The Sleep-Mood Connection: Temperament Modulates Neuroinflammation, Clock Genes, and Dopaminergic Receptors Expression in Rats

The Sleep-Mood Connection: Temperament Modulates Neuroinflammation, Clock Genes, and Dopaminergic Receptors Expression in Rats | bioRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (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];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-M677548'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results The Sleep-Mood Connection: Temperament Modulates Neuroinflammation, Clock Genes, and Dopaminergic Receptors Expression in Rats Camila Nayane Carvalho Lima , Francisco Eliclécio Rodrigues da Silva , Michele Albuquerque Jales de Carvalho , Jose Eduardo de Carvalho Lima , Adriano José Maia Chaves-Filho , Gabriel R. Fries , Manoel A. Sobreira-Neto , Deiziane Viana da Silva Costa , Marta Maria França Fonteles , View ORCID Profile Danielle S. Macêdo doi: https://doi.org/10.1101/2025.06.09.658634 Camila Nayane Carvalho Lima 1 Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara , Fortaleza, CE, Brazil 2 Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth) , Houston, TX, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Francisco Eliclécio Rodrigues da Silva 1 Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara , Fortaleza, CE, Brazil 2 Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth) , Houston, TX, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michele Albuquerque Jales de Carvalho 1 Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara , Fortaleza, CE, Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jose Eduardo de Carvalho Lima 4 Centro Universitário Dr. Leão Sampaio (Unileão) , Juazeiro do Norte, CE, Brazil 5 Centro Universitário Paraíso (UniFAP) , Juazeiro do Norte, CE, Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site Adriano José Maia Chaves-Filho 1 Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara , Fortaleza, CE, Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gabriel R. Fries 2 Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth) , Houston, TX, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Manoel A. Sobreira-Neto 6 Neurology Service, Hospital Universitário Walter Cantídio; Department of Clinical Medicine, Faculty of Medicine - Universidade Federal do Ceará, Fortaleza , CE, Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site Deiziane Viana da Silva Costa 7 Division of Infectious Diseases and International Health, University of Virginia , Charlottesville, Virginia, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marta Maria França Fonteles 3 Department of Pharmacy, Faculty of Pharmacy , Dentistry and Nursing, Universidade Federal do Ceara , Fortaleza, CE, Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site Danielle S. Macêdo 1 Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceara , Fortaleza, CE, Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Danielle S. Macêdo For correspondence: danielle.macedo{at}ufc.br daniellesilmacedo{at}gmail.com Abstract Full Text Info/History Metrics Supplementary material Preview PDF Abstract Temperament may influence mood disorder risk under sleep disturbances. Using high- and low-exploratory rats as a temperament model, we examined the effects of paradoxical sleep deprivation (PSD) on mood behaviors, neuroinflammation, oxidative stress, clock genes, and dopamine receptor expression. Eighty male Wistar rats were screened for exploratory activity, while 20 were classified as high (HE) and 21 as low (LE) exploratory based on open-field performance. HE and LE rats were subjected to PSD or remained undisturbed (controls). Behavioral assessments included impulsivity, risk-taking, anhedonia, and forced swim test (FST) performance. Neurobiological analyses measured hippocampal lipid peroxidation, pro-inflammatory markers (IL-6, TLR4), gene expression of Clock , Tph2, Tdo2, and protein expression of D1, and D2, which regulate, respectively, circadian rhythms, serotonin synthesis, tryptophan metabolism, and dopaminergic signaling—key pathways implicated in mood disorders. HE rats showed increased impulsivity, risk-taking, and exploratory behaviors, resembling mania, while LE rats exhibited avoidance. PSD intensified these traits, heightening risk-taking in HE rats and inducing depressive-like behaviors in LE rats, including anhedonia and FST immobility linked to reduced Tph2 expression. Both groups had post-PSD working memory deficits. Neurobiologically, HE+PSD rats showed increased lipid peroxidation, neuroinflammation (IL-6, TLR4), and upregulation of Clock and DRD1 genes, while LE+PSD rats had elevated hippocampal Tdo2 expression. Temperament shapes PSD-induced behavioral and neurobiological effects. HE rats showed mania-like traits, while LE rats exhibited depressive behaviors. PSD impaired working memory in both. Oxidative stress, inflammation, and gene expression changes highlight distinct vulnerabilities and potential therapeutic targets for mood disorders. 1. Introduction Temperament refers to innate personality tendencies, including emotional reactivity, affective expressiveness, and sensitivity ( Merikangas et al., 1998 ). It is biologically driven and stable throughout life and shapes exploratory behavior in humans and mammals. Rodent models offer key insights into harm avoidance and novelty seeking ( Steimer and Driscoll, 2005 ). Harm avoidance involves fearfulness and timidity( Cloninger et al., 1993a ), while novelty seeking involves curiosity and exploration( Kazlauckas et al., 2005 ). Understanding individual differences in psychiatric vulnerability is challenging. Given temperament’s role in mental disorders, exploring its neurobiological mechanisms through rodent behavior in novel environments is essential ( Whittle et al., 2006 ). For this purpose, high- (HE) and low-exploratory (LE) rats serve as useful models to simulate novelty seeking and harm avoidance, respectively ( Görisch and Schwarting, 2006 ; Pawlak and Schwarting, 2002 ; Thiel et al., 1999 ). In a previous study, HE and LE Wistar rats exposed to repetitive paradoxical sleep deprivation (PSD) and unpredictable stress (US) exhibited distinct behavioral and immune changes. HE rats showed anxiolytic-like behavior, while both groups displayed memory impairments. Immune dysregulation, marked by Th1/Th2 imbalance, contributed to neuroinflammation and oxidative stress. Lithium treatment partially mitigated these effects ( Lima et al., 2019 ). Circadian rhythms and clock genes are implicated in mood disorders, regulating physiological processes that influence mood ( Jones, 2001 ). Disruptions in these rhythms can cause mood fluctuations seen in bipolar disorder (BD) and depression. These fluctuations often coincide with sleep-wake cycle and other circadian function alterations ( Jagannath et al., 2013 ; Rumble et al., 2015a ). Normalizing sleep/wake cycles and social interactions is crucial for mood stabilization ( Rumble et al., 2015b ). Mania, a fundamental feature of BD, involves hyperactivity, reduced anxiety, and increased risk-taking ( Phillips and Kupfer, 2013 ). Manipulation of Clock ( Roybal et al., 2007a ) or related molecules Per1 and Per2 ( Abarca et al., 2002 ), specifically within the mesolimbic dopamine system, produced animals with an ‘‘HE-like’’ behavioral phenotype. The hippocampus, crucial for learning and memory, expresses core circadian clock genes like CLOCK, Bmal1, Per, and Cry . These genes regulate local oscillations affecting synaptic plasticity, memory consolidation, and mood regulation (A.Kondratova et al., 2010; Wang et al., 2019 ). The circadian clock operates through a biochemical feedback loop in mammals, where Bmal1 and Clock activate Per and Cry transcription. Per and Cry proteins then inhibit Clock : Bmal1 activity, creating a cycle essential for generating circadian rhythms ( Landgraf et al., 2014 ; Mcclung, 2011). These genes also regulate immune responses and, in the hippocampus, dopamine synthesis and receptor activity ( Wang and Li, 2021 ). Disruptions in circadian genes can alter dopaminergic signaling, closely linked to mood disorders like depression and BD ( Jiang et al., 2019 ). Investigating biological clocks may reveal links between exploratory behavior in rats, environmental stressors, and mood disorders. This study hypothesized that HE and LE rats subjected to PSD would exhibit distinct behavioral phenotypes, resembling BD and depression, respectively. These behavioral differences were proposed to be driven by alterations in clock gene expression ( Clock ), neuroinflammatory markers [interleukin-6 (IL-6), toll-like receptor 4 (TLR-4)], oxidative stress (lipid peroxidation), serotonin synthesis (tryptophan hydroxylase 2; Tph2 expression), tryptophan metabolism (tryptophan 2,3-dioxygenase; Tdo2 expression), and dopamine receptor (DR) 1 and 2 protein expression. The primary objective of this study was to evaluate behavioral changes in HE and LE rats with and without PSD exposure. The secondary objective was to investigate the underlying neurobiological mechanisms contributing to these behavioral alterations. 2. Methods and Materials 2.1. Animals Male periadolescent Wistar rats (50–60 g) from the Universidade Federal do Ceará Animal House were housed in groups of five under controlled conditions (22 ± 1°C, 60 ± 5% humidity, 12-h light/dark cycle, lights on at 7:00 a.m.) with ad libitum access to food and water. Blinded raters conducted behavioral tests between 8:00–14:00 h. All procedures complied with Brazilian regulations and NIH guidelines, were approved by the Ethics Committee (protocol 125/14), and aimed to minimize suffering and animal use. 2.2. Behavioral analyses of HE- and LE- rats 2.2.1. Screening for locomotor response to novelty A psychogenic selection method was used to classify periadolescent rats (postnatal day – PND - 30) into high (HE) and low (LE) exploratory groups based on a 10-minute open field test (25th and 75th percentiles). Exploratory profiles remained stable in adulthood (PND 60). Of 80 screened rats, 20 HE (≥75th percentile, >67.25% rearing) and 20 LE (≤25th percentile, <32% rearing) were selected, while 40 median rats were excluded. HE rats showed higher exploratory behavior than LE rats [(HE: 80.60 ± 9.99%, N=20); (LE: 21.90 ± 7.55%, N=21); t=21.29, df=39, p<0.0001]. Reassessment at PND 60 confirmed stable exploratory profiles (t=8.25, p<0.0001) (Supplementary Table 1, Figure 3B and C ). All tests were conducted between ZT2 (8 a.m.) and ZT5 (11 a.m.). 2.2.2. Experimental Protocol After HE and LE classification at PND30, on PND40-49 rats were randomly assigned to PSD or control conditions. PSD followed a 10-day protocol (alternate days) in groups of five per cage (41 cm × 34 cm × 16.5 cm) with 12 small platforms (3 cm diameter) over shallow water, inducing awakening upon muscle atonia. Control rats were housed similarly but without water. Food and water were available ad libitum ( Gessa et al., 1995 ). Rats were divided into four groups (n = 8/group): HE-control, HE+PSD, LE-control, and LE+PSD. Behavioral assessments included risk-taking (cat odor), locomotion (open-field test - OFT), anxiety (elevated plus maze - EPM), depression-like behavior (forced swim test - FST), anhedonia (sucrose preference - SP), working memory (Y-maze), and declarative memory (novel object recognition). After euthanasia, blood and brain tissue were analyzed for uric acid, glutathione (GSH), lipid peroxidation, nitrite levels, and IL-1β, IL-4, and IL-6 immunoassays. Gene expression of Clock, Bmal1, Cry1, Cry2, Per1, Per2, Per3, and protein levels of D1 and D2 receptors were also assessed. 2.3 Behavioral parameters analyzed The aversive exposure to cat odor test measured risk-taking behavior by recording cloth contact and sheltering behavior when rats were exposed to either a predator odor or neutral cloth ( Zangrossi and File, 1992 ). The OFT assessed locomotion and exploration in a 50 × 50 cm arena, analyzing center avoidance, central-to-peripheral locomotion ratio, immobility, quadrant transitions, and rearing. The EPM test measured anxiety by quantifying the percentage of open-arm entries and time spent in open arms of a maze elevated 50 cm above the floor ( Pellow et al., 1985 ). The FST performed in a 60 cm-high water-filled cylinder, evaluated depressive-like behavior based on immobility duration across two sessions (10 min initial exposure, 5 min re-exposure) ( Muscat and Willner, 1992 ; Porsolt et al., 1978 ). The SPT (Scheggi et al., 2018) assessed anhedonia by measuring sucrose intake relative to total liquid consumption after 20 h of food and water deprivation. Cognitive function was evaluated using the Y-maze test, which measured spatial working memory through spontaneous alternation in a three-armed maze (SARTER et al., 1988), and the novel object recognition (NOR) test ( Izquierdo et al., 2006 ), where rats explored two identical objects, followed by the replacement of one with a novel object after 1 or 5 hours, with the recognition index calculated as the proportion of time spent exploring the novel object. All tests were recorded using video tracking software, and appropriate cleaning procedures were applied between trials to prevent olfactory cues. Figure 1 illustrates the experimental timeline and behavioral paradigms employed in this study. Download figure Open in new tab Figure 1. Experimental timeline and behavioral paradigms for High-exploratory (HE) and Low-exploratory (LE) rats during periodolescence and young adulthood A psychogenic selection was employed to study temperament in rodents by dividing them into extremes of exploratory activity. Periadolescent rats on the 30th postnatal day (PND30) were selected based on their performance in a 10-minute open field test session. The rats were divided into two groups: HE (high-exploratory) and LE (low-exploratory) rats, categorized by their 25th and 75th percentile vertical exploratory activity levels. From PND40-49, these animals were randomly selected to be exposed to PSD (paradoxical sleep deprivation) or not, undergoing a ten-day protocol with PSD on alternate days. Behavioral and neurochemical analyses were performed on PND60. 2.4 Determination of oxidative and inflammatory parameters 2.4.1 Uric Acid Levels and Oxidative Stress Determinations Uric acid levels were routinely monitored in the rats’ serum samples using a commercial kit (Randox, San Diego, California). Brain reduced glutathione (GSH) levels were measured at 412 nm using Ellman’s reagent (DTNB) to detect free thiol groups and expressed as ng GSH/g wet tissue ( Uchiyama and Mihara, 1978 ). Lipid peroxidation was assessed via thiobarbituric acid reactive substances (TBARS) ( Reilly and Aust, 1999 ). TBARS were quantified by absorbance at 532 nm, using a malondialdehyde (MDA) standard curve, and expressed as μmol MDA/mg tissue. Nitrite levels in brain homogenates, indirectly indicating nitric oxide (NO) production, were assessed using the Griess reaction ( Radenovic and Selakovic, 2005 ; Tannenbaum et al., 1978 ) Absorbance (550 nm) was measured via microplate reader. Nitrite levels were quantified using a NaNO₂ standard curve (0.75–100 μM) and expressed as μmol/g protein ( Tsikas, 2007 ). 2.4.2 Immunoassay for IL-1β, IL-4, IL-6 The brain areas were homogenized in PBS buffer (1:8 w/v) with a protease inhibitor (EMD Biosciences) and centrifuged (10,000 rpm, 5 min). Cytokine concentrations in 50 μL samples were measured using ELISA (R&D Systems, Minneapolis, MN, USA) per the manufacturer’s protocol and expressed in pg/g tissue. 2.5 Gene expression analyses Total RNA was isolated (PROMEGA) and quantified (NanoDrop, 260/280 >1.8). cDNA was synthesized from 1 µg RNA using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems). m RNA expression was analyzed by quantitative PCR (qPCR) using SYBR Green and primers from Applied Biosystems (sequences in Supplementary Table 2). 50 ng cDNA was added to Clock, Bmal1, Cry1, Cry2, Per1, Per2, Per3, or Gapdh assays in a 20 µL reaction. The thermocycler protocol was 50°C (2 min), 95°C (10 min), followed by 40 cycles of 95°C (15 s) and 60°C (60 s). Gene expression was normalized to Gapdh and analyzed using the ΔΔCt method. 2.6 Western Blotting Hippocampi were homogenized in RIPA buffer (pH 7.6) with protease inhibitors, centrifuged (17 min, 4°C, 13,000 rpm), and supernatants collected. Protein concentrations were determined by the Bradford method. For Western blot, 20 µg protein (Laemmli buffer, 95°C, 5 min) was separated on 10% SDS-PAGE, transferred to PVDF membranes, and blocked with 5% BSA (1h, RT). Membranes were incubated overnight with primary antibodies (D1, D2, α-tubulin), followed by secondary antibodies. Bands were detected using ECL (Bio-Rad ChemiDoc), and densitometry was analyzed with ImageJ (NIH). 2.7. Data analysis HE and LE rats were classified based on rearing frequency in the novel open field, with the upper half assigned to HE and the lower half to LE (see Section 2.4.1 ). These groups were used for behavioral and neurochemical analyses. Student’s t-test was applied to continuous, symmetrically distributed data, while two-way ANOVA (factors: Exploratory Phenotype [HE, LE] and PSD Exposure [PSD, non-PSD]) was used for behavioral tests. RT-PCR results were analyzed using one-way ANOVA with the Tukey post hoc test. Data are presented as mean ± SEM, except for EP results (mean ± SD) for graphical clarity. 3. RESULTS 3.1 Uric Acid Levels Correlate with Impulsivity in HE and LE Rats HE-non-PSD and HE+PSD rats showed higher uric acid levels than their LE counterparts (HE-non-PSD vs. LE-non-PSD, P = 0.0090; HE+PSD vs. LE+PSD, P < 0.0001; F₁,₁₉ = 7.048, P = 0.015, Figure 2A ). Download figure Open in new tab Figure 2. Behavioral and biochemical analysis of High-exploratory (HE) and Low-exploratory (LE) rats: Effects of paradoxical sleep deprivation (PSD) on urate levels, cloth contact, and avoidance behavior HE- and HE-PSD rats showed increased exploration and novelty-seeking behaviors in the cat odor-exposure test. (A) HE-PSD rats displayed a significant increase in serum uric acid (UA) levels compared to LE-PSD rats. (B) (C) In the cat odor-exposure test, HE- and HE-PSD rats had significantly spent more time in contact with the cloth than their respective LE- and LE-PSD rats, which was positively correlated with levels of uric acid. (D) Cat odor testing apparatus. (E) (F) Duration of avoidance was significantly higher for LE compared to HE and significantly higher for LE-PSD compared to HE-PSD, which was negatively correlated with levels of uric acid. Each bar represents the mean ± S.E.M of 8– 10 animals/group. Data were analyzed by one-way ANOVA, with Tukey as a post hoc test. **P < 0.01, ***P < 0.001, ***P < 0.0001. Download figure Open in new tab Figure 3. Exploratory and locomotor behavior in High-exploratory (HE) and Low-exploratory (LE) Rats: Impact of paradoxical sleep deprivation (PSD) on activity and anxiety responses (A) Representation of the animals’ paths in the central and peripheral zones during the behavioral tests. The groups are LE-non-PSD (low-exploratory, no PSD), LE-PSD (low-exploratory, with PSD), HE-non-PSD (high-exploratory, no PSD), and HE-PSD (high-exploratory, with PSD). (B and C) Number of runs per minute in the open field test at postnatal days (PND) 30 (B) and 60 (C), comparing the four groups. (D) Number of rearing movements per 5 minutes in the tests. (E) Number of beam crossings (locomotor activity) per 5 minutes. (F) Time spent in the central zone of the open field (seconds per minute), indicating anxiety behavior. (G) Ratio of time spent in the central zone versus the peripheral zone during the open field test. (H) Freezing time (in seconds per 5 minutes), indicating fear response. For all analyses, p < 0.05, * p < 0.01, ****p < 0.0001. Comparisons between the groups were made using appropriate statistical tests. The results show that paradoxical sleep deprivation induces significant alterations in locomotor activity and anxiety and fear-related behaviors, with differences observed based on exposure levels and the presence or absence of PSD. HE rats spent more time in contact with the cat-odor cloth than LE rats (HE-non-PSD vs. LE-non-PSD, P = 0.0036; HE+PSD vs. LE+PSD, P = 0.0008, Figure 2B ), which correlated positively with uric acid levels (R = 0.8094, P < 0.0001, Figure 2C ). Conversely, avoidance duration was higher in LE rats (LE-non-PSD vs. HE-non-PSD, P < 0.0001; LE+PSD vs. HE+PSD, P < 0.0001, Figure 2E ) and negatively correlated with uric acid (R = -0.9000, P < 0.0001, Figure 2F ). A schematic representation of the cat-odor test is shown in Figure 2D . 3.2 PSD Differentially Modulates Exploratory Behavior in HE and LE Rats We investigated whether PSD alters exploratory behavior in HE and LE rats ( Figure 3A , for representative trajectories). We observed that the number of rearings remained stable in HE, ME, and LE rats on PND30 and 60 ( Figure 3B and C ). Notably, HE-non-PSD rats exhibited higher rearing (P < 0.0001, Figure 3D ) and crossings (P = 0.0022, Figure 3E ) than LE-non-PSD rats. PSD increased rearing frequency in both groups compared to non-PSD rats (F₁,₂₆ = 79.74, P < 0.0001, Figure 3D ). However, only HE rats exhibited increased crossings (F₁,₁₈ = 8.568, P = 0.0090, Figure 3E ), time spent in the central area (F₁,₁₈ = 5.019, P = 0.0379, Figure 3F ), and central/peripheral time ratio (F₁,₁₈ = 5.661, P = 0.0286, Figure 3G ) following PSD. Freezing time remained unchanged across groups ( Figure 3H ). 3.3 PSD Differentially Affects Anxiety, Depression, and Anhedonia in HE and LE Rats We assessed PSD-induced anxiety-like behavior in HE and LE rats using the EPM test ( Figure 4A ). Both “exploratory phenotype” and “PSD exposure” influenced open-arm entries (F₁,₃₀ = 8.252, P = 0.0074) and time spent in open arms (F₁,₃₀ = 10.47, P = 0.0030). In this regard, HE-non-PSD rats exhibited higher risk-taking behavior, with more open-arm entries (P = 0.0017, Figure 4B ) and longer open-arm time (P = 0.0157, Figure 4C ) than LE-non-PSD rats. PSD increased these behaviors in HE rats (open-arm entries, P < 0.0001; open-arm time, P < 0.0001). In contrast, LE rats showed no PSD-induced changes ( Figures 4B-C ). For closed-arm entries ( Figure 4D ), HE-non-PSD rats displayed higher entries than LE-non-PSD rats (P < 0.0001). Additionally, HE+PSD rats spent a greater percentage of time in closed arms compared to LE-non-PSD rats (P < 0.0001). Download figure Open in new tab Figure 4. Anxiety, depressive-like behavior, and reward sensitivity in High-exploratory (HE) and Low-exploratory (LE) rats: Impact of PSD on behavioral and molecular markers (A) Elevated Plus-Maze (EPM) testing apparatus (B) Number of entries into the open arms of the EPM test, showing increased exploration in PSD groups, especially in High-exploratory (HE) compared to Low-exploratory (LE) groups. (C) Percentage of time spent in the open arms, indicating anxiety levels; a significant reduction in the LE-PSD group is observed compared to non-PSD controls. (D) Number of entries into the closed arms of the EPM test, indicating anxiety behaviors, with higher entries observed in the non-PSD groups. (E) Swimming Forced Test (SFT) apparatus (F) Time spent in immobility during the forced swim test, reflecting despair-like behavior, with significant differences between PSD and non-PSD groups in both HE and LE groups. (G) Sucrose Preference Test (SPT) apparatus (H) Percentage preference for sucrose solution in the sucrose preference test, indicating anhedonia, with reduced sucrose preference observed in PSD groups. (I) mRNA expression levels of Tph2 (tryptophan hydroxylase 2) in the brain, showing significant differences in gene expression across the different groups. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Data were analyzed using appropriate statistical tests. The results indicate that PSD induces significant changes in anxiety-like behaviors, despair-like responses, and anhedonia, with variations observed based on exposure levels and PSD status. Depression- and anhedonia-like behaviors induced by PSD in HE and LE rats were assessed using the forced swim test (FST, Figure 4E ) and sucrose preference test (SPT, Figure 4G ). A significant interaction between “Exploratory Phenotype” and “PSD exposure” was observed in SPT (F₁,₁₈ = 37.32, P < 0.0001), while FST was affected by PSD independently of phenotype (F₁,₂₄ = 10.96, P = 0.0029). LE+PSD rats showed increased immobility time compared to LE-non-PSD rats (P = 0.0051, Figure 4F ), whereas HE rats were unaffected by PSD. Sucrose preference decreased in LE+PSD rats compared to LE-non-PSD (P = 0.0001), which was already lower than in HE-non-PSD rats (P < 0.0001, Figure 4H ). Similarly, LE+PSD rats had lower sucrose preference than HE+PSD rats (P < 0.0001), indicating greater vulnerability of LE rats to depression and anhedonia. This was supported by Tph2 mRNA levels, which decreased in LE+PSD rats compared to LE-non-PSD (P = 0.0454, Figure 4I ), whereas HE+PSD rats exhibited increased Tph2 expression relative to HE-non-PSD (P = 0.0193). 3.4 PSD Impairs Memory and Alters Oxidative Stress in HE and LE Rats To assess the effects of PSD on working and declarative memory in HE- and LE-rats, we conducted Y-maze ( Figure 5A ) and NOR tests ( Figure 5C ). PSD impaired working memory in both phenotypes [F(1,27) = 8.241, P = 0.0079], but not declarative memory [F(1,19) = 4.190, P = 0.0548]. However, declarative memory was independently influenced by “Exploratory phenotype” [F(1,19) = 24.39, P < 0.0001] and “PSD exposure” [F(1,19) = 130.9, P < 0.0001]. Download figure Open in new tab Figure 5. Cognitive performance and oxidative stress in High-exploratory (HE) and Low-exploratory (LE) rats: Effects of paradoxical sleep deprivation (PSD) on working memory and redox status (A) Y-maze testing apparatus. (B) Percentage of incorrect alternations in the Y-maze test, showing increased errors in the HE-PSD and LE-PSD group compared to their respective control groups. (C) Novel Object Recognition (NOR) testing apparatus. (D) The discrimination ratio in the NOR test shows enhanced cognitive performance in the HE groups compared to the LE group. However, both HE and LE rats in the PSD groups exhibited a significant decline in cognitive performance when compared to their non-PSD counterparts. (E) Tissue levels of GSH (Glutathione) in the hippocampus showed a significant reduction in the HE-PSD group compared to its control, while a significant increase was observed in the LE-PSD group compared to its control group. (F) TBARS (Thiobarbituric Acid Reactive Substances) levels in hippocampal tissue, reflecting oxidative stress, showed significant increases in both the HE-PSD and LE-PSD groups compared to their respective controls. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Data were analyzed using appropriate statistical tests. The results indicate that PSD induces significant changes in cognitive function and oxidative stress, with variations observed based on exposure levels and PSD status. Y-maze results showed increased incorrect alternations in HE+PSD and LE+PSD rats compared to non-PSD controls ( Figure 5B , P < 0.0001). Additionally, HE-non-PSD rats exhibited more incorrect alternations than LE-non-PSD rats (P = 0.001). In the NOR test, PSD reduced the discrimination ratio [F(1,19) = 4.190, P = 0.0548], with HE+PSD and LE+PSD rats showing significant impairments relative to non-PSD controls (P < 0.0001). LE+PSD rats displayed a more pronounced reduction than HE+PSD rats ( Figure 5D , P = 0.0001). Hippocampal GSH levels exhibited a significant interaction between “Exploratory phenotype” and “PSD exposure” [F(1,19) = 130.4, P < 0.0001]. HE-non-PSD rats showed higher GSH levels than LE-non-PSD (P = 0.0001). PSD reduced GSH in HE+PSD (P = 0.0003) but increased it in LE+PSD (P < 0.0001) relative to controls. Notably, GSH levels in LE+PSD rats were significantly higher than in HE+PSD (P < 0.0001) ( Figure 5E ). Lipid peroxidation ( Figure 5F ) was elevated in HE+PSD (P = 0.0005) and LE+PSD (P = 0.0017) compared to controls. 3.5 Hippocampal Inflammatory and Neuroplasticity Alterations Induced by PSD For hippocampal nitrite and iNOS levels, two-way ANOVA revealed a significant interaction between “Exploratory phenotype” and “PSD exposure” [F(1,22) = 4.733, P = 0.0406; F(1,11) = 6.616, P = 0.0260]. Nitrite levels increased in PSD-exposed HE and LE rats compared to controls (HE+PSD vs. HE-non-PSD, P < 0.0001; LE+PSD vs. LE-non-PSD, P = 0.0003) ( Figure 6A ). Given the observed nitrite differences, iNOS expressions were analyzed. PSD significantly increased iNOS mRNA levels in HE+PSD rats compared to HE-non-PSD (P = 0.0022) ( Figure 6B ). Download figure Open in new tab Figure 6. Inflammatory and molecular markers in High-exploratory (HE) and Low-exploratory (LE) rats: effects of paradoxical sleep deprivation (PSD) on cytokines, nitrite levels, and gene expression. Levels of hippocampal nitrite (A), IL-1β (C), IL-6 (D), IL-4 (E) cytokines and BDNF (K); plasma cytokines IL-1β (F), IL-6 (G), IL-4 (H) by ELISA; and relative m RNA levels of iNOS (B) IDO1 (I), TDO2 (J) by qPCR assay in the hippocampus of the HE- and LE-rats exposed to chronic PSD for 10 days. Each bar represents the mean ± S.E.M of 8–10 animals/group. Data were analyzed by one-way ANOVA, with Tukey as a post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. IL-1β: Interleukin-1 beta, IL-6: Interleukin-6, IL-4: Interleukin-4, iNOS: Inducible Nitric Oxide Synthase, IDO: Indoleamine 2,3-Dioxygenase, TDO: Tryptophan 2,3-Dioxygenase. A significant interaction between “Exploratory phenotype” and “PSD exposure” was observed in hippocampal IL-1β [F(1,30) = 15.02, P = 0.0005], IL-6 [F(1,29) = 0.3274, P = 0.5716], and IL-4 levels in both hippocampus and plasma [F(1,27) = 4.860, P = 0.0362; F(1,22) = 25.69, P = 0.0001]. Post-hoc analysis showed increased hippocampal IL-1β in HE+PSD and LE+PSD compared to controls (P < 0.0001 and P = 0.0042, respectively) ( Figure 6C ). Plasma IL-1β was elevated in HE+PSD vs. HE-non-PSD (P = 0.0078) ( Figure 6F ). IL-4 levels were significantly higher in the hippocampus of HE+PSD compared to HE-non-PSD (P = 0.0031) ( Figure 6E ). Plasma IL-4 was also increased in HE+PSD vs. HE-non-PSD ( Figure 6H ). IL-6 levels were elevated in HE+PSD and LE+PSD rats relative to controls (HE: P = 0.0024; LE: P = 0.0323) ( Figure 6D ). For Ido 1 gene expression, a two-way interaction was observed [F(3,12) = 1.579, P = 0.2329], with increased Ido 1 mRNA in HE+PSD vs. HE-non-PSD (P = 0.0040) ( Figure 6I ). Tdo 2 expression was higher in LE+PSD vs. HE+PSD (P = 0.0267) and in LE-non-PSD vs. HE-non-PSD (P = 0.0081) ( Figure 6J ). BDNF levels were elevated in HE+PSD vs. HE-non-PSD (P < 0.0001) and in LE+PSD vs. LE-non-PSD (P = 0.0018) ( Figure 6K ). 3.6 PSD Modulates Circadian Clock Gene Expression in HE and LE Rats The expression of key circadian clock genes was significantly altered by PSD exposure, with distinct effects observed in HE and LE rats. A Student’s t-test revealed significant differences in the expression of Bmal1 , Clock , Per1 , Per2 , Per3 , Cry1 , and Cry2 ( Figure 7A-G ). Download figure Open in new tab Figure 7. PSD alters the expression of circadian clock genes in High-exploratory (HE) and Low-exploratory (LE) rats. m RNA expression levels of Bmal1 (A), Clock (B), Per1 (C), Per2 (D), Per3 (E), Cry1 (F), and Cry2 (G) were analyzed in the hippocampus of HE and LE rats exposed to PSD or control conditions. Data are presented as mean ± SEM. Statistical comparisons were performed using Student’s t-test. P < 0.05 was considered statistically significant. Clock: Circadian Locomotor Output Cycles Kaput, Bmal1: Brain and Muscle ARNT-Like Protein 1, Per1: Period Circadian Regulator, Per2: Period Circadian Regulator 2, Per3: Period Circadian Regulator 3, Cry1: Cryptochrome Circadian Regulator 1 and Cry2: Cryptochrome Circadian Regulator 2. HE-non-PSD rats exhibited higher basal expression levels of Clock , Bmal1 , Per1 , Per2 , Per3 , and Cry1 compared to LE-non-PSD rats. Following PSD exposure, HE+PSD rats showed an upregulation of Clock (P = 0.0044), Bmal1 (P = 0.0023), Per1 (P = 0.0056), Per2 (P = 0.0023), Per3 (P = 0.0007), and Cry1 (P = 0.0009) relative to HE-non-PSD rats. Conversely, in LE+PSD rats, PSD significantly reduced the expression of Clock (P < 0.0001), Bmal1 (P < 0.0001), Per1 (P = 0.0001), Per2 (P = 0.0008), Per3 (P = 0.0058), and Cry1 (P = 0.0015) compared to LE-non-PSD. Additionally, Cry2 expression was significantly decreased in both HE-PSD and LE-PSD groups (P < 0.0001 for both) compared to their respective controls. These findings suggest a differential regulation of circadian rhythm genes in HE and LE rats in response to PSD exposure, with HE rats exhibiting an upregulation and LE rats showing a downregulation in gene expression. 3.7 Chronic PSD Differentially Modulates D1 and D2 Expression in HE and LE Rats Chronic PSD exposure increased hippocampal D1 expression in HE+PSD compared to HE-non-PSD rats (P < 0.001, Figure 8A ). Significant differences were also observed between HE+PSD and LE+PSD rats (P < 0.001, Figure 8A ). In contrast, D2 expression was only elevated in LE+PSD compared to HE+PSD rats (P < 0.05, Figure 8B ). Download figure Open in new tab Figure 8. Dopamine receptor expression in High-exploratory (HE) and Low-exploratory (LE) rats: Effects of paradoxical sleep deprivation (PSD) on D1 and D2 protein levels Hippocampal relative m RNA levels of D1(A) and D2 (B) by qPCR assay in rats HE and LE exposed to chronic PSD (10 days). All fold changes were calculated by the ΔΔCt method. Each bar represents the mean ± S.E.M of 8–10 animals/group. Data were analyzed by one-way ANOVA, with Tukey as a post hoc test. *P < 0.05, **P < 0.01. D1: Dopamine receptor 1, D2: Dopamine receptor 2, qPCR: Quantitative polymerase chain reaction. 4. DISCUSSION Our study demonstrated that PSD differentially affects behavior, neuroinflammation, oxidative stress, and circadian regulation in HE and LE rats, highlighting phenotype-dependent stress susceptibility and resilience mechanisms. HE rats exhibited higher uric acid levels, increased risk-taking and exploratory behavior, and greater circadian gene upregulation ( Bmal1, Clock, Per1-3, Cry1 ) following PSD. In contrast, LE rats showed greater vulnerability to depressive-like behaviors, including reduced sucrose preference, increased immobility, and downregulation of circadian genes. Oxidative stress responses also varied, with HE rats showing higher basal GSH, which was depleted by PSD, whereas LE rats exhibited a PSD-induced GSH increase, suggesting differential redox resilience. Additionally, both phenotypes exhibited heightened neuroinflammation, with increased nitrite, iNOS, IL-1β, and IL-6, though IL-4 was selectively elevated in HE rats, indicating a potential anti-inflammatory adaptation. Lastly, D1 and D2 were altered by PSD, further linking dopamine-circadian interactions to mood regulation. Together, these findings emphasize how individual phenotypes shape behavioral and molecular responses to chronic stress, providing insights into mechanisms of stress vulnerability and resilience. Our findings reveal that uric acid levels are associated with impulsivity-related behaviors, with HE rats exhibiting higher uric acid concentrations and greater exploratory behavior, whereas LE rats showed increased avoidance behavior negatively correlated with uric acid. These results align with previous studies linking uric acid to impulsivity in clinical and nonclinical populations (Albert et al., 2015; Manowitz et al., 1993 ; Sutin et al., 2013 ), suggesting a potential role of purinergic metabolism in modulating risk-taking behavior. Additionally, PSD differentially affected exploratory behavior, anxiety, depression, and anhedonia in HE and LE rats. While HE rats exhibited increased risk-taking and exploratory behavior following PSD, LE rats displayed greater vulnerability to depressive-like behaviors, indicating that LE rats might be more prone to mood disturbances under sleep deprivation ( Katz, 1982 ; Mällo et al., 2007 ; Stedenfeld et al., 2011a , 2011b ; Veenema et al., 2003). These findings suggest that individual differences in exploratory phenotypes influence susceptibility to PSD-induced mood alterations. Changes in Tph2 m RNA levels further support the notion of altered serotonergic activity contributing to these behavioral outcomes ( Lieb et al., 2019 ). Increased expression of the Tdo2 gene and reduced expression of the Tph2 gene in the brain suggest significant alterations in tryptophan metabolism, which can have implications for serotonin synthesis and overall neurochemical balance ( Chen and Miller, 2012 ; Hattori et al., 2018 ; Kanai et al., 2009 ; Markett et al., 2017). The combination of increased Tdo2 and reduced Tph2 expression suggests a scenario where tryptophan is preferentially metabolized via the kynurenine pathway at the expense of serotonin synthesis ( Höglund et al., 2019 ; Miura et al., 2008 ) .This imbalance in tryptophan metabolism could be associated with changes in mood, behavior, and cognitive function, potentially influenced by stress, inflammation, or other physiological stressors ( Allison and Ditor, 2014 ; Karu et al., 2016 ; O’Connor et al., 2021 ; Parrott et al., 2016 ). Our study also demonstrates that PSD impairs working and declarative memory, particularly in LE rats, while also altering oxidative stress responses. The behavioral heterogeneity of Wistar rats influences data dispersion in behavioral evaluations (de Oliveira-Júnior et al., 2024; Palm et al., 2011 ; Redei et al., 2023 ; Theilmann et al., 2016 ). Therefore, we suggest associating the PSD model with the exploratory standard (temperamental base), as temperament can modify individual vulnerability to mood disorders ( Middeldorp et al., 2011 ; Simonetti et al., 2023). Temperaments may carry a genetic influence ( Cloninger et al., 1993b ; Smoller and Finn, 2003 ). Selecting animals based on exploratory standards can facilitate modeling natural neurobiological substrates and potential, representing temperament differences and possibly carrying a genetic predisposition to different mood disorders. HE rats exhibited higher basal GSH levels, which were significantly reduced by PSD, whereas LE rats showed an increase in GSH after PSD exposure. This suggests differential oxidative stress resilience mechanisms, with HE rats being more resistant to oxidative insults but more sensitive to PSD-induced GSH depletion. Furthermore, PSD-induced hippocampal neuroinflammatory alterations were observed in both HE and LE rats, with increased nitrite levels, iNOS expression, and pro-inflammatory cytokines (IL-1β and IL-6). Interestingly, IL-4 levels were selectively elevated in HE rats, suggesting a compensatory anti-inflammatory response. Elevated pro-inflammatory cytokines (IL-1β, IL-6) and BDNF levels suggest an inflammatory response to PSD, contributing to behavioral and cognitive alterations ( Khadrawy et al., 2011 ; Rosa Neto et al., 2010). We also found that circadian clock genes expression was differentially regulated by PSD, with HE rats exhibiting upregulation and LE rats showing downregulation of key circadian genes ( Bmal1, Clock, Per1-3, and Cry1 ). These changes were accompanied by PSD-induced alterations in hippocampal D1 and D2 expression, further supporting the role of dopaminergic signaling in modulating circadian disruptions and mood-related behaviors. PSD is capable of inducing essential changes in the dopaminergic system, with hyperdopaminergic states linked to mania alterations ( Frey et al., 2006 ; Young et al., 2010). Previous studies have reported that Clock gene manipulation, specifically within the mesolimbic dopamine system, produced animals with a behavioral phenotype similar to HE+PSD ( Roybal et al., 2007b ). Our results indicate that Clock gene expression and D1 protein levels increased in the hippocampus of HE+PSD rats. This aligns with studies showing transcriptional changes in the Clock and Per1 genes in the mesolimbic system after treatment with cocaine or methamphetamine ( Michihiko et al., 2002 ; Nikaido et al., 2001 ; Uz et al., 2005 ; Yuferov et al., 2003 ). In contrast, LE+PSD rats showed a behavior profile similar to depression and anhedonia. This genetic LE+PSD profile is similar to mice exposed to chronic moderate stress, which produced chronic clock gene changes, such as decreased heterodimer Clock/Bmal1 and reduced expression of Cry2, Per1, and Per2 ( Calabrese et al., 2016 ). These gene changes could be related to a link between stress exposure and clock gene dysfunction, represented by changes in HPA axis function ( Buijs and Kalsbeek, 2001 ). As mentioned above, we found that LE+PSD rats reduced tryptophan hydroxylase 2 ( Tph2 ) gene expression, suggesting reduced serotonin synthesis, which plays a role in depression pathophysiology ( Cowen and Browning, 2015 ). Our results, along with previous studies, indicate differential activation of D1 in HE rats and D2 in LE rats ( Easton et al., 2003 ; Freyberg and McCarthy, 2017 ; Hood et al., 2010 ; Imbesi et al., 2008 ; Zhang et al., 2021 ); however, the mechanisms by which dopamine and D1- or D2-activation positively or negatively regulate Clock gene expression in the hippocampus remain to be resolved. Future experiments are needed to elucidate if PSD-induced changes in Clock gene expression are responsible for differential behavior regulation in these animals. The main limitation is species differences, as rats have lower uric acid levels than primates, limiting generalizability. Additionally, while associations between clock genes and dopaminergic alterations were observed, causal mechanisms remain unclear. Despite this, the study provides key insights into temperament and neuropsychiatric disorders, supporting future cross-species research. Overall, our results highlight the complex interplay between exploratory phenotype, oxidative stress, neuroinflammation, and circadian gene regulation in response to PSD, providing insights into individual differences in stress susceptibility and resilience mechanisms. Disclosures Camila Nayane Carvalho Lima: No financial conflicts of interest to disclose. Francisco Eliclécio Rodrigues da Silva: No financial conflicts of interest to disclose. Michele Albuquerque Jales de Carvalho: No financial conflicts of interest to disclose. Jose Eduardo de Carvalho Lima: No financial conflicts of interest to disclose. Adriano José Maia Chaves-Filho: No financial conflicts of interest to disclose. Gabriel R. Fries: No financial conflicts of interest to disclose. Manoel A. Sobreira-Neto: No financial conflicts of interest to disclose. Deiziane Viana da Silva Costa: No financial conflicts of interest to disclose Marta Maria França Fonteles: No financial conflicts of interest to disclose. Danielle S. Macedo: No financial conflicts of interest to disclose. Declaration of generative AI and AI-assisted technologies in the writing process During the preparation of this work, the authors used CHAT GPT 4o to revise the manuscript grammar to improve readability. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. Acknowledgments We thank the Brazilian National Council for Scientific and Technological Development (CNPq) for financial support through a doctoral fellowship. We also acknowledge CAPES and FUNCAP for their support with scholarships. Funder Information Declared Conselho Nacional de Desenvolvimento Cientifico e tecnologico (CNPq) Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico, https://ror.org/007pgtp80 Coordenação de Aperfeicoamento de Pessoal de Nível Superior, https://ror.org/00x0ma614 References ↵ Abarca , C. , Albrecht , U. , Spanagel , R ., 2002 . Cocaine sensitization and reward are under the influence of circadian genes and rhythm . Proc Natl Acad Sci U S A 99 , 9026 – 30 . doi: 10.1073/pnas.142039099 OpenUrl Abstract / FREE Full Text A.Kondratova, A., V.Dubrovsky, Y., Antoch, M.P., Kondratov, R. V., 2010 . Circadian clock proteins control adaptation to novel environment and memory formation . Aging 2 , 285 – 297 . doi: 10.18632/aging.100142 OpenUrl CrossRef PubMed Albert, U., De Cori, D., Aguglia, A., Barbaro, F., Bogetto, F., Maina, G., 2015 . Increased uric acid levels in bipolar disorder subjects during different phases of illness . J Affect Disord 173 , 170 – 175 . doi: 10.1016/j.jad.2014.11.005 OpenUrl CrossRef PubMed ↵ Allison , D.J. , Ditor , D.S ., 2014 . The common inflammatory etiology of depression and cognitive impairment: A therapeutic target . J Neuroinflammation 11 , 1 – 12 . doi: 10.1186/S12974-014-0151-1/FIGURES/6 OpenUrl CrossRef PubMed ↵ Buijs , R.M. , Kalsbeek , A ., 2001 . Hypothalamic integration of central and peripheral clocks . Nat Rev Neurosci 2 , 521 – 526 . doi: 10.1038/35081582 OpenUrl CrossRef PubMed Web of Science ↵ Calabrese , F. , Savino , E. , Papp , M. , Molteni , R. , Riva , M.A ., 2016 . Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: Modulatory effects of prolonged lurasidone treatment . Pharmacol Res 104 , 140 – 150 . doi: 10.1016/j.phrs.2015.12.023 OpenUrl CrossRef PubMed ↵ Chen , G.L. , Miller , G.M ., 2012 . Advances in Tryptophan Hydroxylase-2 Gene Expression Regulation: New Insights into Serotonin-Stress Interaction and Clinical Implications . Am J Med Genet B Neuropsychiatr Genet 159B , 152. doi: 10.1002/AJMG.B.32023 OpenUrl CrossRef ↵ Cloninger , C.R. , Svrakic , D.M. , Przybeck , T.R ., 1993a . A Psychobiological Model of Temperament and Character . Arch Gen Psychiatry 50 , 975 . doi: 10.1001/archpsyc.1993.01820240059008 OpenUrl CrossRef PubMed Web of Science ↵ Cloninger , C.R. , Svrakic , D.M. , Przybeck , T.R ., 1993b . A psychobiological model of temperament and character . Arch Gen Psychiatry 50 , 975 – 990 . doi: 10.1001/ARCHPSYC.1993.01820240059008 OpenUrl CrossRef PubMed Web of Science ↵ Cowen , P.J. , Browning , M ., 2015 . What has serotonin to do with depression? World Psychiatry . doi: 10.1002/wps.20229 OpenUrl CrossRef PubMed de Oliveira-Júnior, B.A., Marques, D.B., Rossignoli, M.T., Prizon, T., Leite, J.P., Ruggiero, R.N., 2024 . Multidimensional behavioral profiles associated with resilience and susceptibility after inescapable stress . Scientific Reports 2024 14 : 1 14, 1–18. doi: 10.1038/s41598-024-59984-7 OpenUrl CrossRef ↵ Easton , A. , Arbuzova , J. , Turek , F.W ., 2003 . The circadian Clock mutation increases exploratory activity and escape-seeking behavior . Genes Brain Behav 2 , 11 – 19 . doi: 10.1034/J.1601-183X.2003.00002.X OpenUrl CrossRef PubMed Web of Science ↵ Frey , B.N. , Valvassori , S.S. , Réus , G.Z. , Martins , M.R. , Petronilho , F.C. , Bardini , K. , Dal-Pizzol , F. , Kapczinski , F. , Quevedo , J ., 2006 . Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania . J Psychiatry Neurosci 31 , 326 – 32 . OpenUrl PubMed ↵ Freyberg , Z. , McCarthy , M.J ., 2017 . Dopamine D2 receptors and the circadian clock reciprocally mediate antipsychotic drug-induced metabolic disturbances . npj Schizophrenia 2017 3:1 3 , 1 – 8 . doi: 10.1038/s41537-017-0018-4 OpenUrl CrossRef PubMed ↵ Gessa , G.L. , Pani , L. , Fadda , P. , Fratta , W ., 1995 . Sleep deprivation in the rat: an animal model of mania . European Neuropsychopharmacology 5 , 89 – 93 . doi: 10.1016/0924-977X(95)00023-I OpenUrl CrossRef PubMed ↵ Görisch , J. , Schwarting , R.K.W ., 2006 . Wistar rats with high versus low rearing activity differ in radial maze performance . Neurobiol Learn Mem 86 , 175 – 187 . doi: 10.1016/j.nlm.2006.02.004 OpenUrl CrossRef PubMed ↵ Hattori , S. , Takao , K. , Funakoshi , H. , Miyakawa , T ., 2018 . Comprehensive behavioral analysis of tryptophan 2,3-dioxygenase (Tdo2) knockout mice . Neuropsychopharmacol Rep 38 , 52 . doi: 10.1002/NPR2.12006 OpenUrl CrossRef PubMed ↵ Höglund , E. , Øverli , Ø. , Winberg , S ., 2019 . Tryptophan metabolic pathways and brain serotonergic activity: A comparative review . Front Endocrinol (Lausanne ) 10 , 435368 . doi: 10.3389/FENDO.2019.00158/BIBTEX OpenUrl CrossRef ↵ Hood , S. , Cassidy , P. , Cossette , M.P. , Weigl , Y. , Verwey , M. , Robinson , B. , Stewart , J. , Amir , S ., 2010 . Endogenous Dopamine Regulates the Rhythm of Expression of the Clock Protein PER2 in the Rat Dorsal Striatum via Daily Activation of D2 Dopamine Receptors . The Journal of Neuroscience 30 , 14046 . doi: 10.1523/JNEUROSCI.2128-10.2010 OpenUrl Abstract / FREE Full Text ↵ Imbesi , M. , Yildiz , S. , Dirim Arslan , A. , Sharma , R. , Manev , H. , Uz , T ., 2008 . Dopamine receptor-mediated regulation of neuronal “clock” gene expression . Neuroscience 158 , 537 . doi: 10.1016/J.NEUROSCIENCE.2008.10.044 OpenUrl CrossRef PubMed ↵ Izquierdo , I. , Bevilaqua , L.R.M. , Rossato , J.I. , Bonini , J.S. , Medina , J.H. , Cammarota , M ., 2006 . Different molecular cascades in different sites of the brain control memory consolidation . Trends Neurosci 29 , 496 – 505 . doi: 10.1016/j.tins.2006.07.005 OpenUrl CrossRef PubMed Web of Science ↵ Jagannath , A. , Peirson , S.N. , Foster , R.G ., 2013 . Sleep and circadian rhythm disruption in neuropsychiatric illness . Curr Opin Neurobiol 23 , 888 – 894 . doi: 10.1016/j.conb.2013.03.008 OpenUrl CrossRef PubMed ↵ Jiang , P. , Scarpa , J.R. , Gao , V.D. , Vitaterna , M.H. , Kasarskis , A. , Turek , F.W ., 2019 . Parkinson’s Disease is Associated with Dysregulations of a Dopamine-Modulated Gene Network Relevant to Sleep and Affective Neurobehaviors in the Striatum . Sci Rep 9 , 4808 . doi: 10.1038/s41598-019-41248-4 OpenUrl CrossRef PubMed ↵ Jones , S.H ., 2001 . Circadian rhythms, multilevel models of emotion and bipolar disorder - An initial step towards integration? Clin Psychol Rev . doi: 10.1016/S0272-7358(01)00111-8 OpenUrl CrossRef PubMed Web of Science ↵ Kanai , M. , Funakoshi , H. , Takahashi , H. , Hayakawa , T. , Mizuno , S. , Matsumoto , K. , Nakamura , T ., 2009 . Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice . Mol Brain 2 , 1 – 16 . doi: 10.1186/1756-6606-2-8/FIGURES/6 OpenUrl CrossRef PubMed ↵ Karu , N. , McKercher , C. , Nichols , D.S. , Davies , N. , Shellie , R.A. , Hilder , E.F. , Jose , M.D ., 2016 . Tryptophan metabolism, its relation to inflammation and stress markers and association with psychological and cognitive functioning: Tasmanian Chronic Kidney Disease pilot study . BMC Nephrol 17 , 1 – 13 . doi: 10.1186/S12882-016-0387-3/FIGURES/2 OpenUrl CrossRef PubMed ↵ Katz , R.J ., 1982 . Animal model of depression: Pharmacological sensitivity of a hedonic deficit . Pharmacol Biochem Behav 16 , 965 – 968 . doi: 10.1016/0091-3057(82)90053-3 OpenUrl CrossRef PubMed Web of Science ↵ Kazlauckas , V. , Schuh , J. , Dall’Igna , O.P. , Pereira , G.S. , Bonan , C.D. , Lara , D.R ., 2005 . Behavioral and cognitive profile of mice with high and low exploratory phenotypes . Behavioural Brain Research 162 , 272 – 278 . doi: 10.1016/j.bbr.2005.03.021 OpenUrl CrossRef PubMed Web of Science ↵ Khadrawy , Y.A. , Nour , N.A. , Aboul Ezz , H.S ., 2011 . Effect of oxidative stress induced by paradoxical sleep deprivation on the activities of Na+, K+-ATPase and acetylcholinesterase in the cortex and hippocampus of rat . Translational Research 157 , 100 – 107 . doi: 10.1016/J.TRSL.2010.11.005 OpenUrl CrossRef PubMed ↵ Landgraf , D. , McCarthy , M.J. , Welsh , D.K ., 2014 . Circadian clock and stress interactions in the molecular biology of psychiatric disorders . Curr Psychiatry Rep 16 , 483 . doi: 10.1007/s11920-014-0483-7 OpenUrl CrossRef PubMed ↵ Lieb , M.W. , Weidner , M. , Arnold , M.R. , Loupy , K.M. , Nguyen , K.T. , Hassell , J.E. , Schnabel , K.S. , Kern , R. , Day , H.E.W. , Lesch , K.P. , Waider , J. , Lowry , C.A ., 2019 . Effects of maternal separation on serotonergic systems in the dorsal and median raphe nuclei of adult male Tph2-deficient mice . Behavioural brain research 373 , 112086 . doi: 10.1016/J.BBR.2019.112086 OpenUrl CrossRef PubMed ↵ Lima , C.N. de C. , da Silva , F.E.R. , Chaves Filho , A.J.M. , Queiroz, A.I. de G., Okamura, A.M.N.C., Fries, G.R., Quevedo, J., de Sousa, F.C.F., Vasconcelos, S.M.M., de Lucena, D.F., Fonteles, M.M. de F., Macedo, D.S., 2019 . High Exploratory Phenotype Rats Exposed to Environmental Stressors Present Memory Deficits Accompanied by Immune-Inflammatory/Oxidative Alterations: Relevance to the Relationship Between Temperament and Mood Disorders . Front Psychiatry 10 . doi: 10.3389/fpsyt.2019.00547 OpenUrl CrossRef ↵ Mällo , T. , Alttoa , A. , Kõiv , K. , Tõnissaar , M. , Eller , M. , Harro , J ., 2007 . Rats with persistently low or high exploratory activity: Behaviour in tests of anxiety and depression, and extracellular levels of dopamine . Behavioural Brain Research 177 , 269 – 281 . doi: 10.1016/J.BBR.2006.11.022 OpenUrl CrossRef PubMed ↵ Manowitz , P. , Amorosa , L.F. , Goldstein , H.S. , Carlton , P.L ., 1993 . Uric acid level increases in humans engaged in gambling: A preliminary report . Biol Psychol 36 , 223 – 229 . doi: 10.1016/0301-0511(93)90019-5 OpenUrl CrossRef PubMed Markett, S., De Reus, M.A., Reuter, M., Montag, C., Weber, B., Schoene-Bake, J.C., Van den Heuvel, M.P., 2017 . Serotonin and the Brain’s Rich Club—Association Between Molecular Genetic Variation on the TPH2 Gene and the Structural Connectome . Cerebral Cortex 27 , 2166 – 2174 . doi: 10.1093/CERCOR/BHW059 OpenUrl CrossRef PubMed Mcclung, C. a., 2011 . Circadian rhythms and mood regulation: Insights from pre-clinical models . European Neuropsychopharmacology 21 , S683 – S693 . doi: 10.1016/j.euroneuro.2011.07.008 OpenUrl CrossRef PubMed ↵ Merikangas , K.R. , Swendsen , J.D. , Preisig , M.A. , Chazan , R.Z ., 1998 . Psychopathology and temperament in parents and offspring: Results of a family study . J Affect Disord 51 , 63 – 74 . doi: 10.1016/S0165-0327(98)00157-8 OpenUrl CrossRef PubMed ↵ Michihiko , I. , Takato , N. , Masashi , A. , Takahiro , M. , Shigenobu , S ., 2002 . Methamphetamine-induced, suprachiasmatic nucleus-independent circadian rhythms of activity and mPer gene expression in the striatum of the mouse . European Journal of Neuroscience 16 , 921 – 929 . doi: 10.1046/j.1460-9568.2002.02140.x OpenUrl CrossRef PubMed Web of Science ↵ Middeldorp , C.M. , De Moor , M.H.M. , McGrath , L.M. , Gordon , S.D. , Blackwood , D.H. , Costa , P.T. , Terracciano , A. , Krueger , R.F. , De Geus , E.J.C. , Nyholt , D.R. , Tanaka , T. , Esko , T. , Madden , P.A.F. , Derringer , J. , Amin , N. , Willemsen , G. , Hottenga , J.J. , Distel , M.A. , Uda , M. , Sanna , S. , Spinhoven , P. , Hartman , C.A. , Ripke , S. , Sullivan , P.F. , Realo , A. , Allik , J. , Heath , A.C. , Pergadia , M.L. , Agrawal , A. , Lin , P. , Grucza , R.A. , Widen , E. , Cousminer , D.L. , Eriksson , J.G. , Palotie , A. , Barnett , J.H. , Lee , P.H. , Luciano , M. , Tenesa , A. , Davies , G. , Lopez , L.M. , Hansell , N.K. , Medland , S.E. , Ferrucci , L. , Schlessinger , D. , Montgomery , G.W. , Wright , M.J. , Aulchenko , Y.S. , Janssens , A.C.J.W. , Oostra , B.A. , Metspalu , A. , Abecasis , G.R. , Deary , I.J. , Räikkönen , K. , Bierut , L.J. , Martin , N.G. , Wray , N.R. , Van Duijn , C.M. , Smoller , J.W. , Penninx , B.W.J.H. , Boomsma , D.I. , 2011 . The genetic association between personality and major depressi0on or bipolar disorder. A polygenic score analysis using genome-wide association data . Transl Psychiatry 1 . doi: 10.1038/tp.2011.45 OpenUrl CrossRef ↵ Miura , H. , Ozaki , N. , Sawada , M. , Isobe , K. , Ohta , T. , Nagatsu , T ., 2008 . A link between stress and depression: Shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression . Stress 11 , 198 – 209 . doi: 10.1080/10253890701754068 OpenUrl CrossRef PubMed Web of Science ↵ Muscat , R. , Willner , P ., 1992 . Suppression of sucrose drinking by chronic mild unpredictable stress: a methodological analysis . Neurosci Biobehav Rev 16 , 507 – 17 . doi: 10.1016/s0149-7634(05)80192-7 OpenUrl CrossRef PubMed Web of Science ↵ Nikaido , T. , Akiyama , M. , Moriya , T. , Shibata , S ., 2001 . Sensitized increase of period gene expression in the mouse caudate/putamen caused by repeated injection of methamphetamine . Mol Pharmacol 59 , 894 – 900 . OpenUrl Abstract / FREE Full Text ↵ O’Connor , J.C. , Porter , G.A. , O’Connor , J.C ., 2021 . Chronic Unpredictable Stress Alters Brain Tryptophan Metabolism and Impairs Working Memory in Mice without Causing Depression-Like Behaviour . Neurol Neurobiol (Tallinn ) 4 , doi: 10.31487/j.nnb.2021.03.03 . 10.31487/J.NNB.2021.03.03 OpenUrl CrossRef ↵ Palm , S. , Hävermark , Å. , Meyerson , B.J. , Nylander , I. , Roman , E ., 2011 . When is a Wistar a Wistar? Behavioral profiling of outbred Wistar rats from five different suppliers using the MCSF test . Appl Anim Behav Sci 135 , 128 – 137 . doi: 10.1016/J.APPLANIM.2011.08.010 OpenUrl CrossRef ↵ Parrott , J.M. , Redus , L. , Santana-Coelho , D. , Morales , J. , Gao , X. , O’Connor , J.C ., 2016. Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation . Translational Psychiatry 2016 6 : 10 6, e918–e918. doi: 10.1038/tp.2016.200 OpenUrl CrossRef ↵ Pawlak , C.R. , Schwarting , R.K.W ., 2002 . Object preference and nicotine consumption in rats with high vs. low rearing activity in a novel open field . Pharmacol Biochem Behav 73 , 679 – 687 . doi: 10.1016/S0091-3057(02)00852-3 OpenUrl CrossRef PubMed ↵ Pellow , S. , Chopin , P. , File , S.E. , Briley , M ., 1985 . Validation of open : closed arm entries in an elevated plus-maze as a measure of anxiety in the rat . J Neurosci Methods 14 , 149 – 167 . doi: 10.1016/0165-0270(85)90031-7 OpenUrl CrossRef PubMed Web of Science ↵ Phillips , M.L. , Kupfer , D.J ., 2013 . Bipolar Disorder 2 - Bipolar disorder diagnosis: Challenges and future directions . The Lancet . doi: 10.1016/S0140-6736(13)60989-7 OpenUrl CrossRef PubMed Web of Science ↵ Porsolt , R.D. , Bertin , A. , Jalfre , M ., 1978 . “Behavioural despair” in rats and mice: Strain differences and the effects of imipramine . Eur J Pharmacol 51 , 291 – 294 . doi: 10.1016/0014-2999(78)90414-4 OpenUrl CrossRef PubMed Web of Science ↵ Radenovic , L. , Selakovic , V ., 2005 . Differential effects of NMDA and AMPA/kainate receptor antagonists on nitric oxide production in rat brain following intrahippocampal injection . Brain Res Bull 67 , 133 – 141 . doi: 10.1016/j.brainresbull.2005.06.019 OpenUrl CrossRef PubMed Web of Science ↵ Redei , E.E. , Udell , M.E. , Solberg Woods , L.C. , Chen , H ., 2023 . The Wistar Kyoto Rat: A Model of Depression Traits . Curr Neuropharmacol 21 , 1884 . doi: 10.2174/1570159X21666221129120902 OpenUrl CrossRef PubMed ↵ Reilly , C.A. , Aust , S.D ., 1999 . Measurement of Lipid Peroxidation . Curr Protoc Toxicol 00 . doi: 10.1002/0471140856.tx0204s00 OpenUrl CrossRef Rosa Neto, J.C., Lira, F.S., Venancio, D.P., Cunha, C.A., Oyama, L.M., Pimentel, G.D., Tufik, S., Do Nascimento, C.M.O., Santos, R.V.T., De Mello, M.T., 2010 . Sleep deprivation affects inflammatory marker expression in adipose tissue . Lipids Health Dis 9 . doi: 10.1186/1476-511X-9-125 OpenUrl CrossRef ↵ Roybal , K. , Theobold , D. , Graham , A. , DiNieri , J.A. , Russo , S.J. , Krishnan , V. , Chakravarty , S. , Peevey , J. , Oehrlein , N. , Birnbaum , S. , Vitaterna , M.H. , Orsulak , P. , Takahashi , J.S. , Nestler , E.J. , Carlezon , W.A. , McClung , C.A ., 2007a . Mania-like behavior induced by disruption of CLOCK . Proc Natl Acad Sci U S A 104 , 6406 – 11 . doi: 10.1073/pnas.0609625104 OpenUrl Abstract / FREE Full Text ↵ Roybal , K. , Theobold , D. , Graham , A. , DiNieri , J.A. , Russo , S.J. , Krishnan , V. , Chakravarty , S. , Peevey , J. , Oehrlein , N. , Birnbaum , S. , Vitaterna , M.H. , Orsulak , P. , Takahashi , J.S. , Nestler , E.J. , Carlezon , W.A. , McClung , C.A ., 2007b . Mania-like behavior induced by disruption of CLOCK . Proc Natl Acad Sci U S A 104 , 6406 – 11 . doi: 10.1073/pnas.0609625104 OpenUrl Abstract / FREE Full Text ↵ Rumble , M.E. , White , K.H. , Benca , R.M ., 2015a . Sleep Disturbances in Mood Disorders . Psychiatric Clinics of North America . doi: 10.1016/j.psc.2015.07.006 OpenUrl CrossRef PubMed ↵ Rumble , M.E. , White , K.H. , Benca , R.M ., 2015b . Sleep Disturbances in Mood Disorders . Psychiatric Clinics of North America . doi: 10.1016/j.psc.2015.07.006 OpenUrl CrossRef PubMed SARTER, M., BODEWITZ, G., STEPHENS, D.N., 1988 . Attenuation of scopolamine-induced impairment of spontaneous alternation behaviour by antagonist but not inverse agonist and agonist β-carbolines . Psychopharmacology (Berl ) 94 , 491 – 495 . doi: 10.1007/BF00212843 OpenUrl CrossRef PubMed Scheggi, S., De Montis, M.G., Gambarana, C., 2018 . Making sense of rodent models of anhedonia . International Journal of Neuropsychopharmacology . doi: 10.1093/ijnp/pyy083 OpenUrl CrossRef PubMed Simonetti, A., Luciano, M., Sampogna, G., Della Rocca, B., Mancuso, E., De Fazio, P., Di Nicola, M., Di Lorenzo, G., Pepe, M., Sambataro, F., Signorelli, M.S., Koukopoulos, A.E., Chiaie, R.D., Fiorillo, A., Sani, G., 2023 . Effect of affective temperament on illness characteristics of subjects with bipolar disorder and major depressive disorder . J Affect Disord 334 , 227 – 237 . doi: 10.1016/J.JAD.2023.04.130 OpenUrl CrossRef PubMed ↵ Smoller , J.W. , Finn , C.T ., 2003 . Family , Twin, and Adoption Studies of Bipolar Disorder. American Journal of Medical Genetics - Seminars in Medical Genetics . doi: 10.1002/ajmg.c.20013 OpenUrl CrossRef PubMed ↵ Stedenfeld , K.A. , Clinton , S.M. , Kerman , I.A. , Akil , H. , Watson , S.J. , Sved , A.F ., 2011a . Novelty-Seeking Behavior Predicts Vulnerability in a Rodent Model of Depression . Physiol Behav 103 , 210 . doi: 10.1016/J.PHYSBEH.2011.02.001 OpenUrl CrossRef PubMed ↵ Stedenfeld , K.A. , Clinton , S.M. , Kerman , I.A. , Akil , H. , Watson , S.J. , Sved , A.F ., 2011b . Novelty-Seeking Behavior Predicts Vulnerability in a Rodent Model of Depression . Physiol Behav 103 , 210 . doi: 10.1016/J.PHYSBEH.2011.02.001 OpenUrl CrossRef PubMed ↵ Steimer , T. , Driscoll , P ., 2005 . Inter-individual vs line/strain differences in psychogenetically selected Roman High-(RHA) and Low-(RLA) Avoidance rats: Neuroendocrine and behavioural aspects . Neurosci Biobehav Rev 29 , 99 – 112 . doi: 10.1016/j.neubiorev.2004.07.002 OpenUrl CrossRef PubMed Web of Science ↵ Sutin , A.R. , Cutler , R.G. , Camandola , S. , Uda , M. , Feldman , N.H. , Cucca , F. , Zonderman , A.B. , Mattson , M.P. , Ferrucci , L. , Schlessinger , D. , Terracciano , A. , 2013 . Impulsivity is Associated with Uric Acid: Evidence from Humans and Mice . Biol Psychiatry 75 , doi: 10.1016/j.biopsych.2013.02.024 . 10.1016/J.BIOPSYCH.2013.02.024 OpenUrl CrossRef PubMed Web of Science ↵ Tannenbaum , S.R. , Fett , D. , Young , V.R. , Land , P.D. , Bruce , W.R ., 1978 . Nitrite and nitrate are formed by endogenous synthesis in the human intestine . Science (1979) 200, 1487–1489. doi: 10.1126/science.663630 OpenUrl Abstract / FREE Full Text ↵ Theilmann , W. , Kleimann , A. , Rhein , M. , Bleich , S. , Frieling , H. , Löscher , W. , Brandt , C ., 2016 . Behavioral differences of male Wistar rats from different vendors in vulnerability and resilience to chronic mild stress are reflected in epigenetic regulation and expression of p11 . Brain Res 1642 , 505 – 515 . doi: 10.1016/J.BRAINRES.2016.04.041 OpenUrl CrossRef PubMed ↵ Thiel , C.M. , Muller , C.P. , Huston , J.P. , Schwarting , R.K.W ., 1999 . High versus low reactivity to a novel environment: behavioural, pharmacologival and neurochemical assessments . Neuroscience 93 , 243 – 251 . OpenUrl CrossRef PubMed Web of Science ↵ Tsikas , D ., 2007 . Analysis of nitrite and nitrate in biological fluids by assays based on the Griess reaction: Appraisal of the Griess reaction in the l-arginine/nitric oxide area of research . Journal of Chromatography B 851 , 51 – 70 . doi: 10.1016/j.jchromb.2006.07.054 OpenUrl CrossRef PubMed ↵ Uchiyama , M. , Mihara , M ., 1978 . Determination of malonaldehyde precursor in tissues by thiobarbituric acid test . Anal Biochem 86 , 271 – 278 . doi: 10.1016/0003-2697(78)90342-1 OpenUrl CrossRef PubMed Web of Science ↵ Uz , T. , Ahmed , R. , Akhisaroglu , M. , Kurtuncu , M. , Imbesi , M. , Dirim Arslan , A. , Manev , H ., 2005 . Effect of fluoxetine and cocaine on the expression of clock genes in the mouse hippocampus and striatum . Neuroscience 134 , 1309 – 1316 . doi: 10.1016/j.neuroscience.2005.05.003 OpenUrl CrossRef PubMed Web of Science Veenema, A.H., Meijer, O.C., De Kloet, E.R., Koolhaas, J.M., Bohus, B.G., 2003 . Differences in basal and stress-induced HPA regulation of wild house mice selected for high and low aggression . Horm Behav 43 , 197 – 204 . doi: 10.1016/S0018-506X(02)00013-2 OpenUrl CrossRef PubMed Web of Science ↵ Wang , L. , Zhang , R. , Hou , X. , Wang , C. , Guo , S. , Ning , N. , Sun , C. , Yuan , Y. , Li , L. , Hölscher , C. , Wang , X ., 2019 . DA-JC1 improves learning and memory by antagonizing Aβ31–35-induced circadian rhythm disorder . Mol Brain 12 , 14 . doi: 10.1186/s13041-019-0432-9 OpenUrl CrossRef PubMed ↵ Wang , X.-L. , Li , L ., 2021 . Circadian Clock Regulates Inflammation and the Development of Neurodegeneration . Front Cell Infect Microbiol 11 , 696554 . doi: 10.3389/fcimb.2021.696554 OpenUrl CrossRef PubMed ↵ Whittle , S. , Allen , N.B. , Lubman , D.I. , Y??cel, M., 2006 . The neurobiological basis of temperament: Towards a better understanding of psychopathology . Neurosci Biobehav Rev 30 , 511 – 525 . doi: 10.1016/j.neubiorev.2005.09.003 OpenUrl CrossRef PubMed Web of Science Young , J.W. , Goey, a. K.L., Minassian, A., Perry, W., Paulus, M.P., Geyer, M. a., 2010 . GBR 12909 administration as a mouse model of bipolar disorder mania: Mimicking quantitative assessment of manic behavior . Psychopharmacology (Berl ) 208 , 443 – 454 . doi: 10.1007/s00213-009-1744-8 OpenUrl CrossRef PubMed Web of Science ↵ Yuferov , V. , Kroslak , T. , Laforge , K.S. , Zhou , Y. , Ho , A. , Kreek , M.J ., 2003 . Differential gene expression in the rat caudate putamen after ‘binge’ cocaine administration: advantage of triplicate microarray analysis . Synapse 48 , 157 – 69 . doi: 10.1002/syn.10198 OpenUrl CrossRef PubMed Web of Science ↵ Zangrossi , H. , File , S.E ., 1992 . Behavioral consequences in animal tests of anxiety and exploration of exposure to cat odor . Brain Res Bull 29 , 381 – 388 . doi: 10.1016/0361-9230(92)90072-6 OpenUrl CrossRef PubMed Web of Science ↵ Zhang , R. , Manza , P. , Tomasi , D. , Kim , S.W. , Shokri-Kojori , E. , Demiral , S.B. , Kroll , D.S. , Feldman , D.E. , McPherson , K.L. , Biesecker , C.L. , Wang , G.J. , Volkow , N.D ., 2021 . Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward . J Clin Invest 131 . https://doi.org/10.1172/JCI149722 View the discussion thread. Back to top Previous Next Posted June 11, 2025. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following The Sleep-Mood Connection: Temperament Modulates Neuroinflammation, Clock Genes, and Dopaminergic Receptors Expression in Rats Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share The Sleep-Mood Connection: Temperament Modulates Neuroinflammation, Clock Genes, and Dopaminergic Receptors Expression in Rats Camila Nayane Carvalho Lima , Francisco Eliclécio Rodrigues da Silva , Michele Albuquerque Jales de Carvalho , Jose Eduardo de Carvalho Lima , Adriano José Maia Chaves-Filho , Gabriel R. Fries , Manoel A. Sobreira-Neto , Deiziane Viana da Silva Costa , Marta Maria França Fonteles , Danielle S. Macêdo bioRxiv 2025.06.09.658634; doi: https://doi.org/10.1101/2025.06.09.658634 Share This Article: Copy Citation Tools The Sleep-Mood Connection: Temperament Modulates Neuroinflammation, Clock Genes, and Dopaminergic Receptors Expression in Rats Camila Nayane Carvalho Lima , Francisco Eliclécio Rodrigues da Silva , Michele Albuquerque Jales de Carvalho , Jose Eduardo de Carvalho Lima , Adriano José Maia Chaves-Filho , Gabriel R. Fries , Manoel A. Sobreira-Neto , Deiziane Viana da Silva Costa , Marta Maria França Fonteles , Danielle S. Macêdo bioRxiv 2025.06.09.658634; doi: https://doi.org/10.1101/2025.06.09.658634 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Animal Behavior and Cognition Subject Areas All Articles Animal Behavior and Cognition (7635) Biochemistry (17697) Bioengineering (13895) Bioinformatics (41951) Biophysics (21456) Cancer Biology (18594) Cell Biology (25520) Clinical Trials (138) Developmental Biology (13381) Ecology (19903) Epidemiology (2067) Evolutionary Biology (24323) Genetics (15612) Genomics (22510) Immunology (17738) Microbiology (40401) Molecular Biology (17184) Neuroscience (88622) Paleontology (667) Pathology (2833) Pharmacology and Toxicology (4825) Physiology (7644) Plant Biology (15158) Scientific Communication and Education (2046) Synthetic Biology (4296) Systems Biology (9825) Zoology (2271)