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Bagot, R. C.

Publications and source records attributed to Bagot, R. C..

12 recordsLinked to original sources

Shared Latent Decision Strategies Underlie Reward-Guided Behavior Across Species

Adaptive behavior requires that organisms learn which actions are rewarded and to update action selection when the environment changes. While human and non-human animals exhibit adaptive behavior, whether apparently similar behavior reflects common decision strategies remains unclear. Probabilistic reversal learning provides a cross-species assay of reward-guided choice, yet standard metrics such as accuracy or reward rate can obscure underlying strategies that generate choices. Here, we applied parallel probabilistic reversal learning tasks in mice and humans and used a generalized linear model-hidden Markov model to infer latent decision strategies from trial-by-trial behavior. Across species, choices were organized into stable behavioral states with differing reliance on choice history, reward history, and response bias. Among these latent states, we identify a conserved reward-learning strategy in mice and humans characterized by the greatest feedback sensitivity, reward efficiency, and adaptation after reversal. Simulating choice behavior using state-specific decision policies reproduced the empirical hierarchy of performance, confirming that the latent states capture meaningful behavioral strategies. Although mice and humans differ in the temporal dynamics of reward learning, both species ultimately converge on the same optimized strategy. These findings identify a conserved latent reward-learning strategy in mice and humans, defining a translational framework for studying how adaptive decision-making is shaped by task experience, stress, affective processes, and neural circuit function.

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Sex-specific exploration accounts for differences in valence learning in male and female mice

Valence, the quality by which something is perceived as good or bad, appetitive or aversive, is a fundamental building block of emotional experience and a primary driver of adaptive behavior. Pavlovian fear and reward learning paradigms are widely used in preclinical research to probe mechanisms of valence learning but with limited consideration of sex as a biological variable despite known sex differences in neuropsychiatric disorders associated with impaired valence. Here, we compare appetitive-only, aversive-only and mixed-valence cue-outcome Pavlovian conditioning paradigms in male and female mice to dissociate effects of context, valence and salience in a sex-specific manner. Using a data-driven approach to identify behaviors indicative of valence learning in an unbiased manner, we compare task performance between paradigms in male and female mice. We show that while male and female mice acquire appetitive and aversive associations in both single- and mixed-valence paradigms, sex differences emerge in single-valence paradigms. Ultimately, we show that these apparent sex differences in valence learning are driven by non-specific baseline differences in exploratory behavior. Males explore more at baseline, altering their trajectory of cue-reward association acquisition whereas females explore less at baseline, increasing shock facilitated freezing in aversive-only contexts, masking cue discrimination. Overall, our findings illustrate how task design differentially impacts behavioral expression in male and female mice and demonstrate that mixed-valence paradigms afford a more accurate assessment of valence learning in both sexes.

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Whole brain dimensional approach identifies shared and sex-specific networks of stress susceptibility in male and female mice.

Stress is a major risk factor for depression and anxiety, two highly comorbid disorders with sex differences in symptom presentation and prevalence. Accumulating evidence on the chronic variable stress (CVS) mouse model has revealed that stress susceptibility is sex-specific, as females require less stress exposure (6 days) compared to males (21-28 days) to develop comparable adaptations in depressive- and anxiety-like behaviors. However, the neuroanatomical changes associated with stress susceptibility remain unclear in each sex. Given this differential susceptibility, elucidating these mechanisms requires a phenotype-matched approach in which stress duration is titrated in a sex-specific manner to induce comparable behavioral adaptations. Here, we used a multi-variate brain-behavior and connectomic analysis to examine signatures of stress susceptibility in female and male mice. Using structural magnetic resonance imaging (MRI), we investigate whole-brain neuroanatomical changes associated with behavioral susceptibility within each sex. We then examined the structural connectome underlying neuroanatomical changes associated with behavioral susceptibility within each sex, and putative molecular basis for behaviorally-relevant changes using spatial gene expression analyses. CVS induced significant neuroanatomical changes in regions commonly implicated in anxiety- and depressive-like phenotypes in both sexes (e.g. nucleus accumbens and hippocampus); however qualitative differences between sexes in the direction of change were observed. In addition to these changes, in females stress-induced neuroanatomical changes were associated with both depressive- and anxiety-like behavior, whereas in males we observed two orthogonal dimensions of neuroanatomical changes associated with anxiety-like behavior or social preference. The connectomic topology underlying these brain-behavior dimensions revealed the cortical hub regions for females and subcortical hub regions for males. In females, neuroanatomical changes were associated with genes enriched for protein localization to the cell surface, suggesting alterations in cholinergic signaling By implementing a phenotype-matched CVS protocol, our findings indicate that the neuroanatomical signature of stress susceptibility encompasses similar brain regions across both sexes, however the direction of change, association to behavior and connectomic properties may differ in each sex.

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Single-cell sequencing reveals psilocybin induces sustained cell-type specific plasticity in mouse medial prefrontal cortex

Despite enormous interest in psychedelics for psychiatric interventions, potential underlying biological mechanisms remain unclear. Here, we confirm that a single dose of psilocybin increases synaptic transmission in mouse medial prefrontal cortex. Using scRNA-sequencing, we identify cell-type specific mechanisms of sustained neuroplastic effects. We show that, 24h post-psilocybin, expression of plasticity-related genes is increased in excitatory neurons and that transcription in a type of deep layer near projecting neuron, L5/6 NP, is robustly altered. Analyzing receptor expression patterns reveals that this cell-type specificity does not align with 5-HT2A expression but aligns with 5-HT2C expression patterns. Further, multivariate analyses identify psilocybin-induced gene expression patterns in L5/6 NP neurons predict 5-HT2C, but not 5-HT2A, transcript levels. Pharmacologic manipulation with a 5-HT2C antagonist attenuates the post-acute sustained effect of psilocybin on synaptic transmission, highlighting 5-HT2C signaling and L5/6 NP neurons as key mediators of psychedelic drug actions sustained neuroplastic effects in mPFC.

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Uncertainty gates redundancy in reward integration in prefrontal-cortical and ventral-hippocampal nucleus accumbens inputs to tune engagement

The NAc, a highly integrative brain region controlling motivated behavior, is thought to receive distinct information from various glutamatergic inputs yet strong evidence of functional specialization of inputs is lacking. While circuit neuroscience commonly seeks specific functions for specific circuits, redundancy can be highly adaptive and is a critical motif in circuit organization. Using dual-site fiber photometry in an operant reward task, we simultaneously recorded from two NAc glutamatergic afferents to assess circuit specialization. We identify a common neural motif that integrates reward history in medial prefrontal cortex (mPFC) and ventral hippocampus (vHip) inputs to NAc. Then, by systematically degrading task complexity, dissociating reward from choice and action, we identify key circuit-specificity in the behavioral conditions that recruit encoding. While mPFC-NAc invariantly encodes reward, vHip-NAc encoding is uniquely anchored to loss. Ultimately, using optogenetic stimulation we demonstrate that both inputs co-operatively modulate task engagement. We illustrate how similar encoding, with differential gating by behavioral state, supports state-sensitive tuning of reward-motivated behavior.

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Data-driven analysis identifies female-specific social modulation deficit after chronic social defeat stress

BackgroundChronic social defeat stress is a widely used depression model in male mice. Several proposed adaptations extend this model to females with variable, often marginal effects. We examine the if widely used male-defined metrics of stress are suboptimal in females and reveal sex-specific adaptations. MethodsUsing a data-driven method we comprehensively classified social interaction behavior in 761 male and female mice after chronic social witness/defeat stress, examining social modulation of behavioral frequencies and associations with conventional metrics (i.e., social interaction (SI) ratio). ResultsSocial stress induces distinct behavioral adaptation patterns in males and females. SI ratio leads to underpowered analyses in females with limited utility to differentiate susceptibility/resilience. Data-driven analyses reveal failure of social adaptation in stressed female mice that is captured in attenuated velocity change from no target to target tests ({Delta}Velocity) and validate this in three female social stress models. Combining SI ratio and {Delta}Velocity optimally differentiates susceptibility/ resilience in females and this metric reveals resilient-specific adaptation in a resilience-associated neural circuit in female mice. ConclusionsWe demonstrate that psychological or physical social defeat stress induces similar deficits in females that is qualitatively distinct from male deficits and inadequately sampled by male-defined metrics. We identify modulation of locomotion as a robust and easily implementable metric for rigorous research in female mice. Overall, our findings highlight the need to critically evaluate sex differences in behavior and implement sex-based considerations in preclinical model design.

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Prefrontal Cortex Astroglia Modulate Anhedonia-like Behavior

Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.

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Sexually dimorphic neural encoding of threat discrimination in nucleus accumbens afferents drives suppression of reward behavior

Learning to predict threat is essential but equally important yet often overlooked is learning about the absence of threat. Interrogating neural activity in two nucleus accumbens afferents in male and female mice during aversive and neutral cues reveals sex-specific encoding of cue discrimination and cuemediated suppression of reward behavior. Sexual dimorphisms in neural bases of threat discrimination may reflect sex differences in behavioral strategy relevant to differential psychiatric risk.

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Early or late gestational exposure to maternal immune activation alters neurodevelopmental trajectories in mice: an integrated neuroimaging, behavioural, and transcriptional study

Prenatal maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders. How gestational timing of MIA-exposure differentially impacts downstream development remains unclear. Here, we characterize neurodevelopmental trajectories of mice exposed to MIA induced by poly I:C either early (gestational day [GD]9) or late (GD17) in gestation using longitudinal structural magnetic resonance imaging from weaning to adulthood. Early MIA-exposure associated with accelerated brain volume increases in adolescence/early-adulthood that normalized in later adulthood, in regions including the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety, stereotypic, and sensorimotor gating behaviours observed in adolescence normalized in adulthood. In contrast, MIA-exposure in late gestation had less impact on anatomical and behavioural profiles. Using a multivariate technique to relate imaging and behavioural variables for the time of greatest alteration, i.e. adolescence/early adulthood, we demonstrate that variation in anxiety, social, and sensorimotor gating associates significantly with volume of regions including the dorsal and ventral hippocampus, and anterior cingulate cortex. Using RNA sequencing to explore the molecular underpinnings of region-specific alterations in early MIA-exposed mice in adolescence, we observed the most transcriptional changes in the dorsal hippocampus, with regulated genes enriched for fibroblast growth factor regulation, autistic behaviours, inflammatory pathways, and microRNA regulation. This indicates that MIA in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders. Our findings demonstrate the inherent strength of an integrated hypothesis- and data-driven approach in linking brain-behavioural alterations to the transcriptome to understand how MIA confers risk for major mental illness.

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Adolescent Social Isolation Reprograms the Medial Amygdala: Transcriptome and Sex Differences in Reward

Adolescence is a sensitive window for reward- and stress-associated behavior. Although stress during this period causes long-term changes in behavior in males, how females respond is relatively unknown. Here we show that social isolation stress in adolescence, but not adulthood, induces persistent but opposite effects on anxiety- and cocaine-related behaviors in male vs. female mice, and that these effects are reflected in transcriptional profiles within the adult medial amygdala (meA). By integrating differential gene expression with co-expression network analyses, we identified crystallin mu (Crym), a thyroid-binding protein, as a key driver of these transcriptional profiles. Manipulation of Crym specifically within adult meA neurons recapitulates the behavioral and transcriptional effects of social isolation and re-opens a window of plasticity that is otherwise closed. Our results establish that meA is essential for sex-specific responses to stressful and rewarding stimuli through transcriptional programming that occurs during adolescence.

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Early life stress alters transcriptomic patterning across reward circuitry in male and female mice

Abuse, neglect, and other forms of early life stress (ELS) significantly increase risk for psychiatric disorders including depression. In this study, we show that ELS in a postnatal sensitive period increases sensitivity to adult stress in female mice, consistent with our earlier findings in male mice. We used RNA-sequencing in the ventral tegmental area, nucleus accumbens, and prefrontal cortex of male and female mice to show that adult stress is distinctly represented in the brains transcriptome depending on ELS history. We identify: 1) biological pathways disrupted after ELS and associated with increased behavioral stress sensitivity, 2) putative transcriptional regulators of the effect of ELS on adult stress response, and 3) subsets of primed genes specifically associated with latent behavioral changes. We also provide transcriptomic evidence that ELS increases sensitivity to future stress through enhancement of known programs of cortical plasticity.

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Zfp189 Mediates Stress Resilience Through a CREB-Regulated Transcriptional Network in Prefrontal Cortex

Stress resilience involves numerous brain-wide transcriptional changes. Determining the organization and orchestration of these transcriptional events may reveal novel antidepressant targets, but this remains unexplored. Here, we characterize the resilient transcriptome with co-expression analysis and identify a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189-dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience.

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