman\u0026rsquo;s rank correlation was used to examine the age-related changes in taurine.\u003c/p\u003e \u003cp\u003eFor CR analysis the number of head movements, in response to the CS, was expressed as a percentage for each minute of conditioning on each of the 3 days. The results from a given day were then averaged and differences between consecutive days were analyzed using one-way ANOVA and Tukey's post hoc test.\u003c/p\u003e \u003cp\u003eThe significance of the glutamate/GABA ratio after TS and EE was determined using an unpaired Student's t-test.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eTaurine level in the mice somatosensory cortex decreases with age.\u003c/span\u003e \u003c/p\u003e \u003cp\u003eWith the HPLC technique, we examined how aging affects taurine levels in the somatosensory cortex. Spearman's rho analysis revealed that taurine levels were negatively correlated with age (rs = -0.76, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, a statistically significant decrease was only seen in old (O; 2-year-old mice), despite the downward trend already visible between young (Y) and aged animals (A) (one-way ANOVA: F\u003csub\u003e(15,2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19.25, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Tukey's post hoc test: Y vs. O: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; A vs. O p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eBoth TS and EE are effective in supporting experience-dependent plasticity in aged animals.\u003c/span\u003e \u003c/p\u003e \u003cp\u003eAnalysis of autoradiograms showed, that both TS and exposure of aged animals to EE enabled the induction of plastic change as a result of the short (3-days lasting) conditioning regimen, which, as we have shown earlier, was not possible in aged mice. In both strategies we confirmed a significant enlargement of trained row representation in the aged group following TS and EE when compared to control hemisphere (one-way ANOVA, F\u003csub\u003e(2,14)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;47.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, Dunett\u0026rsquo;s post hoc test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for TS and F\u003csub\u003e(2,14)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;168.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, Dunett\u0026rsquo;s post hoc test p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 for EE) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003eThe between-group analysis showed also that the labeling width of row B of vibrissae representation in the control hemisphere was not significantly different from that measured in the control age-matched mice, which were not subjected to the conditioning procedure (549.0\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6 \u0026micro;m vs. 544.3\u0026thinsp;\u0026plusmn;\u0026thinsp;16.68 \u0026micro;m for TS, one-way ANOVA, F\u003csub\u003e(2,14)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;47.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, Dunett\u0026rsquo;s post hoc test p\u0026thinsp;=\u0026thinsp;0.9; and 523.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7 \u0026micro;m vs. 551.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.6 \u0026micro;m for EE; one-way ANOVA, F\u003csub\u003e(2,14)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;168.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, Dunett\u0026rsquo;s post hoc test p\u0026thinsp;=\u0026thinsp;0.3).\u003c/p\u003e \u003cp\u003eFollowing TS, the width of trained row of vibrissae representation labeling was on average 18.2% greater than the width of the representation of control row of vibrissae (contralateral control hemisphere) (671.0\u0026thinsp;\u0026plusmn;\u0026thinsp;34.9 \u0026micro;m, trained row representation vs. 549.0\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6 \u0026micro;m control row representation ; paired Student's t-test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.005). As for the EE strategy, the width of the labeling of the trained row of vibrissae representation in layer IV of the barrel cortex of aged mice was on average 24.79% larger than the control row representation (696.5\u0026thinsp;\u0026plusmn;\u0026thinsp;17.4 \u0026micro;m vs. 523.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7 \u0026micro;m; paired Student's t-test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.005) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ef).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eThe course and dynamics of the CR development is different for TS and EE\u003c/h2\u003e \u003cp\u003eSimilarly to young animals (repeated measures ANOVA; F\u003csub\u003e(5,45)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19.98; Tukey's post hoc, day 1 vs. day 2; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea), aged mice present a CR in the course of 3-day conditioning paradigm (repeated measures ANOVA with; F\u003csub\u003e(6,72)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;7.9; Tukey's post hoc, day 1 vs. day 2; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 and day 2 vs. day 3 p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb), even though they do not develop the plastic change in the form of broadening the trained row of vibrissae representation. These results have already been described in our previous publications (see Cybulska-Klosowicz et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2013\u003c/span\u003e, Liguz-Lecznar et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e, Posluszny et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). In the current publication, we have replicated and included them in this section for comparative purposes.\u003c/p\u003e \u003cp\u003eAnalysis of the CR acquired by the aged animals during fear conditioning (minifreezing) following TS and EE showed, that in both groups, the number of head movements toward the CS decreased in the course of the 3-day conditioning. In the case of TS, the average percentage of CSs associated with head movement was 47.73\u0026thinsp;\u0026plusmn;\u0026thinsp;4.43% on the first day of conditioning and significantly decreased to 32.73\u0026thinsp;\u0026plusmn;\u0026thinsp;4.11% on day 2 (repeated measures ANOVA; F\u003csub\u003e(10,90)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;26.85; Tukey's post hoc, day 1 vs. day 2; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and on day three to 18.86\u0026thinsp;\u0026plusmn;\u0026thinsp;2.91% (repeated measures ANOVA; F\u003csub\u003e(10,90)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;26.85;Tukey's post hoc, day 2 vs. day 3; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Thus, a 28.86% reduction in the number of head movements was observed throughout conditioning (repeated measures ANOVA; F\u003csub\u003e(10,90)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;26.85; Tukey's post hoc, day 1 vs. day 3; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Aged mice after TS presented specific course of the acquisition of the CR, different from young (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea) or aged mice housed in the standard conditions (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). No significant differences were observed in successive minutes during a single session, while on each successive day of conditioning, the level of head movements in the first minute of the session was similar to the number of head movements from the last minute of the previous day's session (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003eAged mice housed in EE also developed a normal CR during the 3-day conditioning session. The reduction in the number of CSs (expressed as %) followed by head movement ranged from 64.62\u0026thinsp;\u0026plusmn;\u0026thinsp;5.31% on the first day, to 27.88\u0026thinsp;\u0026plusmn;\u0026thinsp;4.41% on the second day (repeated measures ANOVA; F\u003csub\u003e(12,108)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;97.43; Tukey's post hoc, day 1 vs. day 2; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) to 25.38\u0026thinsp;\u0026plusmn;\u0026thinsp;4.43% on day 3 (repeated measures ANOVA; F\u003csub\u003e(12,108)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;97.43, Tukey's post hoc, day 2 vs. day 3; p\u0026thinsp;=\u0026thinsp;ns). A 39.24% reduction in the number of head movements was recorded throughout conditioning (repeated measures ANOVA; F\u003csub\u003e(12,108)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;97.43;Tukey's post hoc ; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In this group of animals, a different course of acquisition of the CR was observed than in the TS, young, or aged group. It was found that during the first two sessions, mice significantly reduced the number of head movements (one-way ANOVA, 1 min vs. 10 min - day 1; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, 1 min vs. 10 min - day 2; p\u0026thinsp;\u0026lt;\u0026thinsp;0.005). In addition, it was noted that in the first minute of subsequent conditioning sessions, animals reacted to more CSs with head movement than in the last minute of the previous session (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eNeither TS nor EE restores Glutamate/GABA ratio values to those observed in young animals.\u003c/span\u003e \u003c/p\u003e \u003cp\u003eOur previous studies have shown an imbalance between the levels of two primary neurotransmitters glutamate and GABA in the somatosensory cortex of aging mice as measured by the glutamate/GABA ratio (5.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13 in young and 4.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 in aged animals, see Liguz-Lecznar et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHere, HPLC analysis showed, that in aged animals following TS, the glutamate/GABA ratio in the somatosensory cortex remained significantly lower (4.93\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04) than in young (5.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13) animals (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A similar situation was observed following EE in aged mice. It did not lead to a restoration of the balance between the two major cortical neurotransmitters with a glutamate/GABA ratio of 5.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06 in aged animals p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eTS and EE differently influence conditioning-induced levels of SOM.\u003c/span\u003e \u003c/p\u003e \u003cp\u003eAs we have shown previously, the subclass of GABAergic interneurons involved in conditioning-induced plasticity in young animals are somatostatin-containing cells (SOM INs). A significant increase of SOM level can be seen in the somatosensory cortex of the experimental hemisphere in comparison to the control hemisphere with the experimental/control hemisphere ratio of 1.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1 (paired Student's t-test, p\u0026thinsp;=\u0026thinsp;0.002). It was significantly higher than in the aged group (one-way ANOVA, F\u003csub\u003e(3,20)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;5.42, p\u0026thinsp;=\u0026thinsp;0.04), which did not present the upregulation of SOM in the experimental hemisphere. Both, TS and EE induced significant SOM levels increase in aged somatosensory cortex after training [experimentalcontrol hemisphere ratios: 1.186\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 (paired Student's t-test, p\u0026thinsp;=\u0026thinsp;0.003) and 1.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13 (paired Student's t-test, p\u0026thinsp;=\u0026thinsp;0.002), respectively]. However, in comparison to the aged conditioned animals ratio, only EE induced a significantly higher increase (one-way ANOVA, F\u003csub\u003e(3,20)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;5.42, p\u0026thinsp;=\u0026thinsp;0.006; Tukey\u0026rsquo;s post hoc; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSeveral studies have shown an association between lifestyle factors and the structure and function of the aging brain, mainly cognitive functions (Krivanek et al. \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Dietary approaches like caloric restriction and intermittent fasting or pharmacological interventions involving antioxidants, telomerase, and probiotics seem to have the potential to decelerate or reverse aging-related processes. The plasticity of somatosensory cortical representations induced by classical conditioning, involving unilateral tactile stimulation of vibrissae as a conditioned stimulus and an aversive stimulus administered to the tail, is compromised in aging but can be stimulated with an extended conditioning paradigm (Liguz-Lecznar et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). The prerequisite for this type of plastic change is the proper functioning of the GABAergic system (Posluszny, et al. 2015). Furthermore, it is accompanied by an extensive mobilization of the GABAergic system, as indicated by an increase in the level and expression of several GABAergic markers including GAD mRNA and protein level, mRNA for α1 subunit of the GABAA receptor, GABA level, density of GABA-immunoreactive cells in layer IV cortical representation of trained row of vibrissae, number of inhibitory synapses on dendritic spines, increase in tonic inhibition ( Siucinska, Kossut, and Stewart \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e1999\u003c/span\u003e, Gierdalski, et al. 2001, Siucinska \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Jasinska et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2010\u003c/span\u003e, Urban-Ciecko et al. \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e2010\u003c/span\u003e, Liguz-Lecznar et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Liguz-Lecznar et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHere, we have shown the effectiveness of two approaches supporting plasticity in aging animals' somatosensory cortex. The first one was taurine supplementation. Taurine is a biogenic amino acid found in various organs, including the brain, heart, and kidneys (Aerts and Van Assche \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). It has been shown to decline with age in the hippocampus, striatum, and cerebellum (Dawson et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Suarez et al., 2016). We confirmed a decrease of taurine levels in the somatosensory cortex, but only in 2-year-old animals. This means that at the time of plasticity investigation (1-year-old mice), the taurine level in the somatosensory cortex was not significantly altered.\u003c/p\u003e \u003cp\u003eAmong other effects, taurine affects the function of the GABAergic system. It has been shown to act as a GABAA receptor agonist being a structural analog of glycine and GABA (El Idrissi and Trenkner \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; El Idrissi et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). Thus, taurine supplementation might positively modulate the GABAergic system, offering hope that it can effectively counteract the changes observed in aging and stimulate the neuroplastic potential. Indeed, six weeks of TS (5% aqueous solution) enabled the initiation of the plastic change in the somatosensory cortex of aged mice with a plasticity extent similar to the young animals. Chronic supplementation with low doses of taurine was shown to improve learning in old mice and performance on a spatial task in a water pool (Trenkner et al. \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e1998\u003c/span\u003e) and in the Y maze test (Singh et al., \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). It also allowed restoration of plasticity damaged after alcohol administration and in a mouse model of Alzheimer's disease, in addition to improving visual discrimination impaired in old mice (Kim and Cha \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Paulucio et al., \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). The present paper shows, for the first time, the positive influence of TS on experience-dependent learning-associated plasticity in the somatosensory cortex. Thus, taurine appears to support neuroplasticity potential in various brain areas significantly. In addition to its direct action on the GABAergic system, the beneficial effects of taurine in the aging nervous system may be related to its multiple actions in various cellular processes, including the maintenance of calcium homeostasis (El Idrissi \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Wu et al. \u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Foos and Wu \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2002\u003c/span\u003e), protection against glutamate excitotoxicity, apoptosis (Foos and Wu \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Galindo-Leon et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2009\u003c/span\u003e), inflammation (Kim and Cha \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2014\u003c/span\u003e), telomerase deficiency, DNA damage, mitochondrial dysfunction (Singh et al., \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) and oxidative stress (Menzie et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). These processes play an essential role in aging and may also affect plasticity induction.\u003c/p\u003e \u003cp\u003eThe second strategy was an exposition of aged animals to the environmental enrichment, whose positive effects on the phenomenon of neuronal plasticity have been widely verified. Several experimental studies have demonstrated that EE mitigates age-related alterations in the brain, including cortical thickness, dendritic branching, spine density, neurogenesis, and gliogenesis. These effects consistently correlate with enhanced performance in diverse learning tasks among older animals (Mora et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Kolb et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Mora 2022). Environmental enrichment has also been shown to reduce cognitive deficits and Aβ levels in animal models of AD (Lazarov et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). In animal studies, EE that provides cognitive stimulation was associated with improved cognitive functioning across the lifespan (Sampedro-Piquero and Begega \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2017\u003c/span\u003e), as well as increased neurogenesis, positive regulation of neuronal growth factors, and increased synapse density and synaptic plasticity (van Praag et al., \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e2000\u003c/span\u003e, Pham et al., \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2002\u003c/span\u003e, Cotman and Berchtold \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2002\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne of the critical parameters for synaptic plasticity and cognitive functions such as learning and memory is the balance between excitation and inhibition, and we have shown that it was disturbed in the somatosensory cortex of aging animals (Liguz-Lecznar et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). The link between the reduced ability to induce plastic change in the somatosensory cortex and the glutamate/GABA imbalance in aged animals, coupled with the lack of GABAergic system mobilization following conditioning, allowed us to speculate that one of the reasons for the reduced plastic potential in aging somatosensory cortex may be dysregulation of neurotransmission. Both TS and EE, by affecting elements of the GABAergic system, glutamatergic system, or both, can potentially affect the balance between them. Chronic supplementation of taurine in mice resulted in increased levels of GABA and glutamate (El Idrissi and Trenkner \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2004\u003c/span\u003e) and upregulation of GAD levels in the cortex and hippocampus (El Idrissi et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). After EE, increased levels of glutamate and GABA were observed in the hippocampus of old rats (Segovia et al., \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Still, there were also reports of reduced GABA release and reduced inhibition in the visual system of mice and humans after EE, which was associated with improved plasticity (Sale et al., \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Begenisic et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). This indicates that this strategy may work differently depending on the area studied. Nevertheless, in our experiments, neither TS nor EE restored the glutamate/GABA balance in the aged somatosensory cortex as their ratio remained reduced compared to young animals due to a decrease in glutamate level. This result does not allow us to conclude unquestionably that there is no effect of the applied strategies on the homeostasis between excitation and inhibition since it is determined not only by the neurotransmitter levels but also by receptors functioning and activation of relevant signaling pathways. The aforementioned parameters can be influenced by both of the strategies we used. Taurine is an agonist of GABAA and glycine receptors and a weak agonist of presynaptic NMDA receptors, which alters their affinity for glycine (Su\u0026aacute;rez and Sol\u0026iacute;s \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). EE resulted in increased expression of the GLUR1 subunit gene of the AMPA receptor in the hippocampus (Mlynarik, Johansson, and Jezova \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Glutamate metabotropic receptor levels in the prefrontal cortex, striatum (Melendez et al. \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2004\u003c/span\u003e), and hippocampus (Cortese et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) in rats were also altered. Still, the direction of the changes depended on the subunit and area studied.\u003c/p\u003e \u003cp\u003eOur previous research showed that a specific subclass of GABAergic neurons containing the somatostatin peptide plays a pivotal role in forming the conditioning-induced plastic change in the mice's somatosensory cortex. There was a significant increase in the number of SOM-containing GABAergic interneurons in the representation of the conditioned vibrissae (Cybulska-Klosowicz et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Moreover, chemogenetic silencing of somatostatin interneurons in the barrel cortex prevented fear conditioning-induced plasticity in this area (Dobrzanski et al., 2020). Here, we demonstrated an increase in the level of SOM in the somatosensory cortex of the experimental barrel cortex of young mice, which could not be seen in aged conditioned animals. It was, however, observed in the experimental barrel cortex of aged animals subjected to both TS and EE. Long-term administration of low doses of taurine increased the level of SOM in the brain (El Idrissi et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2005\u003c/span\u003e), and the number of SOM neurons in the cortex and hippocampus (El Idrissi et al., 2013), which, given the involvement of a subset of somatostatin-containing interneurons in the plasticity we studied, could have induced the desired effects of enabling the plastic change of cortical representation. This is most likely related to the involvement of SOM INs, particularly those located in cortical layer IV, in the disinhibitory loop on excitatory neurons. One of the functions of SOM INs is to regulate the activity of parvalbumin-containing neurons (PV INs), which are activated by tactile stimuli and, in turn, exert a strong inhibitory effect on excitatory cells (O'Connor et al., \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Scala et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). This effect can be weakened by the inhibitory action of SOM INs on the PV INs in layer IV of SI. In this way, SOM INs boost the information from the thalamus, leading to plastic change induced by associative learning (Letzkus et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Liguz-Lecznar et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAn essential aspect of conditioning is acquiring a conditioned response (CR), indicating the association between CS and UCS. During the fear conditioning, we observe so-called \u0026ldquo;minifreezing\u0026rdquo;, understood as refraining from the animal's natural reflex of turning its head toward a tactile stimulus (CS). In young conditioned animals, the course of CR acquisition is quite repetitive. It is characterized by a significant reduction in the number of CS-associated head movements in the first 2\u0026ndash;3 minutes of the first conditioning session. This effect persists for subsequent sessions (Cybulska-Klosowicz et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Aged mice, even though they did not develop the plastic change, presented correct CR at the end of the conditioning. However, it developed with different dynamics than in the young group. That means that they developed an association between CS and UCS, but this did not translate into a plastic change expressed as a broadening of the cortical representation of the trained row of vibrissae. Interestingly, the dynamics of the CR development in the aged animals following TS or EE differed from each other and other groups investigated. The described differences in the behavioral response of animals to conditioning suggest that there may be differences in the mechanisms of the learning process in each particular group. These differences do not seem to be linked to the SOM level in the cortex, which was augmented every time the plasticity was present. Perhaps other types of interneurons may also be involved here. In preliminary studies, in the somatosensory cortex of the experimental hemisphere, we found a decrease in Neuropeptide Y mRNA in young animals (data not shown). Neuropeptide Y in the cerebral cortex often co-occurs with SOM and lowers the excitability of neuronal circuits. It can have both stimulatory and impairing effects on memory, depending on the type of memory, the brain area studied, and the receptor subtypes activated (Beck and Pouri\u0026eacute; \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Intrathecal administration of NPY before fear conditioning induces an anti-anxiety effect and is associated with impaired memory acquisition (Karlsson et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2005\u003c/span\u003e); (G\u0026oslash;tzsche and Woldbye \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). On the other hand, deleting the \u003cem\u003eNpy\u003c/em\u003e gene or its Y1 receptor results in enhanced fear response acquisition (Verma et al., \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). Thus, the downregulation of Npy we observed in the experimental barrel cortex in young animals may enhance the UCS effect and support conditioning. Obviously, this hypothesis, requires further investigations.\u003c/p\u003e \u003cp\u003eOur findings demonstrated that promoting brain plasticity through specific dietary patterns or environmental reinforcement can effectively offset the negative effects of aging on learning-induced experience-dependent plasticity. This plasticity is crucial in the aging brain, enabling individuals to continually adapt to new information and environments and fostering cognitive resilience. Its effective stimulation by forming and strengthening neural connections can counteract age-related decline and promote cognitive flexibility, contributing to overall well-being in aging.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests:\u003c/h2\u003e \u003cp\u003eThe author(s) declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAG, RZ, AS, AC carried out the experiments and analyzed the results; ACK and MK contributed to the interpretation of the results; ACK, MK and MLL wrote the manuscript with input from all authors; MLL supervised the project, designed the figures and took the lead in writing the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe work was supported by a National Science Centre Grant (2013/09/B/NZ3/00540) to MLL. Some of the results presented in this publication were obtained using equipment supported by a project financed by the Polish Ministry of Science and Higher Education: Polish Euro-BioImaging Node \u0026ldquo;Advanced Light Microscopy Node Poland, No 2022/WK/05.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAerts, L. \u0026amp; Van Assche, F. A. Taurine and taurine-deficiency in the perinatal period. J. Perinat. Med. 30, 281\u0026ndash;6 (2002).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlm\u0026aacute;si, Z., D\u0026aacute;vid, C., Witte, \u0026amp; M. Staiger, J. F. Distribution patterns of three molecularly defined classes of GABAergic neurons across columnar compartments in mouse barrel cortex. Front Neuroanat 13: 45 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBae, M. A., Gao, R., Kim, S. H. \u0026amp; Chang, K. J. Past taurine intake has a positive effect on present cognitive function in the elderly. Adv. Exp. Med. Biol. 975 Pt 1, 67\u0026ndash;77 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBa\u0026ntilde;uelos, C., \u003cem\u003eet al\u003c/em\u003e. Prefrontal cortical Gabaergic dysfunction contributes to age-related working memory impairment. J. Neurosci. 34, 3457\u0026ndash;66 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeck, B., \u0026amp; Pouri\u0026eacute;, G. Ghrelin, neuropeptide Y, and other feeding-regulatory peptides active in the hippocampus: role in learning and memory. Nutr. Rev. 71, 541\u0026ndash;61 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBegenisic, T. \u003cem\u003eet al\u003c/em\u003e. Environmental enrichment decreases GABAergic inhibition and improves cognitive abilities, synaptic plasticity, and visual functions in a mouse model of Down Syndrome. Front. Cell Neurosci. 5: 29 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBories, C., Husson, Z., Guitton, M. J. \u0026amp; De Koninck, Y. Differential balance of prefrontal synaptic activity in successful versus unsuccessful cognitive aging. J. Neurosci. 33, 1344\u0026ndash;56 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen, C. \u003cem\u003eet al\u003c/em\u003e. Roles of taurine in cognitive function of physiology, pathologies and toxication. Life Sci. 231, 116584 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConsultancy, lntertek Scientific \u0026amp; Regulatory. Office of Food Additive Safety (HFS-200), Center for Food Safety and Applied Nutrition (CFSAN), and Food and Drug Administration (FDA). 2015. Gras Exemption Claim for Taurine for Use in Enhanced Water Beverages.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCortese, G. P., Olin, A., O'Riordan, K., Hullinger, R. \u0026amp; Burger, C. Environmental enrichment improves hippocampal function in aged rats by enhancing learning and memory, LTP, and mGluR5-Homer1c activity. Neurobiol. Aging 63, 1\u0026ndash;11 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCotman, C. W. \u0026amp; Berchtold, N. C. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 25, 295\u0026ndash;301 (2002).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCox, L.A., Puppala, S., Chan, J., Zimmerman, K.D., Hamid, Z., Ampong, I., Huber, H.F., Li, G., Jadhav, A.Y.L., Wang, B., Li, C., Baxter, M.G., Shively, C., Clarke, G.D., Register, T.C., Nathanielsz, P.W., Olivier, M. Integrated multi-omics analysis of brain aging in female nonhuman primates reveals altered signaling pathways relevant to age-related disorders. Neurobiol. Neurobiol Aging. 132, 109\u0026ndash;119 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCybulska-Klosowicz, A. \u003cem\u003eet al\u003c/em\u003e. Interneurons containing somatostatin are affected by learning-induced cortical plasticity. Neuroscience 254, 18\u0026ndash;25 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCybulska-Klosowicz, A., Zakrzewska, R. \u0026amp; Kossut, M. Brain activation patterns during classical conditioning with appetitive or aversive UCS. Behav. Brain Res. 204, 102\u0026ndash;11 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDawson, Jr R., Pelleymounter, M. A., Cullen, M. J., Gollub, M. \u0026amp; Liu, S. An age-related decline in striatal taurine is correlated with a loss of dopaminergic markers. Brain Res Bull 48, 319\u0026ndash;24 (1999).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDobrzanski, G. \u003cem\u003eet al\u003c/em\u003e. Learning-induced plasticity in the barrel cortex is disrupted by inhibition of layer 4 somatostatin-containing interneurons. Biochim. Biophys. Acta Mol. Cell. Res. 1869, 119146 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl Idrissi, A. \u0026amp; Trenkner, E. Taurine as a modulator of excitatory and inhibitory neurotransmission. Neurochem. Res. 29, 189\u0026ndash;97 (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl Idrissi, A. \u003cem\u003eet al\u003c/em\u003e. Decreased GABA(a) receptor expression in the seizure-prone fragile X mouse.\" Neurosci. Lett. 377, 141\u0026ndash;6 (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl Idrissi, A. Taurine improves learning and retention in aged mice. Neurosci. Lett. 436, 19\u0026ndash;22 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl Idrissi, A., Messing, J., Scalia, J. \u0026amp; Trenkner E. Prevention of epileptic seizures by taurine. Adv. Exp. Med. Biol. 526: 515\u0026ndash;25 (2003).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl Idrissi, A., Shen, C. H. \u0026amp; L'amoreaux, W. J. Neuroprotective role of taurine during aging. Amino Acids 45, 735\u0026ndash;50 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl Idrissi, A., Shen, C. H. \u0026amp; L'amoreaux, W. J.. Neuroprotective role of taurine during aging. Amino Acids 45, 735\u0026ndash;50 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFoos, T. M. \u0026amp; Wu, J. Y. The Role of taurine in the central nervous system and the modulation of intracellular calcium homeostasis. Neurochem Res. 27, 21\u0026ndash;6 (2002).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFu, Y., Kaneko, M., Tang, Y., Alvarez-Buylla, A. \u0026amp; Stryker, M. P. A. Cortical disinhibitory circuit for enhancing adult plasticity. Elife 4, e05558 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGalindo-Leon, E. E., Lin, F. G. \u0026amp; Liu, R. C. Inhibitory plasticity in a lateral band improves cortical detection of natural vocalizations. Neuron 62, 705\u0026ndash;16 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGelfo, F., Mandolesi, L., Serra, L., Sorrentino, G., \u0026amp; Caltagirone, C. The neuroprotective effects of experience on cognitive functions: evidence from animal studies on the neurobiological bases of brain reserve. Neuroscience, 370, 218\u0026ndash;235 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGierdalski, M. \u003cem\u003eet al\u003c/em\u003e. Rapid regulation of Gad67 mRNA and protein level in cortical neurons after sensory learning. Cereb. Cortex 11, 806\u0026ndash;15 (2001).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eG\u0026oslash;tzsche, C. R. \u0026amp; Woldbye, D. P. The role of Npy in learning and memory. Neuropeptides 55, 79\u0026ndash;89 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHwang, D. F., Hour, J. L. \u0026amp; Cheng, H. M. Effect of taurine on toxicity of oxidized fish oil in rats. Food Chem. Toxicol. 38, 585\u0026ndash;91 (2000).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJablonska, B., Gierdalski, M., Kossut, M. \u0026amp; Skangiel-Kramska, J. Partial blocking of NMDA receptors reduces plastic changes induced by short-lasting classical conditioning in the SI barrel cortex of adult mice. Cereb. Cortex 9, 222\u0026ndash;31 (1999).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJasinska, M. \u003cem\u003eet al\u003c/em\u003e. Rapid, Learning-induced inhibitory synaptogenesis in murine barrel field. J. Neurosci. 30, 1176\u0026ndash;84 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarlsson, R. M., Holmes, A., Heilig, M. \u0026amp; Crawley, J. N. Anxiolytic-like actions of centrally-administered neuropeptide Y, but not galanin, in C57bl/6j Mice. Pharmacol. Biochem. Behav. 80, 427\u0026ndash;36 (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaushik, M., Kaushik, P., Panwar, S., Joshi, S.D., Parvez, S. Environment enrichment facilitates long-term memory consolidation through behavioral tagging. \u003cem\u003eeNeuro\u003c/em\u003e. 10, ENEURO.0365-22.2023 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, C. \u0026amp; Cha, Y. N. Taurine chloramine produced from taurine under inflammation provides anti-inflammatory and cytoprotective effects. Amino Acids 46, 89\u0026ndash;100 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKolb, B., Gibb, R. \u0026amp; Gorny, G. Experience-dependent changes in dendritic arbour and spine density in neocortex vary qualitatively with age and sex. Neurobiol Learn Mem. 79, 1\u0026ndash;10 (2003).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKossut, M., Hand, P. J., Greenberg, J. \u0026amp; Hand C. L. Single vibrissal cortical column in SI cortex of rat and its alterations in neonatal and adult vibrissa-deafferented animals: a quantitative 2DG study. \u003cem\u003eJ. Neurophysiol.\u003c/em\u003e 60, 829\u0026thinsp;\u0026ndash;\u0026thinsp;52 (1988).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKrivanek, T. J., Gale, S. A., McFeeley, B. M., Nicastri, C. M. \u0026amp; Daffner, K. R. Promoting successful cognitive aging: a ten-year update. J. Alzheimers Dis. 81, 871\u0026ndash;920 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLazarov, O. \u003cem\u003eet al\u003c/em\u003e. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. \u003cem\u003eCell\u003c/em\u003e 120, 701\u0026thinsp;\u0026ndash;\u0026thinsp;13 (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLetzkus, J. J., Wolff, S. B. \u0026amp; L\u0026uuml;thi, A. Disinhibition, a circuit mechanism for associative learning and memory. \u003cem\u003eNeuron\u003c/em\u003e 88, 264\u0026thinsp;\u0026ndash;\u0026thinsp;76 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, S. \u003cem\u003eet al\u003c/em\u003e. Environmental novelty activates Β2-adrenergic signaling to prevent the impairment of hippocampal Ltp by Aβ oligomers. \u003cem\u003eNeuron\u003c/em\u003e 77, 929\u0026thinsp;\u0026ndash;\u0026thinsp;41 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiguz-Lecznar, M. \u003cem\u003eet al\u003c/em\u003e. Altered Glutamate/Gaba equilibrium in aged mice cortex influences cortical plasticity. Brain Struct. Funct. 220, 1681\u0026ndash;93 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiguz-Lecznar, M. \u003cem\u003eet al\u003c/em\u003e. Altered Glutamate/Gaba equilibrium in aged mice cortex influences cortical plasticity. Brain Struct. Funct. 220, 1681\u0026ndash;93 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiguz-Lecznar, M., Siucinska, E., Zakrzewska, R. \u0026amp; Kossut, M. Impairment of experience-dependent cortical plasticity in aged mice. Neurobiol Aging 32, 1896\u0026ndash;905 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiguz-Lecznar, M., Urban-Ciecko, J. \u0026amp; Kossut, M. Somatostatin and somatostatin-containing neurons in shaping neuronal activity and plasticity. Front. Neural Circuits 10: 48 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMelendez, R. I., Gregory, M. L., Bardo, M. T. \u0026amp; Kalivas, P. W. Impoverished rearing environment alters metabotropic glutamate receptor expression and function in the prefrontal cortex. Neuropsychopharmacology 29, 1980\u0026ndash;7 (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMenzie, J., Prentice, H. \u0026amp; Wu, J. Y. Neuroprotective mechanisms of taurine against ischemic stroke. Brain Sci. 3, 877\u0026ndash;907 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMlynarik, M., Johansson, B. B. \u0026amp; Jezova, D. Enriched environment influences adrenocortical response to immune challenge and glutamate receptor gene expression in rat hippocampus. Ann. N Y Acad. Sci. 1018, 273\u0026ndash;80 (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohd Sahini, S.N., Mohd Nor Hazalin, N.A., Srikumar, B.N., Jayasingh, Chellammal, H.S., Surindar Singh, G.K. Environmental enrichment improves cognitive function, learning, memory and anxiety-related behaviours in rodent models of dementia: Implications for future study. Neurobiol Learn Mem. 208, 10788 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoore, K., Hughes, C. F., Ward, M., Hoey, L. \u0026amp; McNulty, H. Diet, Nutrition and the ageing brain: current evidence and new directions. \u003cem\u003eProc. Nutr. Soc.\u003c/em\u003e 77, 152\u0026ndash;163 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMora, F. Successful brain aging: plasticity, environmental enrichment, and lifestyle. Dialogues Clin. Neurosci. 15, 45\u0026ndash;52 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMora, F., Segovia, G. \u0026amp; del Arco, A. Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain Res. Rev. 55, 78\u0026ndash;88 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMora, F., Segovia, G. \u0026amp; del Arco, A. Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain Res Rev. 55, 78\u0026ndash;88 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Connor, D. H. \u003cem\u003eet al\u003c/em\u003e. Neural coding during active somatosensation revealed using illusory touch. Nat. Neurosci. 16, 958\u0026ndash;65 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaulucio, D. \u003cem\u003eet al\u003c/em\u003e. Acute effect of ethanol and taurine on frontal cortex absolute beta power before and after exercise. PLoS One 13, e0194264 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePham, T. M., Winblad, B., Granholm, A. C. \u0026amp; Mohammed, A. H. Environmental influences on brain neurotrophins in rats. Pharmacol. Biochem. Behav. 73, 167\u0026ndash;75 (2002).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePosluszny, A. \u003cem\u003eet al\u003c/em\u003e. Learning-dependent plasticity of the barrel cortex is impaired by restricting Gaba-ergic transmission. PLoS One 10, e0144415 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePotier, B., Jouvenceau, A., Epelbaum, J. \u0026amp; Dutar P. Age-related alterations of Gabaergic input to Ca1 pyramidal neurons and its control by nicotinic acetylcholine receptors in rat hippocampus. Neuroscience 142, 187\u0026ndash;201 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReed, H. E. \u003cem\u003eet al\u003c/em\u003e. Effects of vasoactive intestinal polypeptide on neurones of the rat suprachiasmatic nuclei in vitro. J. Neuroendocrinol. 14, 639\u0026ndash;46 (2002).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRowley, H. L., Martin, K. F. \u0026amp; Marsden, C. A. Determination of in vivo amino acid neurotransmitters by high-performance liquid chromatography with O-phthalaldehyde-sulphite derivatisation. J. Neurosci. Methods 57, 93\u0026ndash;9 (1995).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSale, A. \u003cem\u003eet al\u003c/em\u003e. Environmental enrichment in adulthood promotes amblyopia recovery through a reduction of intracortical inhibition. Nat. Neurosci. 10, 679\u0026ndash;81 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSale, A., Berardi, N. \u0026amp; Maffei, L. Environment and brain plasticity: towards an endogenous pharmacotherapy. Physiol. Rev. 94, 189\u0026ndash;234 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSampedro-Piquero, P. \u0026amp; Begega, A. Environmental enrichment as a positive behavioral intervention across the lifespan. Curr. Neuropharmacol. 15, 459\u0026ndash;470 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScala, F. \u003cem\u003eet al\u003c/em\u003e. Layer 4 of mouse neocortex differs in cell types and circuit organization between sensory areas. Nat. Commun. 10, 4174 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmidt, S., Haase, M., Best, L., Groth, M., Lindner, J., Witte, O.W., Kaleta, C., Frahm, C. Restoring age-related cognitive decline through environmental enrichment: a transcriptomic approach. Cells, 11, 3864 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSegovia, G., Yague, A. G., Garcia-Verdugo, J. M. \u0026amp; Mora, F. Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats. Brain Res Bull. 70, 8\u0026ndash;14 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSegovia, G., Yag\u0026uuml;e, A. G., Garc\u0026iacute;a-Verdugo, J. M. \u0026amp; Mora, F. Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and Gaba in the hippocampus of aged rats. Brain Res. Bull. 70, 8\u0026ndash;14 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh, P. \u003cem\u003eet al\u003c/em\u003e. Taurine deficiency as a driver of aging. Science, 380(6649), eabn9257 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiucinska, E. \u0026amp; Kossut, M. Short-lasting classical conditioning induces reversible changes of representational maps of vibrissae in mouse SI cortex - a 2DG study. Cereb. Cortex 6, 506\u0026ndash;13 (1996).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiucinska, E. Gad67-positive puncta: contributors to learning-dependent plasticity in the barrel cortex of adult mice. Brain Res. 1106, 52\u0026ndash;62 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiucinska, E., Kossut M. \u0026amp; Stewart, M. G. Gaba immunoreactivity in mouse barrel field after aversive and appetitive classical conditioning training involving facial vibrissae. Brain Res. 843, 62\u0026ndash;70 (1999).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSokoloff, L. \u003cem\u003eet al\u003c/em\u003e. The [14C]Deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J. Neurochem. 28, 897\u0026ndash;916 (1977).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStanley, E. M., Fadel, J. R. \u0026amp; Mott, D. D. Interneuron loss reduces dendritic inhibition and Gaba release in hippocampus of aged rats. Neurobiol. Aging 33, 431.e1-13 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStrominger, R. N. \u0026amp; Woolsey, T. A. Templates for locating the whisker area in fresh flattened mouse and rat cortex. J. Neurosci. Methods 22, 113\u0026ndash;8 (1987).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSu\u0026aacute;rez, L. M. \u0026amp; Sol\u0026iacute;s, J. M. Taurine potentiates presynaptic NMDA receptors in hippocampal schaffer collateral axons. Eur. J. Neurosci. 24, 405\u0026ndash;18 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSu\u0026aacute;rez, L. M., Mu\u0026ntilde;oz, M. D., del R\u0026iacute;o, R. M. \u0026amp; Sol\u0026iacute;s, J. M. Taurine content in different brain structures during ageing: effect on hippocampal synaptic plasticity. Amino Acids 48, 1199\u0026ndash;1208 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrenkner, E., El Idrissi, A., Dumas, R. \u0026amp; A. Rabe, A. Functional consequences of calcium uptake modulation by taurine in vivo and in vitro. Adv. Exp. Med. Biol. 442: 277\u0026ndash;84 (1998).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUrban-Ciecko, J., Kossut, M. \u0026amp; Mozrzymas, J. W. Sensory learning differentially affects GABAergic tonic currents in excitatory neurons and fast spiking interneurons in layer 4 of mouse barrel cortex. J. Neurophysiol. 104, 746\u0026ndash;54 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Praag, H., Kempermann, G. \u0026amp; Gage, F. H. Neural consequences of environmental enrichment. Nat. Rev. Neurosci. 1, 191\u0026ndash;8 (2000).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerma, D., Tasan, R. O., Herzog, H. \u0026amp; Sperk, G. Npy controls fear conditioning and fear extinction by combined action on Y₁ and Y₂ receptors. Br. J. Pharmacol. 166, 461\u0026ndash;73 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, H. L., Li, A. \u0026amp; T. Wu, T. Vasoactive intestinal polypeptide enhances the GABAergic synaptic transmission in cultured hippocampal neurons. Brain Res. 746, 294\u0026ndash;300 (1997).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeuve, J. \u003cem\u003eet al\u003c/em\u003e. Physical activity, including walking, and cognitive function in older women. JAMA 292, 1454\u0026ndash;61 (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWong, T. P. \u003cem\u003eet al\u003c/em\u003e. Imbalance towards inhibition as a substrate of aging-associated cognitive impairment. Neurosci. Lett. 397, 64\u0026ndash;8 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWoolsey, T. A. \u0026amp; Van der Loos, H. The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The Description of a Cortical Field Composed of Discrete Cytoarchitectonic Units. \u003cem\u003eBrain Res.\u003c/em\u003e 17, 205\u0026thinsp;\u0026ndash;\u0026thinsp;42 (1970).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu, H. \u003cem\u003eet al\u003c/em\u003e. Mode of action of taurine as a neuroprotector. Brain Res. 1038, 123\u0026ndash;31 (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu, J. Y. \u0026amp; Prentice H. Role of taurine in the central nervous system. \u003cem\u003eJ. Biomed. Sci.\u003c/em\u003e 17(Suppl 1), S1 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu Z-Y, Wang W, Fritschy J-M, Witte OW, Redecker C. Changes in neocortical and hippocampal GABAA receptor subunit distribution during brain maturation and aging. Brain Res. 1099, 73\u0026ndash;81 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhu, M., Akimana, C., Wang, E. \u0026amp; Ng, C. K. \u003csup\u003e1\u003c/sup\u003eH-MRS quantitation of age-dependent taurine changes in mouse brain. Mol. Imaging Biol. 21, 812\u0026ndash;817 (2019).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4372981/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4372981/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAging-related biochemical changes in nerve cells lead to dysfunctional synapses and disrupted neuronal circuits, ultimately affecting vital processes such as brain plasticity, learning, and memory. The imbalance between excitation and inhibition in synaptic function during aging contributes to cognitive impairment, emphasizing the importance of compensatory mechanisms. Fear conditioning-related plasticity of somatosensory barrel cortex, relying on the proper functioning and extensive upregulation of GABAergic system, in particular interneurons containing somatostatin, is compromised in aging (one-year-old) mice. The present research explores two potential interventions, taurine supplementation and environmental enrichment, revealing their effectiveness in supporting learning-induced plasticity in the aging mouse brain. They do not act through a mechanism normalizing the Glutamate/GABA balance that is disrupted in aging, but they do allow for increase in somatostatin levels, an effect observed in young animals after learning. These findings highlight the potential of lifestyle interventions and diet supplementation to mitigate age-related cognitive decline by promoting experience-dependent plasticity.\u003c/p\u003e","manuscriptTitle":"Mitigation of aging-related plasticity decline through taurine supplementation and environmental enrichment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-14 19:34:52","doi":"10.21203/rs.3.rs-4372981/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-07T05:15:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-06T20:16:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-20T02:20:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"154426292260249952760453765189851123195","date":"2024-05-17T14:09:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"177927691485068884444308784554632280233","date":"2024-05-14T19:08:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-14T16:43:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-14T16:35:53+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-07T22:15:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-07T21:45:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-05-05T20:18:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0e8ebc90-d0b2-4117-8855-845a1a40fa28","owner":[],"postedDate":"May 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":31799377,"name":"Biological sciences/Neuroscience/Learning and memory"},{"id":31799378,"name":"Biological sciences/Neuroscience/Neural ageing"},{"id":31799379,"name":"Biological sciences/Neuroscience/Somatosensory system"},{"id":31799380,"name":"Biological sciences/Neuroscience/Synaptic plasticity"},{"id":31799381,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2024-08-26T16:06:47+00:00","versionOfRecord":{"articleIdentity":"rs-4372981","link":"https://doi.org/10.1038/s41598-024-70261-5","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-08-22 15:58:03","publishedOnDateReadable":"August 22nd, 2024"},"versionCreatedAt":"2024-05-14 19:34:52","video":"","vorDoi":"10.1038/s41598-024-70261-5","vorDoiUrl":"https://doi.org/10.1038/s41598-024-70261-5","workflowStages":[]},"version":"v1","identity":"rs-4372981","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4372981","identity":"rs-4372981","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}