Auditory Entrainment Reverses Working Memory Deficits in a Rodent Model of Autism

Auditory Entrainment Reverses Working Memory Deficits in a Rodent Model of Autism | 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 Auditory Entrainment Reverses Working Memory Deficits in a Rodent Model of Autism Miguel Remondes, Jorge Cardoso, Marta Luis, Catarina Mesquita, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7517068/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Individuals on the autism spectrum often show atypical responses to sensory input and difficulties with behavioral regulation, reflecting neural activity changes in core sensory-motor circuits. Although higher cognitive impairments can be present in autism, they remain understudied in rodent models compared to sensory-motor deficits. Sensory processing differences suggest that patterned sensory stimulation could help modulate altered neural activity and thereby reduce symptoms. In this study, we examined higher cognitive function in the valproic acid (VPA) rodent model of autism and tested whether auditory entrainment could improve observed deficits. Pregnant dams received VPA on embryonic day 12.5, and working memory (WM) was evaluated in their offspring using a standard delayed non-match to place (DNMP) task. VPA-exposed animals showed impaired performance and disrupted learning dynamics, indicating WM deficits. Auditory stimulation at 40Hz increased oscillatory power at several relevant bands, namely gamma, theta and beta, across brain regions relevant for WM. Notably such manipulation eliminated working memory impairments both during stimulation and for six daily recorded sessions thereafter. These findings highlight the therapeutic potential of sensory entrainment to restore cognitive function in autism. Health sciences/Diseases/Psychiatric disorders/Autism spectrum disorders Biological sciences/Neuroscience valproate rodent model of autism working memory deficits sensory entrainment Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Adaptive behavior relies on the ability to make decisions based on the surrounding environment. For this, the organism must select relevant sensory inputs from the full set of environmental stimuli, encode and store such information in retrievable form, namely within cortico-hippocampal circuits, forming so-called cognitive maps expressed in a variety of neural response patterns to both egocentric (self-referenced) and allocentric (world-referenced) contextual variables 1 – 3 . Supporting these functions, neural populations act in synchrony, orchestrated by population oscillatory activity on the theta and gamma frequencies, to which individual neurons tend to align 4 – 9 . Emerging evidence suggests that the neural circuits connecting early sensory processing, memory formation, and anterior executive regions involved in behavioral control are altered in autism spectrum disorders (ASD), namely through disrupted anatomical and functional connectivity, manifested by dysregulated oscillations and neural desynchrony 10 – 14 . These alterations may contribute to the hallmark inflexibility observed in ASD manifesting as rigid, self-centered rather than adaptive, context-sensitive behaviors, thoughts, and emotions 15 . While a wide range of spontaneous and stimulus-driven behaviors have been documented in animals prenatally exposed to valproic acid (VPA)—a well-established rodent model of ASD—higher cognitive functions, such as spatial working memory and decision-making, remain relatively unexplored in this model. If VPA exposure indeed mimics core ASD phenotypes, deficits in higher cognitive functions, including the ability to utilize allocentric spatial information to guide decisional behavior, would be expected. Recent studies in neurodegenerative models have shown that patterned sensory stimulations - specifically sensory entrainment - can mitigate cognitive deficits in Alzheimer’s disease presumably through improved clearance of waste metabolites, leading to their decreased accumulation and reversal of otherwise ensuing neurodegenerative processes 16 , 17 . Given the reliance of higher cognitive processes on effective sensory integration, and the unique sensory processing features in ASD, we hypothesize that sensory entrainment may also alleviate cognitive impairments associated with ASD, although through distinct mechanisms. We propose that auditory gamma-frequency stimulation can entrain neural populations and restore otherwise defective neural oscillatory synchrony, thus rescuing working memory and goal-directed decision-making in VPA-exposed rodents. To test these hypotheses, we employed a Delayed Non-Match to Place (DNMP) task designed to robustly engage WM over a 20-second delay, for a block of six consecutive daily sessions. In a subsequent 6-session block, animals performed this task while exposed to auditory gamma-frequency (40 Hz) entrainment. The DNMP paradigm requires animals to navigate one arm of a T-maze during a “Sample” run, followed by a 20-second delay, or “retention” period, spent inside a box. In the ensuing “Test” run, both arms are made available, and the animal is rewarded for choosing the arm opposite to the one previously sampled 18 – 24 . We applied this paradigm to animals prenatally exposed to either saline or valproic acid (VPA; 400 or 600 mg/kg body weight, intraperitoneally administered to pregnant dams), modeling varying degrees of ASD-like traits. Importantly, animals were assigned to groups without prior behavioral screening, ensuring an unbiased approach to testing VPA’s impact on memory-guided decision making. To evaluate behavioral performance, we measured both trial-level accuracy (correct/error) and session-level success (% correct trials), analyzing outcomes across individuals, sessions, and groups (CTRL, VPA400, VPA600). To examine the impact of VPA exposure on task performance, we used a multivariable Generalized Linear Mixed Model (GLMM), accounting for both categorical and continuous predictors. Additionally, we conducted trial-by-trial analyses using logistic regression and state-space modeling to assess learning dynamics and estimate the probability of correct choices over time within individual sessions. Given that perseverative behavior—a hallmark of ASD—is often maladaptive in tasks requiring cognitive flexibility, we also quantified individual perseveration biases. A bias index was computed for each animal by calculating the absolute difference in left versus right arm choices during Test trials, normalized by the total number of trials. To determine whether auditory entrainment could modulate the neural dynamic associated with DNMP behavior, in one CTRL and one VPA600 animal we recorded multi-unit neural activity from cortical, subcortical and hippocampal brain areas. We then applied the same stimulation to a dedicated experimental group of VPA600 animals, already trained in DNMP to asymptotic levels, to assess the effect of entrainment in WM. This group underwent three consecutive blocks of six DNMP sessions, with gamma-frequency auditory stimulation applied during the middle block. Behavioral changes across these phases were assessed using the performance metrics described above, enabling us to evaluate the behavioral effects of sensory entrainment. Materials and methods Experimental Design To evaluate WM in a rodent model of ASD we initially compared three groups of animals according to distinct VPA exposure levels, e.g. VPA administered to pregnant dams: CTRL (no exposure, saline was administered), VP400 (400mg/KgBW), VP600 (600mg/KgBW). To assess the effect of auditory entrainment in DNMP performance we trained a separate cohort of VP600 animals, and compared performance levels in three consecutive blocks of 6 daily DNMP sessions each, during the mid-block of which animals were exposed to the sound entrainment stimulus described below (Block 1: no sound, Block 2: sound, Block 3: no sound) for the duration of DNMP sessions. All procedures were performed in accordance with EU and Institutional guidelines. Female and male rats aged 3–6 m, were obtained from Charles River France, kept in a 12hr light/dark cycle, fed ad libitum , housed in groups until mating cycles begun. Timed-mating protocol Timed-mating protocol Pairs of males and females of the same age were formed, and single-caged for 48 hours to reduce stress and prepare females for estrus synchronization. After the separation period, cages were swapped between animals of the same pair to expose females to the scent of the male thus-timing estrus. Estrus was detected using periodic vaginal electrical impedance measurements. Once in peak estrus the pair was rejoined and allowed to mate overnight for a period of 8 hours. In the following morning, the pair was separated, and the female was inspected for the presence of a vaginal plug, in which case the female was labeled 'possibly pregnant' at day 0.5 (E0.5, embryonic day 5) and weighted daily thereafter. VPA treatment Twelve days later, on E12.5, pregnant females received an IP injection of either saline (CTRL), 400 mg/ Kg (VP400), or 600 mg/ Kg (VP600) of sodium valproate (VPA, Sigma P4543) diluted in saline and were housed individually thereafter. The day the pups were born was recorded as post-natal day 0 (P0), and the bedding was left undisturbed for 7 days. After weaning (P21), pups were housed in groups of up to 3 per cage, and assigned experimental groups according to treatment, CTRL (saline), VP400 (400 mg/ kg) and VP600 (600 mg/ kg). Delayed non-matching to place task In preparation for the DNMP task, the above animals (now 6 month old) were food-restricted to 85% BW. The DNMP task was conducted in a T-maze featuring a starting platform (25x30 cm), a central corridor (170 cm) and two lateral exit arms (88 cm each) at whose ends a chocolate reward was placed. An external opaque resting box (57x39x42cm) was used to temporarily house the rat during the inter-trial maze setup. Each trial consisted in three runs: (1) Sample, (2) Delay and (3) Test. In Sample runs one of the lateral arms (randomly defined) was baited with reward while the other arm was blocked. After the rat visited the baited arm and consumed the reward, it was taken out of the maze and placed in the resting box for 20 seconds (the Delay). On the Test run the previous arm block was removed, and once the delay period had elapsed the animal was returned to the maze, now with both lateral arms accessible. The rat was now rewarded for selecting the arm non-matching the one baited before (during Sample), in which case the trial was classified as “correct”, and “error” otherwise. All sessions were recorded using a Flea 3 PointGreyTM at 30 fps acquisition rate (top view) mounted on a cable tray fixed on the ceiling above the T-maze and stored in the acquisition computer running Bonsai software. Sound Entrainment Protocol During the entrainment sessions a synthetically generated sound, consisting of a carrier tone of 8 kHz amplitude-modulated at 40 Hz, was continuously delivered by a speaker (Blow BT-950) placed inside the room, above and aligned with the T-maze central corridor, and modified until the Sound Pressure Level (SPL) reached 70 dB at the maze level. Electrophysiological Recordings Local field potential recordings were performed using a chronically implanted multi-tetrode drive. The data was acquired at 20K sampling rate using Intan RHD2164 amplifier boards connected to the Open-Ephys board, as described earlier 25 . Statistical Analysis Trial outcomes were classified as 1 (“correct”) or 0 (“error”) across all groups, sessions and animals. Pooled, and trial-by-trial data were analyzed using Matlab and Jamovi. Individual performance curves were computed for each individual session, from the individual trial outcomes, using two complementary methods: 1) State Space Model (SSM) 26 applied to estimate the individual subject learning curve using binomial expectation maximization and 2) a predictive binary logistic regression model. In both cases we computed the 95% confidence interval displayed in the main and supplementary plots, in both individual animals and groups. Generalized Linear Mixed Models (GLMM) were employed to analyze the behavioral outcome results. Model selection was based on the Akaike Information Criterion (AIC), with the chosen model being the one that converged and exhibited the lowest AIC value. To assess performance differences between VPA and CTRL groups, we used a GLMM with a binomial distribution and logit link function, with individual subjects as the random effects variable. The same GLMM, followed by a Bonferroni post-hoc test, was conducted to analyze the ratio of correct trials between groups during the experiment. All error bars throughout the manuscript correspond to 95% confidence intervals (CI). Results Group-level performance reveals working memory impairment following prenatal VPA exposure In the DNMP task, animals first complete a "Sample" trial, during which one arm of the T-maze is blocked. In the subsequent "Test" trial, both arms are accessible, and rats are rewarded for choosing the arm opposite to the one previously visited during the Sample trial (Fig. 1 A). A group-level analysis of performance across all animals (Fig. 1 B) revealed a general improvement over sessions 1 to 6 ( χ² = 30.39 , p < 0.001 ; Fixed Effect Omnibus test). However, animals exposed in utero to valproic acid (both VP600 and VP400) displayed significantly impaired performance compared to control animals (CTRL), with a robust effect of treatment (Fig. 1 B–C; Table 2; GLMM: χ² = 15.05 , p < 0.001 ; Fixed Effect Omnibus test). No significant performance difference was observed between the VP600 and VP400 groups ( NS , Bonferroni post hoc test). Interestingly, this performance gap disappeared by session 6, with all groups achieving accuracy well above chance (50%), the CTRL group exhibiting a slight decline in performance by session 6. These findings show that prenatal VPA exposure impairs WM as assessed by the DNMP task. To try and better understand the underlying learning dynamics, we next analyzed performance progression within sessions (S1–S6) by estimating the probability of each consecutive trial in each session being a correct one. VPA-exposed animals exhibit disrupted trial-by-trial learning dynamics and reduced within-session performance stability. To assess within-session behavioral dynamics in individual animals, we analyzed how trial-by-trial performance evolved over time. Specifically, we aimed to estimate the probability of a correct choice on each consecutive trial based on preceding trials. For this, we employed two complementary approaches: Binary Logistic Regression (BLR) and State-Space Modeling (SSM), allowing us to track trial-wise learning and performance maintenance across sessions S1–S6 (see Supplementary Fig. 1 for raw data, BLR and SSM outputs for each animal across groups). In CTRL animals, we observed not only a clear improvement across sessions, as shown earlier, but also a consistent within-session increase in the probability of correct responses. Both BLR and SSM analyses converged on these results, with later sessions showing high and stable performance. Group-level analyses further confirmed this pattern: in 3.2 out of 6 sessions, the 95% confidence intervals (CIs) of the mean trial-wise correct probability exceeded the 50% chance level, indicating reliable and above-chance performance (Fig. 2 A). On average, SSM yielded stable trial-by-trial estimates in 4.8 of 6 sessions per animal (Figure S1 ; Table 1). In contrast, the VP400 group displayed markedly weaker performance. Mean correct trial probabilities were lower, and within-session learning curves were flatter or absent. Only 2.1 out of 6 sessions showed group-level 95% CIs above chance (Fig. 2 B), and SSM failed to provide stable performance estimates in 2.3 of 6 sessions per animal, on average, reflecting considerably less reliable learning in this group compared to CTRL (Figure S1 – data for individual animals; Table 1 – group level analysis and SSM reliability). The VP600 group, with the largest sample size, showed slightly narrower confidence intervals but significantly lower performance overall. Incremental within-session learning was infrequent, and even in later sessions (S5–S6), group-level performance remained well below CTRL levels (Fig. 2 C). Only 1.38 of 6 sessions, on average, yielded group-level 95% CIs above chance performance, and SSM produced stable trial-wise estimates in just 3.2 of 6 sessions per animal (Figure S1 – data for individual animals; Figure S2 – Logit and SSM data, with 95% CIs for each individual animal, Table 1 – group level analysis and SSM reliability). Together, these findings indicate that while VPA-exposed animals are eventually able to reach a performance plateau, their overall success is significantly diminished compared to controls. More importantly, analysis of trial-by-trial dynamics reveals that past trials in VPA animals are poorer predictors of future behavior. This inconsistency prevents a stable and reliable estimation of learning progression, as only a minority of sessions show performance distinguishable from chance—unlike the more robust and predictable behavior observed in CTRL animals (Figure S1 – data for individual animals; Table 1 – group level analysis and SSM reliability). VPA-exposed animals exhibit increased choice perseveration A common behavioral feature in individuals on the autism spectrum is a diminished ability to promptly perceive or respond to external stimuli, and to flexibly guide behavior based on changing circumstances. One potential manifestation of this is a failure to associate actions with their outcomes—such as associating a specific choice with the subsequent delivery or absence of a reward—and to adjust behavior, and either behaving randomly, or persevering in one trajectory, in both cases regardless of existing reward contingencies. Having observed frequent repetitions of trajectories in VPA groups in the raw data, we tested the hypotheses that there is indeed above-chance perseverative behavior in VPA animals. We analyzed DNMP data for signs of choice perseveration, operationalized as a persistent Left/Right Bias (LRB) during decision-making. Our analysis revealed a significant group effect: CTRL animals exhibited lower LRB compared to VPA-exposed groups (Fig. 3 ; Table 2; GLMM: χ² = 13.63 , p < 0.001 ; Fixed Effect Omnibus test), indicating increased perseverative tendencies in VPA animals. Further analysis revealed significant group-by-session interactions. While CTRL animals showed a reduction in LRB after the first DNMP session (S1) suggesting adaptive learning and behavioral flexibility, both VPA groups (VP400 and VP600) maintained elevated LRB on subsequent sessions. Specifically, compared to S1, significant LRB persistence was observed in VP400 and VP600 animals in sessions S2 (VP400: p = 0.009 ; VP600: p = 0.041 ) and S3 (VP400: p = 0.035 ; VP600: p = 0.025 ). In session S4, only VP400 animals continued to show a significant bias (p = 0.048), whereas VP600 animals did not (NS) (Fig. 3 ; Table 2; GLMM: χ² = 13.63, p < 0.001 ; Fixed Effect Omnibus test). These findings support the notion that prenatal VPA exposure impairs the reduction of persevering behavior with DNMP learning. Unlike CTRL animals, VPA-exposed animals fail to flexibly adapt their choices based on past outcomes, instead repeating arm-entries, consistent with the behavioral inflexibility commonly observed in ASD. 40Hz sensory entrainment significantly increases gamma-frequency neural oscillations across brain regions Functional imaging studies in individuals with ASD have consistently reported underconnectivity in parietal regions 27 , 28 , while EEG data reveal disrupted gamma-band oscillations and reduced gamma coherence 29 , 30 , as well as diminished fronto-temporal coherence in the 3–6 Hz range. Notably, the latter findings have shown responsiveness to sensory stimulation therapies 31 – 33 . In parallel, prenatal VPA exposure in rodent models leads to downregulation of Kv10.2 channel expression in the hippocampus, which results in elevated high-frequency oscillatory activity—a phenotype that can be reversed through compensatory gene overexpression 34 . These findings parallel MEG data in ASD patients showing increased power across delta, theta, alpha, and broadband gamma bands (20–120 Hz) in multiple cortical regions, including temporal, parietal, frontal, occipital, and midline areas, with stronger deviations associated with greater symptom severity 35 , 36 . Such gamma-frequency dysregulation is likely mediated by deficits in PV + GABAergic interneurons, whose density is reduced in frontal, motor, and auditory cortices of ASD individuals (reviewed in 37 ). Crucially, abnormal gamma oscillations in ASD patients have been shown to respond to behavioral interventions (e.g., PEERS) 38 , 39 and to transcranial stimulation protocols 40 , 41 , resulting in durable improvements in both neural synchrony and behavior during adolescence. Based on this converging evidence, we hypothesized that auditory gamma-frequency sensory entrainment could mitigate the working memory (WM) deficits observed in VPA-exposed animals, possibly through circuit-plasticity mechanisms. A wealth of evidence suggests that cortical networks in humans and animals can be reliably entrained to external stimuli—particularly light 42 and sound 43 , 44 , delivered at gamma frequencies relevant to cognition. Recent rodent studies further demonstrate that 40 Hz gamma entrainment, via either visual or multimodal (visual and auditory) stimuli, improves cognitive function and induces broad changes in neuropathology and neuroplasticity in Alzheimer's disease models, with persistent therapeutic effects following the intervention 45 – 49 . To test whether 40 Hz auditory stimulation could induce similar effects in the VPA rodent model, we recorded local field potentials (LFPs) in two animals—one VP600 and one CTRL—each implanted with multi-tetrode hyperdrives targeting the hippocampus and cortical regions. During recording sessions, animals received 40 Hz patterned auditory stimulation, and their LFPs were analyzed using Fast Fourier Transform (FFT) and multi-taper spectral analysis 50 . Our analysis confirmed that auditory entrainment at 40 Hz enhances gamma-band power, as well as activity in other relevant frequency bands such as theta and beta (Fig. 4 ). Importantly, we observed sustained changes in oscillatory power that persisted beyond the period of active stimulation. These results demonstrate that 40 Hz auditory stimulation effectively entrains neural circuits in awake-behaving rats, and induces lasting changes in neural dynamics, providing a possible mechanistic basis for therapeutic effects. Auditory gamma entrainment restores working memory performance in VPA-exposed rats Building on our finding that 40 Hz auditory stimulation reliably alters neural activity in both control and VPA-exposed animals, we next tested the therapeutic potential of this intervention relative to the identified working memory (WM) deficits in VP600 animals. To this end, a separate cohort of VP600 animals previously trained to asymptotic levels on the DNMP task, was run through three consecutive sets of six DNMP sessions (Fig. 5 A). The middle block of sessions included auditory entrainment, delivered continuously throughout each behavioral session using a 40 Hz-patterned sound stimulus. As shown in Fig. 5 A (right), the VP600 animals did not improve performance over 6 pre-entrainment sessions, remaining below CTRL levels, but auditory entrainment produced a robust and statistically significant improvement in DNMP performance across these sessions. Specifically, during entrainment sessions performance was markedly enhanced compared to baseline: the average probability of a correct trial increased from 0.66 pre-entrainment to 0.78 during entrainment (GLMM, p < 0.001 ). Strikingly, this performance was statistically indistinguishable from that of the CTRL animals (GLMM, p = 0.497 ), suggesting a full rescue from the previous WM deficit. These findings were further supported by the trial-by-trial analyses using both Binary Logistic Regression (Logit) and State-Space Modeling (SSM) (Fig. 5 C). During the entrainment sessions, VPA600 animals displayed trial-wise performance dynamics that closely resembled that of CTRL animals, with both methods showing increased and more consistent estimates of the probability of correct responses. These results show that auditory gamma entrainment enhances WM performance to levels comparable to those of unexposed controls (please refer to Figure S1 for individual animals´ raw data and analysis). Auditory gamma entrainment abolishes trajectory-perseverative behavior present in VPA-exposed animals Lastly, we investigated whether sensory entrainment (SE) also modulates perseverance behavior, operationalized as Left/Right Bias (LRB), in VPA-exposed animals. While LRB differences across pre-entrainment, entrainment, and post-entrainment sessions in the VP600 group were not statistically significant from those of the CTRL group (Fig. 6 A, GLMM, p = 0.068 ), the data suggested a potential trend worth exploring further. To contextualize this behavior and assess whether LRB presence or absence can emerge by chance during DNMP training, we used the original trial structure (i.e., blocked arm, trial count, group sizes, and sessions) to create seven replicates in which choice responses were randomly assigned from an unbiased distribution, allowing us to establish a comparison baseline, and thus assess the emergence and persistence of LRB across treatment groups (CTRL, VP400, and VP600 and VP600-entrainment). CTRL animals exhibit LRB restricted to the first session, after which it becomes similar to levels resulting from synthetic data, in agreement with the previous finding (Fig. 3 ). VP400 animals exhibited high LRB levels relative to the synthetic control group (Fig. 6 C, GLMM, group effect p < 0.001 ; session-by-group interaction p = 0.597 , n.s.), with only modest attenuation across sessions ( p = 0.064 ). VP600 animals showed similar results (GLMM, group effect p < 0.001 ; session-by-group interaction p = 0.367 , n.s.), with a significant attenuation across sessions ( p = 0.004 ). Notably, sensory entrainment reduced LRB in VP600 animals (GLMM, entrainment effect p = 0.004 ; session effect p = 0.003 ; session-by-group interaction p = 0.463 , n.s.). During entrainment sessions, LRB in VP600 animals was statistically indistinguishable from that of the synthetic replicates ( p = 0.229 ) and significantly reduced compared to pre-entrainment sessions (individual session p values ranging from 0.001 to 0.013 ). These findings indicate that auditory gamma entrainment may transiently normalize perseverance tendencies while rescuing WM impairments. Discussion We have shown that prenatal exposure to Valproic Acid (VPA), a well-established rodent model of ASD, induces robust and persistent deficits in WM performance on the delayed non-match to place (DNMP) task. Importantly, we found that gamma-frequency sensory entrainment (SE) not only modulated neural activity in a frequency-specific and lasting manner but also rescued cognitive functions found defective in VPA-exposed animals. Impaired WM and Learning Dynamics in VPA-Exposed Rats Across sessions, VPA animals exhibited significantly poorer performance in the DNMP task compared to controls, with both VP400 and VP600 groups showing slower learning curves and reduced final performance levels. However, this impairment was not simply a reflection of delayed acquisition. Our trial-by-trial analyses using Binary Logistic Regression (BLR) and State Space Modeling (SSM) revealed that VPA animals lacked consistent within-session improvements and showed noisy or unstable probability estimates of correct responses, suggesting a fundamental disruption in the integration of recent experience to guide future choices. This inability to progressively improve performance likely reflects underlying disruptions in distributed networks critical for goal-directed behavior, where allocentric representations must be reinstated from memory and translated into egocentric action plans 51 – 54 . This transformation relies on synchronized activity across the hippocampus (HIPP), posterior parietal cortex (PPC), retrosplenial cortex (RSC), and prefrontal areas—circuits known to be affected in ASD. Specifically, in addition to neurophysiological changes discussed above, anatomical studies show increased local neuronal density and reduced long-range white matter connections in ASD brains, including decreased myelination and structural thinning of PPC, temporal, and frontal cortices 55 – 60 . These anatomical and neurophysiological features lend support to the hypothesis of impaired distributed coordination in ASD models. Perseverance Behavior as a Signature of Cognitive Rigidity Perseverative responding, quantified here as left/right bias (LRB), was significantly elevated in VPA-exposed animals and showed limited improvement with training - contrasting with the rapid reduction of LRB observed in control animals after session 1. This suggests that VPA animals struggle to update behavior according to reward contingencies, resembling cognitive rigidity seen in ASD. Such rigidity may stem from failures to integrate reinforcement signals with prior action choices. Indeed, ASD patients often show reduced flexibility in reversal learning tasks and diminished engagement of prefrontal-striatal circuits responsible for adaptive choice updating. Moreover, abnormal connectivity patterns—such as reduced long-range frontoparietal coherence and increased local connectivity—have been extensively reported in ASD populations, potentially impairing the ability to coordinate activity across functionally-relevant brain areas. Restoring Function Through Gamma-Frequency Sensory Entrainment Gamma-band oscillations (30–80 Hz) are thought to play a key role in coordinating distributed neural activity and enabling top-down control, attention, and WM maintenance. Disturbances in gamma rhythms are among the most robust electrophysiological findings in ASD, with reports of reduced gamma coherence and impaired phase locking to rhythmic stimuli in both EEG and MEG studies 27 – 30 . Notably, gamma oscillations are tightly regulated by PV + GABAergic interneurons, whose density is reduced across several cortical regions in models of ASD 37 . In our study, auditory 40 Hz stimulation effectively entrained neural activity in behaving rats, enhancing not only gamma but also theta and beta band power. These changes persisted beyond stimulus exposure, suggesting durable network-level modulation. Importantly, when VPA600 animals were subjected to gamma entrainment during DNMP sessions, we observed a complete rescue of WM performance, rendering it statistically indistinguishable from that of controls. Trial-wise modeling further confirmed that entrained animals exhibited stabilized learning curves and correct-trial probabilities, matching CTRL profiles. Moreover, SE also attenuated perseverative bias in VPA600 animals, reducing LRB to levels indistinguishable from unbiased synthetic controls. This suggests that gamma entrainment not only improves task performance but may restore behavioral flexibility by re-engaging circuits underlying adaptive decision-making. Mechanistic and Translational Implications The beneficial effects of gamma entrainment observed here echo findings from sensory stimulation-based interventions in ASD patients—such as transcranial stimulation and behavioral training – which have shown promising results in normalizing gamma activity and improving cognitive and social function. Our results suggest that gamma entrainment may counteract the “local-over-connectivity, long-range underconnectivity” patterns present in ASD by promoting coherent, distributed neural activity. This could facilitate the reinstatement of allocentric memory traces and enable more effective goal-directed action planning. Furthermore, entrainment may exert circuit-based long-term modulation of PV + interneuron function, namely through neural plasticity mechanism, thus stabilizing oscillatory regimes critical for WM and behavioral flexibility. Our findings demonstrate that prenatal VPA exposure impairs WM and induces perseverance behavior in rats, resembling key features of ASD. Trial-by-trial modeling reveals unstable learning dynamics in VPA animals, and the presence of persistent choice bias. However, auditory gamma-frequency sensory entrainment restores both cognitive performance and behavioral flexibility, offering a promising non-invasive intervention to modulate large-scale brain activity. Declarations Data availability All raw data is contained within the figures. Requests of data in tabular form should be directed to and will be fulfilled by the Lead Contact, Miguel Remondes, DVM, PhD ( [email protected] ). Acknowledgements We are indebted to GIMM's Bioimaging, Comparative Pathology, and Rodent facilities for critical help. We want to thank all the members of the Lopes Lab for fruitful discussions and help. Funding Foundation for Science and Technology BD-202009547 (JC) Foundation for Science and Technology IF/00201/2013 (MR) Foundation for Science and Technology PTDC/MED-NEU/29325/2017 (MR, JC, ML, CM) Foundation for Science and Technology 2022.03699.CEECIND (LVL) Foundation for Science and Technology 2022.00811.CEECIND (MR) Competing interests The authors report no competing interests. Supplementary material Supplementary material is available at xxxxx online. References Scoville, W.B., Milner, B., and Scoville WB, M.B. (1957). Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 20 , 11–21. https://doi.org/10.1136/jnnp.20.1.11 . NADEL, L. (1990). Varieties of Spatial Cognition: Psychobiological Considerations. Ann N Y Acad Sci 608 , 613–636. https://doi.org/10.1111/j.1749-6632.1990.tb48912.x . Morris, R.G.M., Garrud, P., Rawlins, J.N.P., and O’Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. 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17:12:51","extension":"png","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":132002,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineCardosoFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/d867c476d4f2aabecfb0fd1b.png"},{"id":92436645,"identity":"9997ad6b-94b9-4457-9785-85ff1bc4fc52","added_by":"auto","created_at":"2025-09-29 17:12:51","extension":"xml","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":150588,"visible":true,"origin":"","legend":"","description":"","filename":"2025MP0020890structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/0a9c396054711e43d7bcd469.xml"},{"id":92436801,"identity":"bfab8f99-49c6-412f-a530-3219634aebbb","added_by":"auto","created_at":"2025-09-29 17:20:52","extension":"html","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":164892,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/b5e512502c478f8ed2d6edd8.html"},{"id":92436620,"identity":"1d076fb1-e434-4d0c-89fb-14318c07454f","added_by":"auto","created_at":"2025-09-29 17:12:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":941915,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDelayed non-match to place (DNMP) performance in CTRL and VPA-exposed animals.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e DNMP task protocol used across six sessions (S1–S6).\u003cbr\u003e\n \u003cstrong\u003e(B)\u003c/strong\u003e Average performance (probability of correct trials) across sessions for CTRL, VP400, and VP600 groups.\u003cbr\u003e\n \u003cstrong\u003e(C)\u003c/strong\u003e Raw behavioral data from individual animals across all sessions. Error trials are marked red and correct trials green. Tick orientation corresponds to the maze arm choice (left vs right).\u003c/p\u003e","description":"","filename":"CardosoFigure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/4261162c6892dec3eeee6f75.jpg"},{"id":92436622,"identity":"c3af6a00-d908-46b7-b0e7-600567405f12","added_by":"auto","created_at":"2025-09-29 17:12:51","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":587836,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrial-by-trial dynamics of performance in CTRL and VPA animals.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eState-space Modeling (darker shade) overlaid on Binary Logistic Regression (BLR) (light shade) trial-by-trial probability estimates, +/-95% CI showing average group-level performance over time, on each of the 6 DNMP sessions (individual plots), for CTRL (grey in panel \u003cstrong\u003eA)\u003c/strong\u003e, VP400 (yellow in panel \u003cstrong\u003eB)\u003c/strong\u003e and VP600 (green in panel \u003cstrong\u003eC) \u003c/strong\u003eanimals.\u003c/p\u003e","description":"","filename":"CardosoFigure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/d062205177c313232d46b6b2.jpg"},{"id":92437505,"identity":"f9c37e09-920c-4c2d-bcb2-0c044afa4202","added_by":"auto","created_at":"2025-09-29 17:28:51","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":190785,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChoice perseveration (left/right bias, LRB) across groups and sessions.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGroup-level comparison of session-by-session LRB showing increased bias in VP400 and VP600 animals relative to CTRL (GLMM, \u003cem\u003ep\u0026lt;0.001\u003c/em\u003e). CTRL animals exhibit a significant reduction of LRB after S1, while VP groups retain elevated bias across sessions.\u003c/p\u003e","description":"","filename":"CardosoFigure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/68a39fad50c5bd88e162c6d0.jpg"},{"id":92437506,"identity":"1fec5527-1c3d-4db4-90d5-df4e1ec8a3bf","added_by":"auto","created_at":"2025-09-29 17:28:51","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":554706,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNeural entrainment to 40 Hz auditory stimulation in awake behaving rats.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePower Spectral Density plots showing power changes at physiologically relevant frequencies under entrainment, often enduring beyond the entrainment stimulus delivery. \u003cstrong\u003e(A)\u003c/strong\u003e Auditory cortex,\u003cstrong\u003e (B) \u003c/strong\u003ePosterior Parietal cortex, \u003cstrong\u003e(C)\u003c/strong\u003e LPMR Thalamus, \u003cstrong\u003e(D) \u003c/strong\u003eMedial occipital secondary (Oc2M) cortex, (E) Hippocampal CA1 subfield during DNMP trials, raw data samples on the right.\u003c/p\u003e","description":"","filename":"CardosoFigure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/494bb1b82af055b22c1c5614.jpg"},{"id":92437508,"identity":"c0e90f51-9ff3-4253-837d-07cd1bde4aaf","added_by":"auto","created_at":"2025-09-29 17:28:51","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1165436,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSensory entrainment (SE) rescues WM deficits in VPA600 animals.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Group-level performance comparison showing improved correct response rates during entrainment when compared to pre-entrainment (\u003cem\u003ep\u0026lt;0.001\u003c/em\u003e), enduring into post-entrainment. \u003cstrong\u003e(B)\u003c/strong\u003e Raw behavioral data from individual animals across all sessions (similar to Figure 1C), during pre-entrainment (sessions 1–6), entrainment (sessions 7–12), and post-entrainment (sessions 13–18). \u003cstrong\u003e(C)\u003c/strong\u003e Overlaid BLR (light shade) and SSM (strong shade) mean +/-95%CI, trial-wise estimates for VP600 animals, for the 6 sessions, across the three epochs of the experiment (similar to Figure 2). Entrainment epoch shows CTRL-like increases in trial-by-trial probability of correct responses. This improvement outlives the delivery of the entrainment stimulus, during post-entrainment.\u003c/p\u003e","description":"","filename":"CardosoFigure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/ce315a05ecc11befc88462f2.jpg"},{"id":92436627,"identity":"27392bb2-f628-42a5-96a1-5655cd53fdf0","added_by":"auto","created_at":"2025-09-29 17:12:51","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":585194,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSensory entrainment reduces LRB in VPA600 animals.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eLRB scores across pre-entrainment, entrainment, and post-entrainment epochs in VP600 group.\u003cstrong\u003e (B) \u003c/strong\u003eComparison of CTRL levels with synthetic data shows a high LRB on Session1 followed by much lower levels, indistinguishable from unbiased simulations.\u003cstrong\u003e (C, D-left panel) \u003c/strong\u003eLRB levels in VP400 and VP600 animals is significantly higher than that of synthetic data. \u003cstrong\u003e(D-right panel)\u003c/strong\u003e LRB levels in VP600 animals decreases during entrainment, to levels similar to synthetic data.\u003c/p\u003e","description":"","filename":"CardosoFigure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/febc8164b5b30fa2d4568b3c.jpg"},{"id":93243875,"identity":"c5e1b7d3-c520-408b-b25a-0be8d0b3d04c","added_by":"auto","created_at":"2025-10-10 15:00:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5188200,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/4dbbe3f0-53ed-4f2e-be54-824fbea94013.pdf"},{"id":92436793,"identity":"fd65f351-918f-4205-936c-4cabc3032668","added_by":"auto","created_at":"2025-09-29 17:20:51","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11307527,"visible":true,"origin":"","legend":"Supplementary Materials for Gamma Auditory Entrainment Reverses Working Memory Deficits in a Rodent Model of Autism by Jorge Cardoso et al.","description":"","filename":"CardosoetalSupplementaryMaterials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7517068/v1/10aeb1a3f7b028d0542837fa.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Auditory Entrainment Reverses Working Memory Deficits in a Rodent Model of Autism","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAdaptive behavior relies on the ability to make decisions based on the surrounding environment. For this, the organism must select relevant sensory inputs from the full set of environmental stimuli, encode and store such information in retrievable form, namely within cortico-hippocampal circuits, forming so-called cognitive maps expressed in a variety of neural response patterns to both egocentric (self-referenced) and allocentric (world-referenced) contextual variables \u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Supporting these functions, neural populations act in synchrony, orchestrated by population oscillatory activity on the theta and gamma frequencies, to which individual neurons tend to align \u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eEmerging evidence suggests that the neural circuits connecting early sensory processing, memory formation, and anterior executive regions involved in behavioral control are altered in autism spectrum disorders (ASD), namely through disrupted anatomical and functional connectivity, manifested by dysregulated oscillations and neural desynchrony \u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. These alterations may contribute to the hallmark inflexibility observed in ASD manifesting as rigid, self-centered rather than adaptive, context-sensitive behaviors, thoughts, and emotions \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. While a wide range of spontaneous and stimulus-driven behaviors have been documented in animals prenatally exposed to valproic acid (VPA)\u0026mdash;a well-established rodent model of ASD\u0026mdash;higher cognitive functions, such as spatial working memory and decision-making, remain relatively unexplored in this model. If VPA exposure indeed mimics core ASD phenotypes, deficits in higher cognitive functions, including the ability to utilize allocentric spatial information to guide decisional behavior, would be expected.\u003c/p\u003e\u003cp\u003eRecent studies in neurodegenerative models have shown that patterned sensory stimulations - specifically sensory entrainment - can mitigate cognitive deficits in Alzheimer\u0026rsquo;s disease presumably through improved clearance of waste metabolites, leading to their decreased accumulation and reversal of otherwise ensuing neurodegenerative processes \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Given the reliance of higher cognitive processes on effective sensory integration, and the unique sensory processing features in ASD, we hypothesize that sensory entrainment may also alleviate cognitive impairments associated with ASD, although through distinct mechanisms. We propose that auditory gamma-frequency stimulation can entrain neural populations and restore otherwise defective neural oscillatory synchrony, thus rescuing working memory and goal-directed decision-making in VPA-exposed rodents.\u003c/p\u003e\u003cp\u003eTo test these hypotheses, we employed a Delayed Non-Match to Place (DNMP) task designed to robustly engage WM over a 20-second delay, for a block of six consecutive daily sessions. In a subsequent 6-session block, animals performed this task while exposed to auditory gamma-frequency (40 Hz) entrainment. The DNMP paradigm requires animals to navigate one arm of a T-maze during a \u0026ldquo;Sample\u0026rdquo; run, followed by a 20-second delay, or \u0026ldquo;retention\u0026rdquo; period, spent inside a box. In the ensuing \u0026ldquo;Test\u0026rdquo; run, both arms are made available, and the animal is rewarded for choosing the arm opposite to the one previously sampled \u003csup\u003e\u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22 CR23\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. We applied this paradigm to animals prenatally exposed to either saline or valproic acid (VPA; 400 or 600 mg/kg body weight, intraperitoneally administered to pregnant dams), modeling varying degrees of ASD-like traits. Importantly, animals were assigned to groups without prior behavioral screening, ensuring an unbiased approach to testing VPA\u0026rsquo;s impact on memory-guided decision making.\u003c/p\u003e\u003cp\u003eTo evaluate behavioral performance, we measured both trial-level accuracy (correct/error) and session-level success (% correct trials), analyzing outcomes across individuals, sessions, and groups (CTRL, VPA400, VPA600). To examine the impact of VPA exposure on task performance, we used a multivariable Generalized Linear Mixed Model (GLMM), accounting for both categorical and continuous predictors. Additionally, we conducted trial-by-trial analyses using logistic regression and state-space modeling to assess learning dynamics and estimate the probability of correct choices over time within individual sessions.\u003c/p\u003e\u003cp\u003eGiven that perseverative behavior\u0026mdash;a hallmark of ASD\u0026mdash;is often maladaptive in tasks requiring cognitive flexibility, we also quantified individual perseveration biases. A bias index was computed for each animal by calculating the absolute difference in left versus right arm choices during Test trials, normalized by the total number of trials.\u003c/p\u003e\u003cp\u003eTo determine whether auditory entrainment could modulate the neural dynamic associated with DNMP behavior, in one CTRL and one VPA600 animal we recorded multi-unit neural activity from cortical, subcortical and hippocampal brain areas. We then applied the same stimulation to a dedicated experimental group of VPA600 animals, already trained in DNMP to asymptotic levels, to assess the effect of entrainment in WM. This group underwent three consecutive blocks of six DNMP sessions, with gamma-frequency auditory stimulation applied during the middle block. Behavioral changes across these phases were assessed using the performance metrics described above, enabling us to evaluate the behavioral effects of sensory entrainment.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eExperimental Design\u003c/h2\u003e\u003cp\u003eTo evaluate WM in a rodent model of ASD we initially compared three groups of animals according to distinct VPA exposure levels, e.g. VPA administered to pregnant dams: CTRL (no exposure, saline was administered), VP400 (400mg/KgBW), VP600 (600mg/KgBW).\u003c/p\u003e\u003cp\u003eTo assess the effect of auditory entrainment in DNMP performance we trained a separate cohort of VP600 animals, and compared performance levels in three consecutive blocks of 6 daily DNMP sessions each, during the mid-block of which animals were exposed to the sound entrainment stimulus described below (Block 1: no sound, Block 2: sound, Block 3: no sound) for the duration of DNMP sessions.\u003c/p\u003e\u003cp\u003eAll procedures were performed in accordance with EU and Institutional guidelines. Female and male rats aged 3\u0026ndash;6 m, were obtained from Charles River France, kept in a 12hr light/dark cycle, fed \u003cem\u003ead libitum\u003c/em\u003e, housed in groups until mating cycles begun.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTimed-mating protocol\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eTimed-mating protocol\u003c/div\u003e\u003cp\u003ePairs of males and females of the same age were formed, and single-caged for 48 hours to reduce stress and prepare females for estrus synchronization. After the separation period, cages were swapped between animals of the same pair to expose females to the scent of the male thus-timing estrus. Estrus was detected using periodic vaginal electrical impedance measurements. Once in peak estrus the pair was rejoined and allowed to mate overnight for a period of 8 hours. In the following morning, the pair was separated, and the female was inspected for the presence of a vaginal plug, in which case the female was labeled 'possibly pregnant' at day 0.5 (E0.5, embryonic day 5) and weighted daily thereafter.\u003c/p\u003e\n\u003ch3\u003eVPA treatment\u003c/h3\u003e\n\u003cp\u003eTwelve days later, on E12.5, pregnant females received an IP injection of either saline (CTRL), 400 mg/ Kg (VP400), or 600 mg/ Kg (VP600) of sodium valproate (VPA, Sigma P4543) diluted in saline and were housed individually thereafter. The day the pups were born was recorded as post-natal day 0 (P0), and the bedding was left undisturbed for 7 days. After weaning (P21), pups were housed in groups of up to 3 per cage, and assigned experimental groups according to treatment, CTRL (saline), VP400 (400 mg/ kg) and VP600 (600 mg/ kg).\u003c/p\u003e\n\u003ch3\u003eDelayed non-matching to place task\u003c/h3\u003e\n\u003cp\u003eIn preparation for the DNMP task, the above animals (now 6 month old) were food-restricted to 85% BW. The DNMP task was conducted in a T-maze featuring a starting platform (25x30 cm), a central corridor (170 cm) and two lateral exit arms (88 cm each) at whose ends a chocolate reward was placed. An external opaque resting box (57x39x42cm) was used to temporarily house the rat during the inter-trial maze setup. Each trial consisted in three runs: (1) Sample, (2) Delay and (3) Test. In Sample runs one of the lateral arms (randomly defined) was baited with reward while the other arm was blocked. After the rat visited the baited arm and consumed the reward, it was taken out of the maze and placed in the resting box for 20 seconds (the Delay). On the Test run the previous arm block was removed, and once the delay period had elapsed the animal was returned to the maze, now with both lateral arms accessible. The rat was now rewarded for selecting the arm non-matching the one baited before (during Sample), in which case the trial was classified as \u0026ldquo;correct\u0026rdquo;, and \u0026ldquo;error\u0026rdquo; otherwise. All sessions were recorded using a Flea 3 PointGreyTM at 30 fps acquisition rate (top view) mounted on a cable tray fixed on the ceiling above the T-maze and stored in the acquisition computer running Bonsai software.\u003c/p\u003e\n\u003ch3\u003eSound Entrainment Protocol\u003c/h3\u003e\n\u003cp\u003eDuring the entrainment sessions a synthetically generated sound, consisting of a carrier tone of 8 kHz amplitude-modulated at 40 Hz, was continuously delivered by a speaker (Blow BT-950) placed inside the room, above and aligned with the T-maze central corridor, and modified until the Sound Pressure Level (SPL) reached 70 dB at the maze level.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eElectrophysiological Recordings\u003c/h2\u003e\u003cp\u003eLocal field potential recordings were performed using a chronically implanted multi-tetrode drive. The data was acquired at 20K sampling rate using Intan RHD2164 amplifier boards connected to the Open-Ephys board, as described earlier \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eTrial outcomes were classified as 1 (\u0026ldquo;correct\u0026rdquo;) or 0 (\u0026ldquo;error\u0026rdquo;) across all groups, sessions and animals. Pooled, and trial-by-trial data were analyzed using Matlab and Jamovi. Individual performance curves were computed for each individual session, from the individual trial outcomes, using two complementary methods: 1) State Space Model (SSM) \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e applied to estimate the individual subject learning curve using binomial expectation maximization and 2) a predictive binary logistic regression model. In both cases we computed the 95% confidence interval displayed in the main and supplementary plots, in both individual animals and groups. Generalized Linear Mixed Models (GLMM) were employed to analyze the behavioral outcome results. Model selection was based on the Akaike Information Criterion (AIC), with the chosen model being the one that converged and exhibited the lowest AIC value. To assess performance differences between VPA and CTRL groups, we used a GLMM with a binomial distribution and logit link function, with individual subjects as the random effects variable. The same GLMM, followed by a Bonferroni post-hoc test, was conducted to analyze the ratio of correct trials between groups during the experiment. All error bars throughout the manuscript correspond to 95% confidence intervals (CI).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eGroup-level performance reveals working memory impairment following prenatal VPA exposure\u003c/h2\u003e\u003cp\u003eIn the DNMP task, animals first complete a \"Sample\" trial, during which one arm of the T-maze is blocked. In the subsequent \"Test\" trial, both arms are accessible, and rats are rewarded for choosing the arm opposite to the one previously visited during the Sample trial (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eA group-level analysis of performance across all animals (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB) revealed a general improvement over sessions 1 to 6 (\u003cem\u003eχ\u0026sup2; = 30.39\u003c/em\u003e, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;\u003cem\u003e0.001\u003c/em\u003e; Fixed Effect Omnibus test). However, animals exposed in utero to valproic acid (both VP600 and VP400) displayed significantly impaired performance compared to control animals (CTRL), with a robust effect of treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB\u0026ndash;C; Table\u0026nbsp;2; GLMM: \u003cem\u003eχ\u0026sup2; = 15.05\u003c/em\u003e, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;\u003cem\u003e0.001\u003c/em\u003e; Fixed Effect Omnibus test). No significant performance difference was observed between the VP600 and VP400 groups (\u003cem\u003eNS\u003c/em\u003e, Bonferroni post hoc test). Interestingly, this performance gap disappeared by session 6, with all groups achieving accuracy well above chance (50%), the CTRL group exhibiting a slight decline in performance by session 6.\u003c/p\u003e\u003cp\u003eThese findings show that prenatal VPA exposure impairs WM as assessed by the DNMP task. To try and better understand the underlying learning dynamics, we next analyzed performance progression within sessions (S1\u0026ndash;S6) by estimating the probability of each consecutive trial in each session being a correct one.\u003c/p\u003e\u003cp\u003e\u003cb\u003eVPA-exposed animals exhibit disrupted trial-by-trial learning dynamics and reduced within-session performance stability.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo assess within-session behavioral dynamics in individual animals, we analyzed how trial-by-trial performance evolved over time. Specifically, we aimed to estimate the probability of a correct choice on each consecutive trial based on preceding trials. For this, we employed two complementary approaches: Binary Logistic Regression (BLR) and State-Space Modeling (SSM), allowing us to track trial-wise learning and performance maintenance across sessions S1\u0026ndash;S6 (see Supplementary Fig.\u0026nbsp;1 for raw data, BLR and SSM outputs for each animal across groups).\u003c/p\u003e\u003cp\u003eIn CTRL animals, we observed not only a clear improvement across sessions, as shown earlier, but also a consistent within-session increase in the probability of correct responses. Both BLR and SSM analyses converged on these results, with later sessions showing high and stable performance. Group-level analyses further confirmed this pattern: in 3.2 out of 6 sessions, the 95% confidence intervals (CIs) of the mean trial-wise correct probability exceeded the 50% chance level, indicating reliable and above-chance performance (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). On average, SSM yielded stable trial-by-trial estimates in 4.8 of 6 sessions per animal (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e; Table\u0026nbsp;1).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn contrast, the VP400 group displayed markedly weaker performance. Mean correct trial probabilities were lower, and within-session learning curves were flatter or absent. Only 2.1 out of 6 sessions showed group-level 95% CIs above chance (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), and SSM failed to provide stable performance estimates in 2.3 of 6 sessions per animal, on average, reflecting considerably less reliable learning in this group compared to CTRL (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e \u0026ndash; data for individual animals; Table\u0026nbsp;1 \u0026ndash; group level analysis and SSM reliability).\u003c/p\u003e\u003cp\u003eThe VP600 group, with the largest sample size, showed slightly narrower confidence intervals but significantly lower performance overall. Incremental within-session learning was infrequent, and even in later sessions (S5\u0026ndash;S6), group-level performance remained well below CTRL levels (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Only 1.38 of 6 sessions, on average, yielded group-level 95% CIs above chance performance, and SSM produced stable trial-wise estimates in just 3.2 of 6 sessions per animal (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e \u0026ndash; data for individual animals; Figure S2 \u0026ndash; Logit and SSM data, with 95% CIs for each individual animal, Table\u0026nbsp;1 \u0026ndash; group level analysis and SSM reliability).\u003c/p\u003e\u003cp\u003eTogether, these findings indicate that while VPA-exposed animals are eventually able to reach a performance plateau, their overall success is significantly diminished compared to controls. More importantly, analysis of trial-by-trial dynamics reveals that past trials in VPA animals are poorer predictors of future behavior. This inconsistency prevents a stable and reliable estimation of learning progression, as only a minority of sessions show performance distinguishable from chance\u0026mdash;unlike the more robust and predictable behavior observed in CTRL animals (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e \u0026ndash; data for individual animals; Table\u0026nbsp;1 \u0026ndash; group level analysis and SSM reliability).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eVPA-exposed animals exhibit increased choice perseveration\u003c/h2\u003e\u003cp\u003eA common behavioral feature in individuals on the autism spectrum is a diminished ability to promptly perceive or respond to external stimuli, and to flexibly guide behavior based on changing circumstances. One potential manifestation of this is a failure to associate actions with their outcomes\u0026mdash;such as associating a specific choice with the subsequent delivery or absence of a reward\u0026mdash;and to adjust behavior, and either behaving randomly, or persevering in one trajectory, in both cases regardless of existing reward contingencies.\u003c/p\u003e\u003cp\u003eHaving observed frequent repetitions of trajectories in VPA groups in the raw data, we tested the hypotheses that there is indeed above-chance perseverative behavior in VPA animals. We analyzed DNMP data for signs of choice perseveration, operationalized as a persistent Left/Right Bias (LRB) during decision-making. Our analysis revealed a significant group effect: CTRL animals exhibited lower LRB compared to VPA-exposed groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; Table\u0026nbsp;2; GLMM: \u003cem\u003eχ\u0026sup2; = 13.63\u003c/em\u003e, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;\u003cem\u003e0.001\u003c/em\u003e; Fixed Effect Omnibus test), indicating increased perseverative tendencies in VPA animals.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFurther analysis revealed significant group-by-session interactions. While CTRL animals showed a reduction in LRB after the first DNMP session (S1) suggesting adaptive learning and behavioral flexibility, both VPA groups (VP400 and VP600) maintained elevated LRB on subsequent sessions. Specifically, compared to S1, significant LRB persistence was observed in VP400 and VP600 animals in sessions S2 (VP400: \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.009\u003c/em\u003e; VP600: \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.041\u003c/em\u003e) and S3 (VP400: \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.035\u003c/em\u003e; VP600: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003e0.025\u003c/em\u003e). In session S4, only VP400 animals continued to show a significant bias (p\u0026thinsp;=\u0026thinsp;0.048), whereas VP600 animals did not (NS) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; Table\u0026nbsp;2; GLMM: \u003cem\u003eχ\u0026sup2; =\u003c/em\u003e 13.63, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;\u003cem\u003e0.001\u003c/em\u003e; Fixed Effect Omnibus test).\u003c/p\u003e\u003cp\u003eThese findings support the notion that prenatal VPA exposure impairs the reduction of persevering behavior with DNMP learning. Unlike CTRL animals, VPA-exposed animals fail to flexibly adapt their choices based on past outcomes, instead repeating arm-entries, consistent with the behavioral inflexibility commonly observed in ASD.\u003c/p\u003e\u003cp\u003e\u003cb\u003e40Hz sensory entrainment significantly increases gamma-frequency neural oscillations across brain regions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFunctional imaging studies in individuals with ASD have consistently reported underconnectivity in parietal regions \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, while EEG data reveal disrupted gamma-band oscillations and reduced gamma coherence \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, as well as diminished fronto-temporal coherence in the 3\u0026ndash;6 Hz range. Notably, the latter findings have shown responsiveness to sensory stimulation therapies \u003csup\u003e\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. In parallel, prenatal VPA exposure in rodent models leads to downregulation of Kv10.2 channel expression in the hippocampus, which results in elevated high-frequency oscillatory activity\u0026mdash;a phenotype that can be reversed through compensatory gene overexpression \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. These findings parallel MEG data in ASD patients showing increased power across delta, theta, alpha, and broadband gamma bands (20\u0026ndash;120 Hz) in multiple cortical regions, including temporal, parietal, frontal, occipital, and midline areas, with stronger deviations associated with greater symptom severity \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Such gamma-frequency dysregulation is likely mediated by deficits in PV\u0026thinsp;+\u0026thinsp;GABAergic interneurons, whose density is reduced in frontal, motor, and auditory cortices of ASD individuals (reviewed in \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e). Crucially, abnormal gamma oscillations in ASD patients have been shown to respond to behavioral interventions (e.g., PEERS) \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e and to transcranial stimulation protocols \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, resulting in durable improvements in both neural synchrony and behavior during adolescence. Based on this converging evidence, we hypothesized that auditory gamma-frequency sensory entrainment could mitigate the working memory (WM) deficits observed in VPA-exposed animals, possibly through circuit-plasticity mechanisms.\u003c/p\u003e\u003cp\u003eA wealth of evidence suggests that cortical networks in humans and animals can be reliably entrained to external stimuli\u0026mdash;particularly light \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e and sound \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e, delivered at gamma frequencies relevant to cognition. Recent rodent studies further demonstrate that 40 Hz gamma entrainment, via either visual or multimodal (visual and auditory) stimuli, improves cognitive function and induces broad changes in neuropathology and neuroplasticity in Alzheimer's disease models, with persistent therapeutic effects following the intervention\u003csup\u003e\u003cspan additionalcitationids=\"CR46 CR47 CR48\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eTo test whether 40 Hz auditory stimulation could induce similar effects in the VPA rodent model, we recorded local field potentials (LFPs) in two animals\u0026mdash;one VP600 and one CTRL\u0026mdash;each implanted with multi-tetrode hyperdrives targeting the hippocampus and cortical regions. During recording sessions, animals received 40 Hz patterned auditory stimulation, and their LFPs were analyzed using Fast Fourier Transform (FFT) and multi-taper spectral analysis \u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. Our analysis confirmed that auditory entrainment at 40 Hz enhances gamma-band power, as well as activity in other relevant frequency bands such as theta and beta (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Importantly, we observed sustained changes in oscillatory power that persisted beyond the period of active stimulation. These results demonstrate that 40 Hz auditory stimulation effectively entrains neural circuits in awake-behaving rats, and induces lasting changes in neural dynamics, providing a possible mechanistic basis for therapeutic effects.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eAuditory gamma entrainment restores working memory performance in VPA-exposed rats\u003c/h2\u003e\u003cp\u003eBuilding on our finding that 40 Hz auditory stimulation reliably alters neural activity in both control and VPA-exposed animals, we next tested the therapeutic potential of this intervention relative to the identified working memory (WM) deficits in VP600 animals. To this end, a separate cohort of VP600 animals previously trained to asymptotic levels on the DNMP task, was run through three consecutive sets of six DNMP sessions (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). The middle block of sessions included auditory entrainment, delivered continuously throughout each behavioral session using a 40 Hz-patterned sound stimulus.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA (right), the VP600 animals did not improve performance over 6 pre-entrainment sessions, remaining below CTRL levels, but auditory entrainment produced a robust and statistically significant improvement in DNMP performance across these sessions. Specifically, during entrainment sessions performance was markedly enhanced compared to baseline: the average probability of a correct trial increased from 0.66 pre-entrainment to 0.78 during entrainment (GLMM, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;\u003cem\u003e0.001\u003c/em\u003e). Strikingly, this performance was statistically indistinguishable from that of the CTRL animals (GLMM, \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.497\u003c/em\u003e), suggesting a full rescue from the previous WM deficit.\u003c/p\u003e\u003cp\u003eThese findings were further supported by the trial-by-trial analyses using both Binary Logistic Regression (Logit) and State-Space Modeling (SSM) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC). During the entrainment sessions, VPA600 animals displayed trial-wise performance dynamics that closely resembled that of CTRL animals, with both methods showing increased and more consistent estimates of the probability of correct responses. These results show that auditory gamma entrainment enhances WM performance to levels comparable to those of unexposed controls (please refer to Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e for individual animals\u0026acute; raw data and analysis).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eAuditory gamma entrainment abolishes trajectory-perseverative behavior present in VPA-exposed animals\u003c/h2\u003e\u003cp\u003eLastly, we investigated whether sensory entrainment (SE) also modulates perseverance behavior, operationalized as Left/Right Bias (LRB), in VPA-exposed animals. While LRB differences across pre-entrainment, entrainment, and post-entrainment sessions in the VP600 group were not statistically significant from those of the CTRL group (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA, GLMM, \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.068\u003c/em\u003e), the data suggested a potential trend worth exploring further.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo contextualize this behavior and assess whether LRB presence or absence can emerge by chance during DNMP training, we used the original trial structure (i.e., blocked arm, trial count, group sizes, and sessions) to create seven replicates in which choice responses were randomly assigned from an unbiased distribution, allowing us to establish a comparison baseline, and thus assess the emergence and persistence of LRB across treatment groups (CTRL, VP400, and VP600 and VP600-entrainment).\u003c/p\u003e\u003cp\u003eCTRL animals exhibit LRB restricted to the first session, after which it becomes similar to levels resulting from synthetic data, in agreement with the previous finding (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). VP400 animals exhibited high LRB levels relative to the synthetic control group (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eC, GLMM, group effect \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;\u003cem\u003e0.001\u003c/em\u003e; session-by-group interaction \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.597\u003c/em\u003e, n.s.), with only modest attenuation across sessions (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003e0.064\u003c/em\u003e). VP600 animals showed similar results (GLMM, group effect \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;\u003cem\u003e0.001\u003c/em\u003e; session-by-group interaction \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.367\u003c/em\u003e, n.s.), with a significant attenuation across sessions (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003e0.004\u003c/em\u003e).\u003c/p\u003e\u003cp\u003eNotably, sensory entrainment reduced LRB in VP600 animals (GLMM, entrainment effect \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.004\u003c/em\u003e; session effect \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.003\u003c/em\u003e; session-by-group interaction \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.463\u003c/em\u003e, n.s.). During entrainment sessions, LRB in VP600 animals was statistically indistinguishable from that of the synthetic replicates (\u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.229\u003c/em\u003e) and significantly reduced compared to pre-entrainment sessions (individual session \u003cem\u003ep\u003c/em\u003e values ranging from \u003cem\u003e0.001\u003c/em\u003e to \u003cem\u003e0.013\u003c/em\u003e). These findings indicate that auditory gamma entrainment may transiently normalize perseverance tendencies while rescuing WM impairments.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe have shown that prenatal exposure to Valproic Acid (VPA), a well-established rodent model of ASD, induces robust and persistent deficits in WM performance on the delayed non-match to place (DNMP) task. Importantly, we found that gamma-frequency sensory entrainment (SE) not only modulated neural activity in a frequency-specific and lasting manner but also rescued cognitive functions found defective in VPA-exposed animals.\u003c/p\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eImpaired WM and Learning Dynamics in VPA-Exposed Rats\u003c/h2\u003e\u003cp\u003eAcross sessions, VPA animals exhibited significantly poorer performance in the DNMP task compared to controls, with both VP400 and VP600 groups showing slower learning curves and reduced final performance levels. However, this impairment was not simply a reflection of delayed acquisition. Our trial-by-trial analyses using Binary Logistic Regression (BLR) and State Space Modeling (SSM) revealed that VPA animals lacked consistent within-session improvements and showed noisy or unstable probability estimates of correct responses, suggesting a fundamental disruption in the integration of recent experience to guide future choices.\u003c/p\u003e\u003cp\u003eThis inability to progressively improve performance likely reflects underlying disruptions in distributed networks critical for goal-directed behavior, where allocentric representations must be reinstated from memory and translated into egocentric action plans \u003csup\u003e\u003cspan additionalcitationids=\"CR52 CR53\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. This transformation relies on synchronized activity across the hippocampus (HIPP), posterior parietal cortex (PPC), retrosplenial cortex (RSC), and prefrontal areas\u0026mdash;circuits known to be affected in ASD. Specifically, in addition to neurophysiological changes discussed above, anatomical studies show increased local neuronal density and reduced long-range white matter connections in ASD brains, including decreased myelination and structural thinning of PPC, temporal, and frontal cortices \u003csup\u003e\u003cspan additionalcitationids=\"CR56 CR57 CR58 CR59\" citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e. These anatomical and neurophysiological features lend support to the hypothesis of impaired distributed coordination in ASD models.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003ePerseverance Behavior as a Signature of Cognitive Rigidity\u003c/h2\u003e\u003cp\u003ePerseverative responding, quantified here as left/right bias (LRB), was significantly elevated in VPA-exposed animals and showed limited improvement with training - contrasting with the rapid reduction of LRB observed in control animals after session 1. This suggests that VPA animals struggle to update behavior according to reward contingencies, resembling cognitive rigidity seen in ASD.\u003c/p\u003e\u003cp\u003eSuch rigidity may stem from failures to integrate reinforcement signals with prior action choices. Indeed, ASD patients often show reduced flexibility in reversal learning tasks and diminished engagement of prefrontal-striatal circuits responsible for adaptive choice updating. Moreover, abnormal connectivity patterns\u0026mdash;such as reduced long-range frontoparietal coherence and increased local connectivity\u0026mdash;have been extensively reported in ASD populations, potentially impairing the ability to coordinate activity across functionally-relevant brain areas.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eRestoring Function Through Gamma-Frequency Sensory Entrainment\u003c/h2\u003e\u003cp\u003eGamma-band oscillations (30\u0026ndash;80 Hz) are thought to play a key role in coordinating distributed neural activity and enabling top-down control, attention, and WM maintenance. Disturbances in gamma rhythms are among the most robust electrophysiological findings in ASD, with reports of reduced gamma coherence and impaired phase locking to rhythmic stimuli in both EEG and MEG studies \u003csup\u003e\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Notably, gamma oscillations are tightly regulated by PV\u0026thinsp;+\u0026thinsp;GABAergic interneurons, whose density is reduced across several cortical regions in models of ASD \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn our study, auditory 40 Hz stimulation effectively entrained neural activity in behaving rats, enhancing not only gamma but also theta and beta band power. These changes persisted beyond stimulus exposure, suggesting durable network-level modulation. Importantly, when VPA600 animals were subjected to gamma entrainment during DNMP sessions, we observed a complete rescue of WM performance, rendering it statistically indistinguishable from that of controls. Trial-wise modeling further confirmed that entrained animals exhibited stabilized learning curves and correct-trial probabilities, matching CTRL profiles.\u003c/p\u003e\u003cp\u003eMoreover, SE also attenuated perseverative bias in VPA600 animals, reducing LRB to levels indistinguishable from unbiased synthetic controls. This suggests that gamma entrainment not only improves task performance but may restore behavioral flexibility by re-engaging circuits underlying adaptive decision-making.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eMechanistic and Translational Implications\u003c/h2\u003e\u003cp\u003eThe beneficial effects of gamma entrainment observed here echo findings from sensory stimulation-based interventions in ASD patients\u0026mdash;such as transcranial stimulation and behavioral training \u0026ndash; which have shown promising results in normalizing gamma activity and improving cognitive and social function.\u003c/p\u003e\u003cp\u003eOur results suggest that gamma entrainment may counteract the \u0026ldquo;local-over-connectivity, long-range underconnectivity\u0026rdquo; patterns present in ASD by promoting coherent, distributed neural activity. This could facilitate the reinstatement of allocentric memory traces and enable more effective goal-directed action planning. Furthermore, entrainment may exert circuit-based long-term modulation of PV\u0026thinsp;+\u0026thinsp;interneuron function, namely through neural plasticity mechanism, thus stabilizing oscillatory regimes critical for WM and behavioral flexibility.\u003c/p\u003e\u003cp\u003eOur findings demonstrate that prenatal VPA exposure impairs WM and induces perseverance behavior in rats, resembling key features of ASD. Trial-by-trial modeling reveals unstable learning dynamics in VPA animals, and the presence of persistent choice bias. However, auditory gamma-frequency sensory entrainment restores both cognitive performance and behavioral flexibility, offering a promising non-invasive intervention to modulate large-scale brain activity.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch3\u003eData availability\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eAll raw data is contained within the figures. Requests of data in tabular form should be directed to and will be fulfilled by the Lead Contact, Miguel Remondes, DVM, PhD ([email protected]).\u003c/p\u003e\n\u003ch3\u003eAcknowledgements\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eWe are indebted to GIMM\u0026apos;s Bioimaging, Comparative Pathology, and Rodent facilities for critical help. We want to thank all the members of the Lopes Lab for fruitful discussions and help.\u003c/p\u003e\n\u003ch3\u003eFunding\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eFoundation for Science and Technology\u0026nbsp;BD-202009547 (JC)\u003c/p\u003e\n\u003cp\u003eFoundation for Science and Technology IF/00201/2013 (MR)\u003c/p\u003e\n\u003cp\u003eFoundation for Science and Technology PTDC/MED-NEU/29325/2017 (MR, JC, ML, CM)\u003c/p\u003e\n\u003cp\u003eFoundation for Science and Technology 2022.03699.CEECIND (LVL)\u003c/p\u003e\n\u003cp\u003eFoundation for Science and Technology 2022.00811.CEECIND (MR)\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eCompeting interests\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eThe authors report no competing interests.\u003c/p\u003e\n\u003ch3\u003eSupplementary material\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eSupplementary material is available at \u003cem\u003exxxxx\u003c/em\u003e online.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eScoville, W.B., Milner, B., and Scoville WB, M.B. 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Neurol. \u003cem\u003e57\u003c/em\u003e, 645\u0026ndash;652.\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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"valproate rodent model of autism, working memory deficits, sensory entrainment","lastPublishedDoi":"10.21203/rs.3.rs-7517068/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7517068/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIndividuals on the autism spectrum often show atypical responses to sensory input and difficulties with behavioral regulation, reflecting neural activity changes in core sensory-motor circuits. Although higher cognitive impairments can be present in autism, they remain understudied in rodent models compared to sensory-motor deficits. Sensory processing differences suggest that patterned sensory stimulation could help modulate altered neural activity and thereby reduce symptoms. In this study, we examined higher cognitive function in the valproic acid (VPA) rodent model of autism and tested whether auditory entrainment could improve observed deficits. Pregnant dams received VPA on embryonic day 12.5, and working memory (WM) was evaluated in their offspring using a standard delayed non-match to place (DNMP) task. VPA-exposed animals showed impaired performance and disrupted learning dynamics, indicating WM deficits. Auditory stimulation at 40Hz increased oscillatory power at several relevant bands, namely gamma, theta and beta, across brain regions relevant for WM. Notably such manipulation eliminated working memory impairments both during stimulation and for six daily recorded sessions thereafter. These findings highlight the therapeutic potential of sensory entrainment to restore cognitive function in autism.\u003c/p\u003e","manuscriptTitle":"Auditory Entrainment Reverses Working Memory Deficits in a Rodent Model of Autism","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-29 17:12:46","doi":"10.21203/rs.3.rs-7517068/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"transferred","content":"Translational Psychiatry","date":"2025-11-06T13:21:00+00:00","index":"","fulltext":""},{"type":"decision","content":"Reject after peer review","date":"2025-10-10T14:49:23+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-10-07T10:45:37+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-10-02T15:06:28+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-19T14:55:34+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-09-19T11:32:53+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-18T14:51:54+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-09-18T13:20:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-04T14:43:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-04T14:43:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Psychiatry","date":"2025-09-03T10:54:06+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2025-09-03T09:48:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"translational-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"tp","sideBox":"Learn more about [Translational Psychiatry](http://www.nature.com/tp/)","snPcode":"41398","submissionUrl":"https://mts-tp.nature.com/cgi-bin/main.plex","title":"Translational Psychiatry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2166abd3-f18a-4565-8ff4-e1e450214abc","owner":[],"postedDate":"September 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":54950815,"name":"Health sciences/Diseases/Psychiatric disorders/Autism spectrum disorders"},{"id":54950816,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2025-11-29T07:50:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-29 17:12:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7517068","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7517068","identity":"rs-7517068","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}