Frontiers in Behavioral Neuroscience

The midsession reversal (MSR) task is frequently used to study behavioral flexibility and decision strategies in animals. In a typical version of the task, subjects complete 80 trials in which they choose between two simultaneously presented stimuli, S1 and S2. During the first 40 trials, responses to S1 are reinforced, whereas responses to S2 are not. The contingencies then reverse without warning: From trial 41 to 80, only responses to S2 are reinforced. In birds, performance in this task is often characterized by anticipatory and perseverative errors around the reversal point, suggesting a reliance on elapsed time since the session began. In contrast, rats tested in operant conditioning chambers typically show near-optimal performance with few errors, a pattern often interpreted as evidence that rats rely primarily on local reinforcement cues rather than temporal information. The present study investigated whether rats exclusively rely on local cues in the MSR task or whether temporal information also contributes to the decision process. Two groups of rats were trained with different intertrial intervals (ITIs; 5 s or 10 s) while the reversal point remained fixed at Trial 41. During acquisition, both groups diplayed similar learning rates and near-optimal steady-state performance with minimal anticipatory or perseverative errors. However, when the ITI was manipulated in probe sessions, systematic shifts in switching behavior emerged. Rats adjusted their choices according to the temporal midpoint experienced during training rather than the nominal trial number of the reversal. These results suggest that rats rely on a mixed strategy that integrates local reinforcement cues with global timing information. Temporal control may therefore be present even when it is not expressed during standard training conditions.

Zebrafish have been used a prominent model for high-throughput phenotypic screens of candidate risk gene mutations for several disorders. This also includes models for attention deficit/hyperactivity disorder (ADHD). Traditional behavioural tests, such as the forced light/dark assay, concentrate on basic locomotion measures. However, recently developed visually-driven locomotion assays, for example closed-loop systems using virtual reality, have allowed extraction of richer data on animal locomotion and decision-making under different sensory stimuli. Here, we have used such a system to assess the behaviour in adgrl3.1 mutant fish, an established model for ADHD. Our results show that mutants exhibit a higher baseline excitability and a lower threshold for initiating motor events, demonstrating that collecting behavioural responses in an interactive environment enables a more precise characterisation of ADHD-relevant phenotypes associated with adgrl3.1 disruption. More generally, we establish a scalable translational platform to screen gene-function relationships and possible therapeutic interventions, not only for ADHD but multiple neurodevelopmental disorders.

Physical activity offers myriad benefits to health and well-being, in humans and other animals as well. In rodents, voluntary wheel running can attenuate the effects of both physical and social stressors on rodent social behavior. Whether wheel running affects rodent social behaviors per se remains less well understood. We conducted the current study to test whether home cage access to running wheels impacts the social behaviors of adult, group-housed C57BL/6J female mice during same-sex interactions with novel females. Group-housed females were either given continuous home cage running wheel access or a standard paper hut starting at weaning, and as adults, social behaviors were measured during interactions with novel females. In two cohorts, we found that 5 weeks of running wheel access during adolescence reduced the time that subject females spent investigating a novel female and also tended to reduce total ultrasonic vocalizations produced during interactions. These effects were not reversed by a 2-week period of running wheel removal but were recapitulated in a different cohort by 2 weeks of running wheel access in adulthood. Unexpectedly, we found that these effects on female social behavior were not due to wheel running per se, because females raised from weaning with immobile running wheels also showed low rates of social behaviors during same-sex interactions in adulthood. Overall, we find that the presence of a running wheel in the home cage has an enduring inhibitory influence on female social behavior during same-sex interactions, a finding that has implications for the design of studies that include same-sex interactions between female mice.

In contrast to static formalisms, computational definitions describe the operational mechanisms of a model. Simulations are an essential part of the cycle of theory development and refinement, assisting researchers in formulating the precise definitions that models require, and making accurate predictions. This manuscript introduces a computational implementation of Pavlovian learning models in a Python environment, termed Pavlovian Associative Learning Models Simulation (PALMS). In addition to the canonical Rescorla-Wagner model, attentional approaches are implemented, including Pearce-Kaye-Hall, Mackintosh Extended, Le Pelleys Hybrid, and a novel extension of the Rescorla-Wagner model featuring a unified variable learning rate that synthesises Mackintoshs and Pearce and Halls opposing conceptualisations. To our knowledge, only the first attentional model has been previously specified computationally in a general design tool. PALMS integrates a graphical interface that permits the input of entire experimental designs in an alphanumeric format, akin to that used by experimental neuroscientists. It uniquely enables the simulation of experiments involving hundreds of stimuli, such as those used with human participants, and the computation of configural cues and configural-cue compounds across all models, thereby substantially broadening their predictive capabilities. A comprehensive description of the models implementation and the environment functionalities is provided in the paper; these include efficient and accurate operation and instant visualisation of predicted results across different models within a single architecture and environment. We evaluate PALMS by simulating five published experiments in the associative learning literature that assessed the predictive scope of existing models, and we show that this implementation provides neuroscientists with a useful tool for identifying critical variables, refining experimental designs, making precise predictions, comparing model fitness, and formulating new theoretical approaches. PALMS is licensed under the open-source GNU Lesser General Public License 3.0. The environment source code and the latest multiplatform release build are accessible as a GitHub repository at https://github.com/cal-r/PALMS-Simulator. Author summaryResearch on associative learning is multidisciplinary, encompassing disciplines such as neuroscience, AI, psychology, psychiatry, behavioural sciences, planning, and marketing. Unlike static formalisms, precise computational definitions specify how a model operates, enabling model simulation, swift and error-free prediction calculations, which are essential for testing theories, comparing predictions, holding models accountable, and providing a common language across fields. We introduce Pavlovian Associative Learning Models Simulation (PALMS), a user-friendly, open-source Python environment for simulating classical conditioning and studying the role of attention in learning. PALMS implements the prescriptive Rescorla-Wagner and attentional models: Pearce-Kaye-Hall, Mackintosh Extended, Le Pelleys Hybrid, and a new hybrid model with a unified variable learning rate that blends Mackintosh and Pearce-Halls conflicting views. Its graphical interface makes it easy for neuroscientists to enter experiments. Our computational implementation supports simulations with hundreds of stimuli, configural cues, and compounds, broadening the models predictive power. Designed for efficiency, it offers instant visual results and useful features. We evaluate PALMS by simulating five published experiments, highlighting its value for model comparison and refinement, and, more generally, as a tool to assist research.

Stress can cause or exacerbate psychiatric illness, and effects on the transcription factor CREB within the nucleus accumbens (NAc) are critically involved. In rodents, stress-induced activation of NAc CREB produces elevations in dynorphin (DYN), an endogenous opioid expressed in dopamine D1-receptor (D1R)-expressing medium spiny neurons (MSNs). In turn, elevated DYN signaling produces features of mood and anxiety disorders via actions at kappa-opioid receptors (KORs). Although individual differences in stress sensitivity have been described--with some appearing susceptible and others resilient--the contribution of NAc DYN to these phenotypes is unclear. Here we examined relationships between social behavior and DYN in D1R-expressing MSNs in mice exposed to chronic social defeat stress (CSDS). We used quantitative (q)RNAscope to assess co-expression of genes encoding CREB (Creb1), D1Rs (Drd1), and DYN (Pdyn) within the NAc. To leverage individual variability, we performed regression analyses across all mice, revealing negative correlations between social interaction behavior and expression of Drd1 and Pdyn, linking higher social avoidance with higher expression of these genes. There was no correlation with Creb1, suggesting stress-induced elevations in Pdyn depend on CREB activation (phosphorylation). These findings suggest that stress-induced elevations in D1R-associated DYN signaling within the NAc is a biomarker of susceptibility.

Behavioral dysfunction is a common characteristic of many mental health disorders. While the causes of these disorders vary, aberrant behaviors may arise from alterations in transcriptional regulation already during early neural development. Because transcription factors (TFs) often belong to families of closely related members, disruption of a single TF may indirectly influence the functionality of other family members. Consequently, mutations in TFs within the same family may lead to overlapping, yet distinct, phenotypes. This feature of TF function has important implications for understanding behavioral phenotypes, but detailed analyses across a single TF family are still lacking. In this study, we present a comprehensive behavioral analysis of adult zebrafish harboring mutations in individual members of the TALE and Hox TF families, that are essential for nervous system development. Using a battery of validated behavioral assays, we uncover elevated stress responses among all TF mutant lines, as well as TF-specific dysregulation in coping strategies, social interaction, learning/memory, and endurance and locomotion. The shared behavioral abnormalities across mutants suggests TF family members converge on core developmental pathways for stress-related behavioral regulation, while mutation-specific phenotypes indicate unique roles for individual TFs in fine-tuning neural function. Our findings provide a systematic behavioral characterization of TALE and Hox mutants in a vertebrate model and provide a framework for understanding how genetic variation within TF families may differentially contribute to vulnerability for mental health disorders.

Traumatic stress can cause long-lasting changes in cognition and affect, sometimes leading to diagnoses such as post-traumatic stress disorder (PTSD). The stress-enhanced fear learning (SEFL) model recapitulates understudied components of PTSD, such as stress-induced sensitization of fear learning. The SEFL procedure entails exposing mice to footshock stress followed later by fear conditioning in a different context. When tested later for recall of fear conditioning, previously stressed mice exhibit enhanced freezing compared to non-stressed controls. Studies have shown that dorsal and ventral dentate gyrus (DG) generates neural ensemble representations of contextual fear, such that fear recall involves reactivation of a sparse set of "engram cells" that were active during fear memory acquisition. How stress affects these hippocampal ensemble representations is unknown. We used SEFL and activity-dependent neuronal tagging with FosTRAP2 mice to investigate effects of stress on fear memory ensembles in rostral and caudal hippocampal DG. FosTRAP2/Ai6 mice received footshock stress or equivalent context exposure without shock in Context A on day 1. Five days later, mice received 1-shock conditioning in Context B and immediately received an injection of 4-OHT (55mg/kg) to tag fear acquisition neurons with the zsGreen reporter. One day later, mice were tested for fear recall in Context B and were perfused 90 minutes after testing. Confirming prior studies, prior stress potentiated 1-shock conditioning in Context B, with stressed mice displaying higher freezing in the Context B test session than non-stressed mice. At the level of neural activity, results showed stress had no effect on the number of zsGreen+ fear ensemble cells or the number of cfos+ recall-activated cells in rostral or caudal DG. However, stress increased reactivation (percentage of zsGreen+ cells expressing cfos) in the caudal but not rostral DG. The results suggest stress potentiates later fear learning by enhancing fear representations in caudal hippocampus, a region of the hippocampus specialized for integrating emotional and motivational valence into memory.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental condition characterized by persistent deficits in working memory (WM) and executive control. Dysregulation of the Cyclin-dependent kinase 5 (Cdk5)/p35 signaling pathway has been implicated in ADHD pathophysiology due to its impact on neuronal connectivity and dopamine regulation. Using p35 knockout (p35KO) mice--a validated model exhibiting ADHD-like phenotypes--we investigated sex-specific WM performance, task-related neuronal activation patterns, and responses to acute treatment with methylphenidate (MPH) or fluoxetine (FLX), administered alone or in combination. Under basal conditions, p35KO mice of both sexes exhibited significant WM impairment in the Y-maze test compared with wild type (WT) counterparts, whereas recognition memory remained intact. Analysis of neuronal activation (c-Fos-IR) 90 min after testing revealed region-, sex-, and genotype-dependent alterations. Overall, p35KO animals of both sexes showed reduced c-Fos-IR expression in prefrontal cortical regions, while exhibiting increased c-Fos-IR in hippocampal regions. Acute MPH or FLX treatment improved WM in p35KO males, but this benefit was not observed following combined treatment (MPH+FLX). In contrast, p35KO females showed no WM improvement with any treatment. Notably, WT females exhibited a pronounced decline in WM after exposure to MPH, FLX, or their combination, indicating sex-specific pharmacological sensitivity in healthy animals. These findings support an important role of Cdk5/p35 signaling in the functional engagement of prefrontal and hippocampal networks and demonstrate that pharmacological responses in this ADHD model are strongly influenced by sex and neurobiological background, highlighting the importance of incorporating sex as a biological variable in preclinical and translational ADHD research. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/696253v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@12b4330org.highwire.dtl.DTLVardef@14826c3org.highwire.dtl.DTLVardef@1e8f3d8org.highwire.dtl.DTLVardef@e108a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

The Mnemonic Similarity Task (MST) is highly sensitive to age-related cognitive decline in humans and has been adapted for rodents using 3D objects, where aged animals show deficits in discriminating similar lures. To improve translational alignment with human testing and increase automation, we developed a touchscreen-based rat analog using a morphed Object-Cued Spatial Choice (OCSC) task with 2D image stimuli. Young (4-month) and aged (21-month) male and female Fischer 344 x Brown Norway hybrid rats were trained in Bussey-Saksida touchscreen chambers and tested on discrimination performance using image pairs that varied parametrically in feature overlap. We also assessed perirhinal cortical engagement in a subset of animals using Arc expression as a readout of activity-related principal cell firing following low-and high-overlap task epochs. Across shaping and procedural training, aged rats required more errors to reach criterion on one stimulus set, but both age groups successfully acquired the task. During morph testing, performance declined systematically as stimulus similarity increased, confirming that the task manipulated discrimination difficulty. However, contrary to expectations, young and aged rats performed similarly across overlap conditions, with no significant age-related impairment. In the Arc experiment, discrimination accuracy was again reduced by greater stimulus overlap, but Arc expression in perirhinal cortex did not differ reliably by age or overlap condition, although expression was associated with behavioral accuracy and deep layers showed higher ensemble similarity than superficial layers. These findings indicate that, while the touchscreen morph OCSC task is sensitive to stimulus similarity, it does not detect the robust age-related mnemonic discrimination deficits previously observed with 3D object-based rodent MST paradigms, underscoring the importance of considering ethological relevance when designing translational cognitive assays.

Background and aimsPerseverative behaviours are commonly assessed using operant paradigms in which rodents work for drugs or food under physiological deprivation, limiting translational relevance to some behavioural addictions. Here we validated an operant paradigm in which the acquired behaviour is driven neither by physiological needs nor hedonic responses. MethodsMice were trained to lever-press for green light. Exp.1 used a within-subjects design to examine lever discrimination and whether responding could be "satiated" by light preexposure. Exp.2 examined instrumental contingency using a between-subjects design, with light delivery equated between contingent and non-contingent groups. Exp.3 replaced green light with dim red light producing less retinal photoreceptor excitation but comparable heat to assess non-photic cues. Exp.4 examined whether green light could affect food seeking different motivational states. ResultsIn Exp.1, green light supported lever discrimination. Among high responders, the satiation effect was modest (<15% reduction) and did not deter lever pressing. In Exp.2, instrumental contingency promoted response acquisition whereas random light delivery did not. In Exp.3, dim red light failed to sustain behaviour, producing [~]50% response decrement. In Exp.4, light potentiated food seeking under ad libitum feeding. Discussion and conclusionsResponse-contingent light serves as a reward to establish operant responding, which cannot be explained by alerting effects or thermal cues. Our study bridges the gap between animal models and findings from humans that coloured light may exacerbate smartphone use and that light therapy may reshape reward circuits in individuals with Internet gaming disorder symptoms [Li et al. (2026) Advanced Science 13:e14044].

BackgroundPavlovian responding is a core component of behavior and can be measured via Pavlovian-instrumental transfer (PIT), where Pavlovian responses bias instrumental actions. Standard single-lever PIT paradigms, which assess responses using a single-choice option, cannot dissociate the contribution of model-free versus model-based reinforcement learning. While indirect evidence suggests a role for model-free responding in single-lever PIT, the contribution of model-based strategies is unclear. It also remains unknown whether internal cognitive states, such as mind wandering, impair specifically model-based but not model-free PIT, as is theoretically expected. MethodsWe developed a novel, trial-by-trial two-stage PIT paradigm designed to computationally dissociate model-free and model-based Pavlovian responding by leveraging probabilistic state transitions and trial-wise outcome predictions. After each two-stage Pavlovian learning trial, participants performed a single-lever PIT trial as well as a query trial of explicit value judgment. Detailed task instructions were provided to support potential model-based strategies. Computational modeling was used to quantify individual learning strategies. We assessed mind-wandering questionnaires and thought probes. ResultsAnalysis of query and PIT trials revealed trial-by-trial updating of outcome expectations based on probabilistic task structure, consistent with model-based Pavlovian responding. Behavioral responses during PIT were best explained by a computational model-based reinforcement learning model. In contrast, we found little evidence for model-free Pavlovian responding. Higher levels of mind wandering were associated with reduced model-based control but did not impact model-free indices. ConclusionWe introduce a novel single-lever PIT paradigm that enables fine-grained dissociation of model-free versus model-based Pavlovian response systems. Our findings provide evidence that single-lever PIT can operate through model-based mechanisms, challenging the assumption that single-lever PIT is predominantly model-free. Our findings also indicate that internal attentional states selectively modulate model-based PIT. Given the involvement of Pavlovian responding in numerous psychiatric conditions, our paradigm offers new avenues for understanding maladaptive behavior. Author SummaryOur daily actions are often influenced by cues like the smell of food or the sound of phone notifications that signal potential rewards or losses. These Pavlovian cues can shape our instrumental behavior even though their outcomes do not depend on what we do - a process known as Pavlovian-instrumental transfer (PIT). Here we study the computational learning mechanisms that underlie such PIT effects. While it is often assumed that Pavlovian responding follows simple, automatic rules without a cognitive model of cue consequences (i.e., model-free), evidence also shows a role for cognitive anticipations in Pavlovian responding (i.e., model-based). In this study, we extend this evidence by showing that PIT responding can be driven by flexible model-based learning. We designed a task to test whether participants use model-free versus model-based strategies to guide PIT, providing detailed task instructions. Using reinforcement learning models, we found that most participants used model-based learning when forming cue-outcome associations. Importantly, peoples attention mattered: when they were more distracted and doing mind wandering, they relied less on model-based strategies. Our findings suggest that Pavlovian learning is complex, flexible, and influenced by internal mental states, opening new windows to understand decision-making problems in mental health conditions like addiction.

Stressors are commonly used in rats to induce models of anxiety or depression. The effectiveness of these stressors is often evaluated using specific behavioural tests. In a previous meta-analysis of chronic variable stress (CVS) procedures, we predicted that longer and more intensive stress procedures would result in larger effect sizes in behavioural tests. However, we found that the duration or intensity of CVS procedures did not correlate strongly with the magnitude of the effect sizes reported in behaviouraltests. In that study, we were concerned that the large and unexplained diversity in CVS procedure design, both in terms of duration and the types of stressors used, made it challenging to detect the factors that were influencing effect size. In an effort to address this, we explore here the use of a much simpler stress procedure - chronic restraint stress (CRS) - to study the relationship between the duration of CRS procedures and the effect sizes obtained in subsequent behavioural tests. We searched PubMed for articles using CRS procedures with rats, systematically documented the total duration of restraint, and carried out a meta-analysis of the effect sizes obtained in four behavioural tests: the forced swim test (FST), the sucrose preference test (SPT), the elevated plus maze (EPM) and the open field test (OFT). We found that chronic restraint stress increased immobility in the FST, decreased sucrose preference in the SPT, decreased time spent in the open arms of the EPM but had no effect on time spent in the centre of the OFT. However, the effect sizes in all behavioural tests, except the SPT, were not moderated by the duration of the CRS procedure, indicating that longer CRS procedures are associated with larger effect sizes in the SPT but not in the FST or EPM.

CaMKII promoter is widely used to label and manipulate hippocampal pyramidal neurons via transgenic mouse lines or viral approaches. While it targets most excitatory neurons, a small subset remains unlabeled and often overlooked. We present an AAV-based strategy combined with CaMKII-driven Cre expression to access and study this remaining population. Furthermore, we provide a detailed protocol for in-house AAV production, targeted stereotaxic delivery, and functional validation of targeted neurons through slice electrophysiology and behavior. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/723440v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@3a31ccorg.highwire.dtl.DTLVardef@9b7e90org.highwire.dtl.DTLVardef@92297borg.highwire.dtl.DTLVardef@1e159eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

Standard rat housing may impede species-typical behaviors and impact rat welfare and research outcomes. This research investigated the effects of housing on behavioral and physiological outcomes of rats through the use of modified large animal cages for housing, and was conducted in two studies. Study A: 70 Sprague Dawley (SD) rats (34 males, 36 females; 5 wk old) were randomly assigned to standard polycarbonate shoebox cages (C: 733.9cm2) or modified stainless steel primate cages (T: 10,416cm2) for 18 days. In Study B: 48 SD rats (24 males, 24 females; 7.5 wk old) were held in T housing for 90 days to assess long term impacts. All rats received gentle handling for 15s 3x/week. Rats were assessed for body weight, anxiety-like behavior in an elevated plus maze, response during a voluntary human approach test, and overall home cage behavior, posture, and space usage. Data were analyzed using generalized linear mixed models, with sex and treatment as fixed effects, and cage as the random effect. The results of study A suggest that the modified large animal cages (T) had positive impacts on rat behavior and welfare. T rats were less anxious (P=0.038) and more active (P<0.0001) and explorative (P=0.0003) compared to C rats. In both groups, activity levels declined towards the end of the 18-day study period (P<0.0001). For study B, similar patterns were observed, with rats becoming more inactive (P<0.0001) over 90 days. However, rats spent significant time on elevated shelves in T housing, which increased throughout the study (P<0.0001), suggesting continued use of the resources the housing provided. In both studies, there were no differences in latency to approach humans (P>0.05), but T rats spent less time in contact with human handlers, suggesting differences in motivation to interact with humans that should be explored further.

Relapse-prevention strategies aimed at reducing relapse following abstinence, primarily focus on reducing cravings that lead to drug-seeking triggered by stress, drug-related cues, or re-exposure to the drug. Because addictive drugs form persistent associative contextual memories, we investigated how reactivation of cocaine-related hippocampal memories influences subsequent drug-seeking. Here, we tagged dorsal dentate gyrus (dDG) memory ensembles involved in encoding either a first or fourth cocaine exposure (15mg/kg, i.p) in male and female c57BL/6 mice using a TetTag approach. Mice underwent cocaine conditioned place preference (CPP), extinction, and reinstatement. We assessed whether optical reactivation of tagged cocaine-related ensembles could substitute for a cocaine priming injection to reinstate CPP, whether reactivation altered cocaine-induced reinstatement, and if these effects differed depending on stage of drug exposure. We also compared these effects to reactivation of saline-associated ensembles. Cocaine produced robust locomotor activation during conditioning, and sensitization developed across repeated drug exposures. Reactivation of a cocaine-related engram alone did not reinstate CPP. However, reactivation of the first cocaine exposure engram attenuated cocaine-induced reinstatement. In contrast, reactivation of the fourth exposure engram did not confer this protective effect. Interestingly, reactivation of saline-associated ensembles also reduced cocaine-induced reinstatement specifically in females, suggesting dDG ensemble reactivation may modulate relapse-related behavior through interference or neuromodulatory disruption of cocaine-associated representations, consistent with our prior work. These findings raise the possibility that early contextual experiences form competing or destabilizing representations that interfere with later cocaine-seeking when reactivated. Females also displayed greater sensitivity to locomotor-inducing effects of cocaine memory reactivation, although this was dissociated from CPP. Together, these findings show that cocaine memories are distinct across drug experience and selective reactivation of dDG engrams can differentially influence drug-seeking.

An increasing number of epidemiological and experimental studies have demonstrated a bidirectional relationship between mood disorders and the circadian system, with disrupted circadian rhythms contributing to depressive states, and their restoration playing a key role in antidepressants effects. In this context, we sought to examine whether key molecular targets of antidepressants exhibit diurnal regulatory patterns. Naive adult male and female C57BL/6 mice were euthanized at 3-hour intervals beginning at Zeitgeber Time 0 (ZT0), and hippocampal (HC) and medial prefrontal cortex (mPFC) tissues were collected for RT-qPCR and western blot analyses. We observed statistically significant diurnal rhythmicity in all analyzed transcripts (cFos, Arc, Nr4a1, Dusp1, Dusp5, and Dusp6) in both HC and mPFC samples, with peak expression occurring during the dark (active) phase (ZT15-18). Phosphorylation levels of TrkBY816 (tropomyosin-related kinase) and GSK3{beta}S9 (glycogen synthase kinase 3{beta}) also showed periodic rhythmicity, peaking during the light (inactive) phase. Levels of p-ERK2T185/Y187 (extracellular-signal regulated kinase) did not display rhythmicity, but peaked during the light phase in the HC, especially in males. Collectively, these findings demonstrate that antidepressant targets are subject to diurnal regulation, highlighting the importance of integrating circadian biology and time-of-day as relevant variables in the development of translationally relevant antidepressant research. HighlightsO_LIKey molecular targets of antidepressants exhibit diurnal regulation in adult mice C_LIO_LIDiurnal patterns were conserved across targets, sexes, and brain regions (HC&PFC) C_LIO_LIcFos, Arc, Nr4a1, Dusp1,5,6 mRNAs display peak expression during the dark phase C_LIO_LITrkBY816 and GSK3{beta}S9 phosphorylation peak during the light (inactive) phase C_LIO_LIAntidepressant mechanisms may be linked with circadian and sleep-wake dynamics C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/716906v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1e65e60org.highwire.dtl.DTLVardef@13e302corg.highwire.dtl.DTLVardef@1ccc25forg.highwire.dtl.DTLVardef@1ed10d3_HPS_FORMAT_FIGEXP M_FIG C_FIG

RationaleAttention-deficit/hyperactivity disorder (ADHD) is associated with executive dysfunction involving inattention and impulsivity, with evidence of disrupted functional expression of the dopamine and noradrenaline transporters. ObjectiveWe investigated the dose-dependent modulation of anti-ADHD drugs on selective and sustained visual attention in low-, mid-and high-attention phenotypes. Two mathematical approaches, signal detection theory and theory of visual attention were applied to further characterise the effects and mechanisms. MethodsRats were trained to detect and respond to the presence or absence of a visual target to obtain food reward on a signal detection task. After attentional performance stabilised, the indirect catecholamine agonist, d-amphetamine (0.1; 0.2; 0.4 mg/kg), the dopamine (DA) and noradrenaline (NA) reuptake inhibitor methylphenidate (0.3; 1; 3 mg/kg), and the NA reuptake inhibitor atomoxetine (0.1; 0.3; 1 mg/kg), were administered systemically. ResultsLow-dose d-amphetamine produced baseline-dependent effects on attention, improving target discrimination only in rats with lower attentive performance, whereas methylphenidate did not significantly improve attention but increased guessing. In contrast, low-dose atomoxetine selectively impaired attention in low-attentive subjects, whereas high-dose atomoxetine generally impaired discrimination performance. All three drugs had expected effects on motor response output. ConclusionsAs well as demonstrating baseline-dependent effects of amphetamine on visual attention, the findings for methylphenidate and atomoxetine suggest important, apparently opposing effects on visual signal detection performance produced via blockade of the DA and NA transporters. The deleterious effects of atomoxetine on performance were especially noteworthy in view of its use as a treatment in ADHD.

Virtual reality (VR) offers immersive and interactive learning environments that can improve student engagement and 3D visualization. However, its application in medical education is mostly limited to clinical settings and its potential for better understanding complex concepts, or empathy with the patients, remains underexplored. Here, we describe SIGHT (Simulated Immersive Guidance for Human Training), an immersive VR application, designed to teach core concepts in the physics and functional neuroanatomy, or neurophysiology of human vision. Its two integrated learning modules allow first-person experience of normal and pathological conditions: the optics module enables users to manipulate lenses, experience refractive errors such as myopia, presbyopia, and astigmatism and correct them through appropriate lens selection; the neurophysiology module allows learners to navigate the visual pathways from the retina to the visual cortex and to simulate lesions, experiencing the corresponding visual field deficits. User authentication and interactive evaluation steps provide analytical feedback of the experience and learning process. A pilot group of medical students reported high usability, engagement and deeper understanding of the vision-related concepts, showing how the approach of SIGHT can support experiential learning in medical education.

Lick microstructure is a term used in behavioural neuroscience to describe the information that can be obtained from a detailed examination of rodent drinking behaviour. Rather than simply recording total intake (volume consumed), lick microstructure examines how licks are grouped, and the spacing of these groups of licks. This type of analysis can provide important insights into why an animal is drinking, for example, whether it is influenced by taste or affected by consequences of consumption (e.g., feeling "full"). Here we present a software package, lickcalc, that allows detailed microstructural analysis of licking patterns. The software is browser-based and is hosted at https://lickcalc.uit.no or the repository can be downloaded and installed locally. Lick timestamps can be loaded from a variety of formats and different analysis and plotting options allow quality control of data and determining critical parameters for microstructural analysis number and size of lick bursts. Data can be divided into epochs for detailed examination of changes across session. Batch processing and custom configurations are supported. In this manuscript, we demonstrate use of the functions exposed by lickcalc by analysing data comparing lick patterns between mice on a protein-restricted and control (non-restricted diet). We show that lickcalc allows quality control of the data and uncovering of subtle differences in lick behaviour that are not apparent when just considering the total number of licks. This software makes microstructural analysis accessible to any researchers who wish to employ it while providing sophisticated analyses with high scientific value.

Graduate-level genomics courses require students to integrate dense material across subfields, concepts and methods. In modular, multi-instructor courses, students may struggle because the coherence between lectures can be difficult to navigate, while the course structure may be visible to instructors. We evaluated a 2025 navigation redesign of BIO322, a graduate genomics course at the Norwegian University of Life Sciences, while preserving course content, multi-instructor teaching, modular organization and assessment framework. The redesign includes introducing a standardized self-learning guide, expanded syllabus, enriched online quiz feedback, and added support for a final group research proposal. Using anonymized course evaluation scores from 2021-2025 and aggregated learning management system access data from 2023-2025, we examined student experience and resource use. In 2025, five of six course evaluation items reached their highest observed BIO322 scores, while one, lecture-specific score remained within the previous range. The consolidated self-learning guide was accessed by nearly all students, whereas access to optional readings declined across the course sequence, despite comparatively stable page views per accessing student. These course-level findings are consistent with improved perceived navigability following the introduction of standardized learning support. However, some students continued to report difficulty identifying priorities and connections among course components, indicating that challenges in perceived course coherence remained for part of the cohort despite the redesign. Practitioner PointsO_LIMaking course structure explicit may improve students perceived navigability in multi-instructor graduate genomics courses. C_LIO_LIA centralized self-learning guide can broaden access to preparatory guidance without changing core course content or assessment. C_LIO_LIOptional learning supports may be used unevenly, so resource availability should not be assumed to translate into uniform resource access. C_LI