搜索结果：Behavioral neuroscience

Autism Spectrum Disorder (ASD) is associated with neuroinflammation and oxidative stress that disrupt neurodevelopmental processes. Resveratrol (RSV) is a polyphenol with antioxidant and anti-inflammatory properties, but its poor bioavailability limits therapeutic use. This study investigated whether PEGylated liposomes encapsulating RSV (LipRSV) could modulate oxidative and behavioral alterations in a valproic acid (VPA)-induced rat model of ASD. PEGylated LipRSV were synthesized, characterized as hemocompatible, and administered to offspring from postnatal day (PND) 6 to 27. Behavioral tests included developmental milestones, olfactory discrimination, negative geotaxis, open field, and three-chamber social interaction. Oxidative stress markers and neurotrophins (BDNF, NGF) were quantified in the following brain regions: hippocampus, hypothalamus, striatum, cerebellum, frontal and posterior cortex. LipRSV exerted limited and region-dependent redox effects, reducing ROS levels only in the hippocampus, cerebellum, and posterior cortex, while failing to improve behavioral outcomes and being associated with unfavorable neurochemical alterations, including reduced BDNF and NGF levels. Importantly, LipRSV also induced behavioral deficits, redox imbalance, and neurochemical alterations in control animals, indicating treatment-related effects in the absence of VPA exposure. LipRSV modulated oxidative stress in a region-dependent manner without improving behavioral deficits in the VPA model and was associated with reduced BDNF and NGF levels. This study provides evidence that modulation of oxidative stress alone is insufficient to rescue behavioral phenotypes in the VPA model of ASD. These findings highlight the partial neurochemical efficacy and translational limitations of this formulation, suggesting the need for optimized nanocarrier design and dosing strategies in ASD pharmacotherapy.

The suprachiasmatic nucleus (SCN), the central circadian clock in mammals, generates robust yet adaptable circadian rhythms through electrically mediated coordination among heterogeneous peptidergic neuronal populations with presumed cell type-specific roles. Previous studies have proposed that circadian changes in membrane excitability of individual SCN neurons arise from time-of-day-dependent shifts in the relative balance of subthreshold Na⁺ and K⁺ conductances. Although multiple channels have been implicated in these processes, how nocturnally dominant K⁺ conductances are implemented in a cell type-specific manner remains poorly understood. Prokineticin 2 (Prok2) has been identified as a SCN signaling peptide essential for behavioral circadian regulation; however, the electrophysiological properties of Prok2-expressing neurons and the mechanisms underlying their diurnal rhythmicity remain largely unexplored. Here, using electrophysiological approaches in mice of either sex, we show that Prok2 neurons exhibit diurnal variations in electrical properties, with higher excitability during the day and reduced excitability at night, and that G protein-coupled inwardly rectifying potassium (GIRK) channel-mediated basal current contributes to nighttime hyperpolarization. Immunofluorescence and single-cell RT-PCR analyses revealed that GIRK1 and GIRK3 are the predominant GIRK subunits expressed in Prok2 neurons. Moreover, Prok2 neuron-specific deletion of GIRK3 using in vivo genome editing resulted in significant nocturnal depolarization and induced abnormalities in behavioral rhythms, including delayed activity onset and circadian period lengthening, with altered SCN network activity. Together, these findings suggest that tonic, G protein-dependent regulation of GIRK channels provides a night-specific inhibitory mechanism that contributes to intrinsic diurnal neuronal excitability in Prok2 neurons and supports the regulation of behavioral circadian rhythms.Significance Statement In the mammalian suprachiasmatic nucleus, neuronal populations expressing distinct peptides interact through coordinated electrical activity to generate circadian rhythms. However, the ion channel mechanisms underlying diurnal rhythmicity of electrical activity in functionally distinct cell types remain incompletely understood. Here, using a comprehensive approach, we identify G protein-coupled inwardly rectifying potassium (GIRK) channels as a key determinant of nocturnal hyperpolarization in prokineticin 2 (Prok2)-expressing neurons, regulatory nodes involved in behavioral circadian rhythms. We further demonstrate that Prok2 neuron-specific loss of the GIRK3 subunit alters behavioral rhythms. These findings suggest that G protein-dependent regulation of GIRK channels is a key mechanism underlying diurnally patterned intrinsic electrical activity in Prok2 neurons and contributes to behavioral circadian rhythms.

Social isolation is an environmental stressor that can adversely affect behavioral function and neuroplasticity-related pathways. Brain-derived neurotrophic factor (BDNF) is one of the key molecules implicated in these changes. Lithium has been reported to influence neuroplasticity-related signaling and may modulate BDNF expression. In this study, we investigated the effects of lithium carbonate on behavioral alterations induced by chronic post-weaning social isolation in male rats and assessed BDNF mRNA expression in the prefrontal cortex. Rats were subjected to social isolation from postnatal day (PND) 21 to PND 70. Lithium carbonate (20 mg/kg, i.p.) was administered once daily during PND 64-70. Behavioral performance was evaluated using the open field test, hot plate test, marble burying test, and forced swim test. Compared with controls, socially isolated rats showed hyperlocomotion, increased rearing, lower pain threshold, altered immobility behavior in the forced swim test, obsessive-compulsive-like behavior, and reduced prefrontal BDNF mRNA expression. Lithium treatment attenuated several isolation-induced behavioral alterations and was accompanied by a partial reversal of reduced prefrontal BDNF mRNA expression toward control levels. Interpretation of molecular findings should be considered preliminary because gene expression analysis was conducted on a limited number of biological samples (n = 3 per group) and only BDNF mRNA, not BDNF protein, was measured. In conclusion, lithium carbonate improved several behavioral abnormalities associated with chronic social isolation and was associated with changes in prefrontal BDNF mRNA expression in male rats. Further studies are needed to clarify the molecular pathways and causal mechanisms underlying these effects.

Huntington's disease is a rare neurodegenerative movement disorder characterized by early disruption of frontostriatal systems, affecting motor, cognitive, and affective domains. Non-invasive brain stimulation targeting prefrontal networks may offer a means to modulate these distributed systems, although controlled evidence in Huntington's disease remains limited, particularly for accelerated stimulation protocols. To investigate whether accelerated intermittent theta-burst stimulation (iTBS) applied to the dorsolateral prefrontal cortex is associated with behavioral, motor and electrophysiological changes reflecting modulation of prefrontal network function in early-stage Huntington's disease. Ten patients with genetically confirmed Huntington's disease participated in a within-subject, fixed-order longitudinal study, which included a sham exposure phase followed by active stimulation. Assessments were conducted at baseline (T0), after sham stimulation (T1), after active accelerated iTBS (T2), and at 60-day follow-up (T3). Clinical scales for motor impairment, behavioral measures targeting executive, affective, and social-cognitive domains were combined with event-related potentials (ERPs) recorded during cognitive and emotional Stroop tasks. The fixed-order design was chosen to minimize potential carry-over effects associated with accelerated stimulation protocols. No significant behavioral or electrophysiological changes were observed during the sham exposure phase. In contrast, active iTBS was associated with domain-specific behavioral changes, particularly in affective, executive, and social-cognitive domains, accompanied by changes in event-related potential activity, particularly within delayed N200-related responses during emotional interference. Effects were domain-specific and were not associated with normalization of electrophysiological latency profiles. Motor scales were not modified by either sham or real stimulation. Accelerated prefrontal iTBS was associated with behavioral and electrophysiological changes following active stimulation of prefrontal network in Huntington's disease. These findings support the feasibility of targeting distributed non-motor circuits in HD and designs accounting for cumulative and time-dependent effects of stimulation in early-phase neuromodulation studies.

Depression remains a leading cause of disability worldwide, yet the predictive validity of many preclinical behavioral assays for antidepressant efficacy remains limited. The differential reinforcement of low-rate behavior (DRL) task has classically been used in rodents to identify antidepressant-like effects, but its utility in non-human primates (NHPs) has not been established. Here, we adapted the DRL task for use in adult male cynomolgus macaques (Macaca fascicularis) and evaluated its pharmacological sensitivity and translational relevance across 19 compounds spanning multiple drug classes. Antidepressants, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and phosphodiesterase-4 (PDE4) inhibitors, generally shifted DRL performance in an antidepressant-like direction, increasing reinforcers earned and inter-response times while decreasing response output. In contrast, benzodiazepine and antipsychotic control compounds did not produce a consistent antidepressant-like profile, whereas stimulant effects were mixed, with nicotine and cocaine also producing overlapping antidepressant-like behavioral effects. Importantly, the primate DRL task identified antidepressant-like effects of PDE4 inhibitors while also capturing emesis, a dose-limiting side effect not observable in rodent models. These findings support the primate DRL task as a translationally relevant platform for screening antidepressant-like efficacy, while also highlighting important design considerations for interpreting pharmacological sensitivity in the NHP setting. By modeling behavioral processes implicated in depression, including response inhibition and temporal regulation, this assay offers a unique opportunity to bridge preclinical and clinical antidepressant development with improved sensitivity to both efficacy and tolerability.

The paraventricular nucleus of the thalamus (PVT) has emerged as an important node in circuits regulating motivated behavior. The neuronal pathway from the lateral hypothalamus (LH) to the PVT has been shown to regulate arousal, feeding, and reward seeking. However, the involvement of the LH-PVT pathway in individual differences in cue-motivated behavior remains unclear. During a Pavlovian conditioned approach paradigm, when a reward is repeatedly preceded by the presentation of a cue, rats come to exhibit a conditioned response to the cue. One extreme of the population, sign-trackers (STs), approach and interact with the cue itself; while the other extreme, goal-trackers (GTs), approach the location of reward delivery. Intermediate responders (IRs) approach and interact with both the cue and reward location, without a preference. We utilized a Pavlovian conditioned approach paradigm in male rats to examine the effects of LH-PVT pathway inhibition on individual differences in cue-motivated behavior. A dual-vector approach was used to express inhibitory chemogenetic receptors in the LH-PVT pathway. We found that inhibition of the LH-PVT pathway selectively attenuates the expression of goal-tracking behavior, without affecting sign-tracking. This effect is driven primarily by IR rats, as inhibition of LH-PVT neurons attenuates goal-tracking behavior in IRs, without impacting the response of STs or GTs. We speculate that the flexibility of responding in IR rats made them especially vulnerable to this manipulation. These findings identify the LH-PVT pathway as a selective contributor to reward-directed conditioned responding and a circuit substrate for behavioral flexibility.Significance Statement Individuals differ in how reward-predictive cues motivate behavior, a feature linked to vulnerability and resilience to maladaptive reward seeking. The paraventricular thalamus (PVT), a midline hub with broad limbic connectivity, and its input from the lateral hypothalamus (LH) influences arousal, feeding, and reward seeking, but the role of the LH-PVT pathway in individual variability in cue-motivated behavior is unclear. We used chemogenetics to selectively suppress LH-PVT neurons during a Pavlovian conditioned approach paradigm. Inhibiting this projection reduced goal-tracking without altering sign-tracking, and this effect was driven primarily by intermediate responders, a phenotype characterized by behavioral flexibility. These results implicate LH-PVT signaling in reward-directed conditioned responding and suggest that this pathway contributes to flexible cue-motivated behavior.

Children with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) may be especially sensitive to early screen exposure due to sensory and emotional vulnerabilities. This study examined whether early screen time differentially affects behavioral trajectories in ASD, ADHD, and neurotypical children. Using data from the Longitudinal Study of Australian Children, linear mixed-effects models assessed outcomes. Screen time before age 2 was categorized as &#x2265;&#x2009;14 vs. <14&#xa0;h/week. Hyperactivity and emotional problems were measured at ages 4, 6, and 8, with ASD and ADHD diagnoses tested as moderators. ASD was linked to higher baseline hyperactivity and emotional problems and steeper increases in both outcomes over time. ADHD was associated with higher baseline hyperactivity and steeper symptom growth in hyperactivity and emotional problems over time. Greater early screen time was associated with steeper increases in emotional problems scores across all subgroups. However, no significant interaction between screen time, age, and diagnosis was found, indicating that screen exposure did not disproportionately worsen trajectories in ASD or ADHD compared to neurotypical peers. Early screen exposure is associated with a statistically significant but small increase in emotional problem scores but does not uniquely amplify risks in ASD or ADHD. While both conditions independently show steeper behavioral symptom growth, these patterns are not exacerbated by screen time. Findings support universal, rather than disorder-specific, screen time guidelines.

Stress-related psychiatric disorders are increasingly common conditions that are notoriously difficult to treat. Identifying the factors that increase the risk of these conditions and defining the biological mechanisms through which they promote the development of these disorders could inform disease pathophysiology and reveal novel therapeutic strategies to improve mental health. Clinical findings suggest that oral antibiotics increase the risk of depression and anxiety, but preclinical studies have had mixed results. Administering antibiotics to rodents has been reported to induce depression- or anxiety-like behavior in some studies but to protect against stress-induced increases in depression- and anxiety-like behavior in others. The reasons for these discrepancies are unclear. The current study examined the effects of antibiotics on stress susceptibility in a model of sub-chronic stress in male and female c57BL/6 mice. Following exposure to oral antibiotics and/or stress, mice were tested in a panel of behavioral assays prior to their brains being examined for potential changes in hippocampal neurogenesis and microglial number. Overall, our results indicate that antibiotics increased susceptibility to stress in several assays, and some of these effects were more pronounced in females than males. Exposure to antibiotics also reduced the proliferation of progenitor cells in the hippocampus of unstressed, but not stressed, animals of both sexes but did not significantly impact the number of microglia or immature neurons in the hippocampus. Future work should examine additional potential mechanisms through which antibiotics impact stress susceptibility and behavior in males and females.

Animals inhabiting aquatic or terrestrial habitats experience different constraints on their physiology and locomotion, and are exposed to fundamentally different sensory environments. Across evolutionary timescales, most species have adapted to live exclusively either in water or on land. Newts are among the vertebrates that defy this rule and split their adult lives between freshwater ponds and terrestrial habitats. In these amphibians, transitions across environments cause remarkable phenotypic plasticity in their body morphology. But whether and how the nervous system and behavior also adapt to these environmental changes remains poorly explored. Here, we establish the Iberian ribbed newt Pleurodeles waltl as a new model to study the neurobiology of environmental plasticity in a vertebrate. We first show that experimental transitions between aquatic and terrestrial laboratory settings recapitulate morphological changes observed in the wild. Furthermore, aquatic and terrestrial newts display plasticity in sensory and motor behaviors, including differences in walking gait and odor responsiveness. In the olfactory system, the transition from water to land involves a profound remodeling of the nasal epithelium, including reversible transcriptomic changes in secretory and support cells, and an increase of neurogenesis. Together, our findings reveal how plasticity of specific cell types in the nervous system supports behavioral adaptations across environments. More broadly, this work establishes newts as a model to study the functional constraints and convergent adaptations that may have shaped the evolution of vertebrate nervous systems in water and on land.

To examine factors contributing to attrition in a telehealth, caregiver-mediated behavioral intervention for young children with tuberous sclerosis complex (TSC). This randomized waitlist-control trial (n&#xa0;=&#x2009;59) included children (12-39&#x2009;months) with TSC and their caregivers. A convergent parallel mixed-methods design investigated factors influencing attrition. Quantitative analyses used negative binomial regression to explore predictors of session completion; qualitative data were thematically analyzed and integrated with quantitative patterns to complement and expand findings. Negative binomial regression did not yield a significant overall model and explained limited variance. Two candidate predictors showed exploratory associations with fewer completed sessions: higher seizure severity (incidence rate ratio [IRR]&#xa0;=&#xa0;0.95, p&#xa0;=&#x2009;0.046) and COVID-era enrollment (IRR&#xa0;=&#xa0;0.77, p&#xa0;=&#x2009;0.046). Distance to site and socioeconomic risk were not associated with attrition. Qualitative data reinforced medical crises as primary reasons for attrition and expanded on perceived benefit and other factors contributing to overall caregiver burden. In this clinical trial, socioeconomic, ethnic, and geographic factors were not associated with attrition, although the study was underpowered to detect small or moderate effects. Families of children facing complex developmental disability may nonetheless require additional adaptation and support to sustain engagement in telehealth caregiver-mediated interventions. Mixed-methods integration highlighted the multifaceted nature of attrition and the need for more precise measures to understand it.

Auditory processing is widely understood to occur differently in autism, though the patterns of brain activity underlying these differences are not well understood. The diversity of autism also means brain-wide networks may change in various ways to produce similar behavioral outputs. We used larval zebrafish to investigate auditory habituation in three genetic lines relevant to autism: fmr1, mecp2, and cntnap2 In free-swimming behavioral tests, we found each line had a unique profile of auditory hyper-responsiveness and/or reduced habituation compared to wild types. Combining the optical transparency of larval zebrafish with genetically encoded calcium indicators and light-sheet microscopy, we then observed brain-wide activity at cellular resolution during repeated sound stimuli. Each line showed unique alterations in brain-wide spontaneous activity, auditory processing, and adaptation in response to repetitive acoustic stimuli. We also observed commonalities in activity across our genetic lines that indicate shared circuit changes underlying certain aspects of their behavioral phenotypes. These were predominantly in regions involved in sensory integration and sensorimotor gating rather than primary auditory areas. Overlapping phenotypes include differences in the activity and functional connectivity of the telencephalon, dopaminergic regions, and the locus coeruleus. Unique phenotypes include increased activity in auditory regions and excitatory/inhibitory imbalance in the cerebellum in fmr1, and differences in network activity over time in mecp2 and cntnap2 Comparing these distinct but overlapping brain-wide auditory networks suggests that diverse genetic factors may contribute to similar behavioral effects through a range of circuit- and network-scale mechanisms.Significance statement Wilde et al. compare auditory habituation phenotypes in three genetic zebrafish models of autism. Of particular interest, several lines had overlapping behavioral phenotypes despite distinct patterns of brain-wide activity and network organization. Rather than pointing to a single mechanism underlying altered sensory responses, the data instead suggest there may be multiple neural routes to superficially similar sensory behaviors. This fits with growing discussions in human research that auditory processing in autism is unlikely to reflect one unified phenotype, but instead a diverse set of sensory profiles and underlying neural processes. Comparing across multiple genetic models and levels of neural organization may therefore help strengthen links between mechanistic animal work and the variability described in human sensory research in autism.

Parkinson patients suffer from levodopa-induced dyskinesia, which occur adversely to chronic dopaminergic treatment. These abnormal involuntary movements can only partly be actively suppressed and affect quality of life. A lowered motor inhibition during hyperdopaminergic states, associated with structural and plasticity changes in the cortico-basal-ganglia motor network, is hypothesized to enable dyskinesia. Multiple oscillatory cortico-subthalamic patterns associated with dyskinesia have been described but their dependence on behavioral states such as movement presence remains unknown, which is crucial for its use in real-life application of adaptive neuromodulation. We studied invasive cortico-subthalamic oscillations in 22 patients with Parkinson's disease during dyskinesia-evoking protocols. Clinical assessments differentiated between non-dyskinetic and dyskinetic periods, and kinematic monitoring detected movement presence, leading to four behavioral states containing rest, voluntary movements, movement suppression during dyskinesia, and dyskinetic movements. Data-driven methods reduced data dimensionalities and optimized frequency-specific signal-to-noise ratios in the neural recordings and allowed feature extraction of spectral magnitudes, variances, and inter-subthalamic and cortico-subthalamic coherences. Subthalamic theta-activity and attenuated beta-activity were elevated during both dyskinetic movement suppression and execution, while cortico-subthalamic gamma-activity was only increased during dyskinetic movement execution. The subthalamic oscillations predicted dyskinesia presence, but varying behavioral states containing fluctuating movement presence affected the predictive performance. Movement-aware classifications improved dyskinesia detection based on cortical and on gamma oscillations. Introducing a movement-aware classification which considered the current behavioral state improved the neural detection of therapeutic states. We propose movement execution during dyskinesia should be considered as a distinct behavioral and neural microstate within a dopamine-depending hyperdopaminergic macrostate. Integrating this state concept may inform future adaptive neuromodulation and enhance its naturalistic robustness during every-day life.

Neural encoding, decoding, and representation-learning approaches have substantially advanced our ability to predict sensory, behavioral, and cognitive variables from neural population activity. At the same time, dynamical systems approaches increasingly model neural computation as the evolution of latent population states governed by recurrent interactions and structured state transitions. Although these frameworks are often presented as competing paradigms, both can successfully reproduce neural observations while still failing to uniquely identify the computational mechanisms implemented by biological circuits. This perspective argues that this reflects a central unresolved challenge in systems neuroscience: observational recordings alone often provide insufficient constraints for distinguishing mechanistically valid neural dynamics from observationally equivalent alternatives. Accordingly, this perspective proposes a unifying framework integrating representational models, latent neural dynamics, identifiability analysis, and perturbation-based validation within a common mechanistic perspective. First, neural representations are discussed as potentially emerging from temporally localized projections of underlying latent dynamical processes evolving on low-dimensional manifolds. Second, recent advances in learning neural evolution operators using recurrent neural networks, latent state-space models, and dynamical system reconstruction methods are reviewed. Third, it is argued that latent trajectories and predictive performance alone do not guarantee mechanistic validity because multiple latent organizations and evolution operators may remain observationally equivalent despite implying distinct causal mechanisms. Finally, perturbation, intervention, and closed-loop neural interfaces are discussed as additional causal constraints capable of falsifying candidate dynamical explanations under targeted manipulation. Across these four principles, the central challenge in modern neuroscience is framed not simply as decoding neural activity or reconstructing latent trajectories, but as determining which inferred dynamical operators remain predictive under intervention and how perturbation can reduce the admissible class of observationally equivalent candidate mechanisms. From this perspective, evolution operators become experimentally testable hypotheses rather than purely descriptive latent models. Integrating latent dynamical modeling with perturbation-based validation may therefore support a transition from prediction-oriented neuroscience toward perturbation-constrained mechanistic dynamical neuroscience.

This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks. We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures. The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI). This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes.

Addiction is a heterogeneous disorder, and the specific psychological processes and neural mechanisms involved are hard to parse in humans. Animal models are useful in this regard, as biological substrates of addiction-relevant behaviors can be examined one at a time. Ventral pallidum GABAergic neurons (VPGABA), are key players in circuits underlying natural and drug reward, but the exact behavioral processes to which they contribute are still not precisely defined. Here we systematically examined the necessity of VPGABA neurons for opioid and food reward seeking and taking behaviors, using reversible chemogenetic inhibition in GAD1:Cre, predominately female, rats. We found that VPGABA inhibition revealed their preferential roles in highly-motivated pursuit and choice of heroin, but lesser involvement in unconditioned heroin effects, or in similarly motivated pursuit and choice of another rewarding opioid drug, remifentanil. Specifically, inhibiting VPGABA decreased cued- but not heroin-primed reinstatement of heroin seeking, decreased progressive ratio heroin pursuit, and increased selection of heroin over food when rats were forced to choose. In contrast, VPGABA inhibition did not alter remifentanil progressive ratio or choice of remifentanil over food, nor did it affect locomotion or food intake after heroin, or general arousal or anxiety-like states. These findings reveal a previously underappreciated specificity in the functions of VPGABA neurons, and show they may play distinct roles in overtly similar behaviors rewarded by different classes of opioid drugs. Results also highlight the usefulness, when investigating the biological substrates of addiction, of parsing heterogeneities not just in neural circuits, but also in the specific behavioral processes they mediate.Significance Statement Opioid addiction is a heterogeneous disorder, which makes it difficult to pinpoint the neural processes underlying its various components. Here we show that VPGABA neurons play surprisingly specific roles in behaviors relevant to opioid use disorder. VPGABA inhibition selectively reduced choice of heroin over food, highly-motivated heroin progressive ratio self-administration, and cue-triggered reinstatement, yet spared other heroin-induced behaviors. In contrast, closely matched behaviors motivated by the similarly-reinforcing fentanyl derivative remifentanil including choice of remifentanil over food, were spared. These results reveal unexpected reward- and process-specific functions of VPGABA neurons, highlighting the importance of comprehensive behavioral profiling in such experiments for identifying how neural mechanisms depend upon particular drugs and behavioral models-an essential step toward developing effective addiction interventions.

Epilepsy is the 4th most prevalent neurological condition with 50 million cases worldwide. Patients with epilepsy bare a disproportionate burden of cognitive decline and psychiatric disorders which remain poorly understood and go unaddressed by current anti-epileptic treatments. Furthermore, pre-clinical work on behavioral comorbidities can be hampered by current testing frameworks which rely on well-defined, discreet tests with limited repeatability. Recent work has demonstrated a role for machine learning modalities such as Motion Sequencing (MoSeq) in assessing behavioral differences between na&#xef;ve and epileptic. In this study we combined MoSeq with a novel analysis pipeline to uncover repetitive behaviors in chronically epileptic mice. These repetitive behaviors emerge alongside epilepsy specific racing behaviors which persist in epileptic mice as disease progresses. We show that epileptic mice have more fragile and dispersed behavioral networks. Finally, we test this pipeline using the FDA approved anti-seizure medication carbamazepine, showing a rescue of racing syllable and a partial rescue of behavioral network dispersion. Together, these results lay a groundwork for extracting clinically relevant phenotypes from MoSeq data throughout disease progression.

Theta-frequency transcranial alternating current stimulation (tACS) over prefrontal cortex has been proposed to modulate working memory (WM), yet behavioral effects are often inconsistent. One potential source of variability is the tACS phase during stimulus presentation. We tested whether behavioral performance during WM depends on the phase of prefrontal theta-tACS. Twenty participants completed two sessions of prefrontal 4 Hz tACS in a within-subject design, receiving active and sham stimulation in separate sessions. Participants performed a visuospatial change detection task (CDT) and a verbal N-back task. Stimulation effects on overall accuracy and reaction time were analyzed. Subsequently, phase-specific analyses related stimulation phase at task-relevant stimulus presentation to behavioral performance using circular regression models. Preferred phases across participants were tested using Rayleigh tests. No significant overall effects of active compared with sham tACS on accuracy or reaction time were observed in either task. However, phase-specific analyses revealed stronger phase-dependent modulation of reaction time during active tACS compared with sham. In the CDT, this effect was present across difficulty levels, whereas in the N-back task it was observed only in the 3-back condition. No reliable phase-dependent effects were observed for accuracy. Preferred phases varied across participants and did not cluster around a common phase. Prefrontal theta-tACS can modulate WM performance in a phase-dependent manner even in the absence of average behavioral effects. The observation of phase-dependent reaction-time modulation across visuospatial and verbal WM tasks suggests that stimulation phase may be a relevant source of variability across cognitive domains.

Oxytocin (OT) and vasopressin (VP) are evolutionarily conserved neuropeptides that regulate social behavior, emotional processing and physiological homeostasis. Although traditionally studied as individual modulators of affiliation, stress and autonomic function, emerging evidence indicates that their actions are best understood at the level of neural circuits. Advances in optogenetics, cell-type-specific electrophysiology and systems neuroscience have revealed that OT and VP act within distributed networks through receptor-defined microcircuits composed of excitatory and inhibitory neuronal populations, astrocytes and long-range projections. Within these circuits, OT and VP can exert complementary, synergistic or opposing effects depending on receptor localization, cellular identity and network state. Here, we synthesize recent circuit-level and electrophysiological evidence to propose a framework in which OT and VP operate as a coordinated neuromodulatory axis. We argue that the functional consequences of OT/VP signaling emerge not from peptide identity alone, but from their engagement of recurrent circuit motifs that redistribute excitation and inhibition across neural networks. These motifs provide a mechanistic substrate for regulating transitions between competing behavioral and physiological states, including social safety vs. threat, affiliation vs. avoidance, and parasympathetic vs. sympathetic dominance. We further discuss how disruption of receptor topology, synaptic integration and circuit architecture may contribute to neurodevelopmental, psychiatric and stress-related disorders. By shifting the focus from peptide-centric models to circuit-level mechanisms, this framework reconciles seemingly contradictory findings across brain regions and behavioral paradigms, and provides a foundation for the development of next-generation circuit-based therapeutic strategies targeting the oxytocin-vasopressin axis.

The touchscreen pairwise discrimination (PD) paradigm is a standardized behavioural assay for assessing cognition in rodents. PD performance is typically quantified by accuracy, but under disease models or pharmacological manipulations, accuracy alone may mask heterogeneity in behavioral strategies, limiting interpretation of the behavioral processes contributing to task performance. Here we introduced dynamic neutral images as reference stimuli to operationally compare two components of observed choice behavior: reward-guided selection of S+ and suppression of responding to S-. When the rewarded correct stimulus(S+) was paired with five different neutral images(S-), mice selected S+ in&#x202f;>&#x202f;80% of trials across all pairings. In contrast, when the unrewarded incorrect stimulus(S-) was paired with the same five neutral images(S+), selection of the incorrect stimulus was highly variable (20-60%). We then extended training in conditions in which the same non-rewarded stimulus was repeatedly presented against different rewarded stimuli. Extended training reduced incorrect-stimulus(S-) choices to&#x202f;<&#x202f;20%; however, when the incorrect stimulus(S-) was re-paired with neutral images(S+), incorrect-stimulus(S-) choice rebounded (20-40%), with mice preferentially choosing neutral images (60-80%). These results indicate that, under a reward-only contingency, high PD accuracy in healthy mice primarily reflects reinforced approach to S+ rather than suppression of responding to S-. Neutral reference patterns reveal behavioral basis of task performance and improve the interpretability and reliability of PD outcomes.