Biology subjects

Barik, J.

Publications and source records attributed to Barik, J..

8 recordsLinked to original sources

bioRxiv2026

Valence-specific ensembles in the laterodorsal tegmentum encode salient stimuli and modulate motivated behavior

The laterodorsal tegmentum (LDT) is a brainstem hub that integrates sensory and motivational signals to regulate adaptive behavior. While LDT neurons are known to modulate reward and aversion, whether salient stimuli recruit distinct neuronal ensembles within this structure remains unknown. Here, combined cell-type-specific calcium imaging, activity-dependent genetic tagging (TRAP2), and optogenetic reactivation to investigate how rewarding and aversive stimuli recruit and functionally define LDT neurons. Notably, single exposures to cocaine or shock in TRAP2;Ai14 mice labeled spatially and neurochemically distinct ensembles, with minimal overlap. We used fiber photometry and TRAP2 system to tag active neuronal ensembles in the LDT during cocaine (coca-LDT) and foot shock (shock-LDT) exposure, expressing GCaMP8m (green) in these neurons and, simultaneously, sRGECO (red) in the whole LDT. Our results demonstrate coca-LDT activation by physical aversive events and valenced odours, with reduced activity in response to rewarding liquids. Shock-LDT showed activation by physical aversive events, odours, and shock-predictive cues. Additionally, optogenetic reactivation of cocaine-TRAPed ensembles in a two-choice operant task biased action selection toward stimulation-paired responses, whereas shock-TRAPed ensemble activation did not drive avoidance. These findings identify functionally segregated LDT ensembles recruited by opposing motivational stimuli and reveal a causal role for reward-activated brainstem ensembles in shaping behavior. This functional segregation may contribute to the brains ability to differentiate stimulus types and, to some extent, valence experiences. Our results may provide evidence on how the LDT influences decision-making processes in addiction and anxiety disorders, potentially paving the way for novel therapeutic approaches.

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bioRxiv2026

Reinforced Hippocampus-Accumbens pathway marks a shift towards cognitive decline in aging

Aging triggers early functional alterations in brain circuits that precede cognitive impairment, yet the underlying mechanisms remain unclear. Spatial navigation and memory, among the earliest affected, depend on hippocampus and downstream targets such as the nucleus accumbens (NAc), which integrates spatial and motivational information to guide goal-directed behaviors. Here we identify age-related, sex-dependent changes of the dorsal hippocampus-NAc (dHPC[->]NAc) pathway. Combining optogenetics with electrophysiology, chemogenetics, and behavioral analyses in mice, we show that aging shifts excitation-inhibition balance in dorsal CA1 toward pyramidal neuron hyperexcitability, strengthening hippocampal outputs. This selectively enhances synaptic drive onto D1 receptor-expressing medium spiny neurons and involves a previously unrecognized long-range parvalbumin-expressing glutamatergic projection. Reducing dHPC[->]NAc excitability improves memory in aged mice. In humans, fMRI reveals heightened posterior hippocampal activity and stronger pHPC-NAc coupling during navigation. Together, we uncover a targetable pathway acting in an intervention-sensitive window of aging to correct negative cognitive trajectories.

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bioRxiv2025

A role for prefrontal dopamine signaling in control of goal-directed actions

Impairments in behavioral flexibility commonly found across psychiatric disorders have often been attributed to a dysfunction of the medial prefrontal cortex (mPFC), notably in relation with altered dopamine transmission. However, how dopamine transmission shapes neuronal activity in the mPFC to allow adapting to a changing situation remains largely elusive. Here, we show that dopamine dynamics in the mPFC encode the value of instrumental actions, in particular during reversal learning. Such signal shapes the activity of mPFC dopaminoceptive neurons during reversal learning through the recruitment of heteromers formed by dopamine D1 and D2 receptors with NMDA receptors. In accordance, blockade of either D1/NMDA or D2/NMDA heteromers in the mPFC selectively impairs reversal of outcome identities but not learning and expression of initial action-outcome associations. Our findings provide mechanistic evidence for a central role of dopamine in the mPFC to allow updating goal-directed actions.

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bioRxiv2025

Cortico-striatal dynamics across working memory stages

Working memory depends on the temporary retention and manipulation of information, bridging the gap between short-term memory and information processing functions. However, when the same working memory task is repeated over several days, it raises the question of whether the rule or task set becomes automated (or proceduralized). The medial prefrontal cortex (mPFC) is crucial for working memory. Yet, the role of the dorsolateral striatum (DLS) in the automation (proceduralization) of rules or task sets remains to be clarified. Using a longitudinal approach of the "delay non-match to place" (DNMP) task in a T-maze combined to chemogenetic inhibition of the mPFC or DLS in mice, we show that the mPFC becomes less critical in the maintenance phase of the task as behaviour progressively shifts toward automation. During this phase, the DLS facilitates automated processing. Accordingly, silencing through chemogenetic inhibition of the DLS during maintenance triggers an adaptation in learning strategies, reactivating a goal-directed behaviour. Our findings strengthen memory traces as a dynamic reorganization of neural networks, challenging the classical view of information migration between brain structures. We here propose that the memory trace remains in a dormant state--less energy-consuming for the system--while still allowing for rapid flexibility in case of task modification.

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bioRxiv2025

Adaptive changes of cholinergic projections to the nucleus accumbens bidirectionally mediate cocaine reinforcing effects

The laterodorsal tegmentum (LDT) sends critical inputs to distinct reward circuit regions, including the nucleus accumbens (NAc), but their functional role in addiction-related behaviors remains underexplored. Here, we demonstrate that LDT-NAc cholinergic projections undergo cocaine-induced adaptations and modulate cocaine-related behaviors. Using cell type-specific tracing, we show that LDT neurons preferentially innervate NAc medium spiny neurons and cholinergic interneurons. Large-scale in vivo recordings reveal that cocaine pre-exposure induces persistent alterations in both LDT and NAc neuronal dynamics and modifies responses to subsequent cocaine challenge. Remarkably, pre-exposure to cocaine triggers population-specific adaptations in the LDT, selectively enhancing excitability of LDT-NAc-projecting cholinergic neurons while reducing that of non-projecting cholinergic cells. Behaviorally, optogenetic activation of LDT-NAc cholinergic projections enhances cocaine conditioning, whereas their inhibition diminishes cocaines reinforcing effects. Our findings identify LDT-NAc cholinergic inputs as key substrates of cocaine-induced plasticity, and critical mediators of cocaines rewarding properties, introducing a novel component to addiction circuitry.

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bioRxiv2023

Nicotine in adolescence freezes dopamine circuits in an immature state

Nicotine use during adolescence is largely associated with negative long-term outcomes, including addiction to nicotine in adulthood. How nicotine acts on developing neurocircuitry in adolescence remains largely unknown, but may hold the key for informing more effective intervention efforts. We found transient nicotine exposure in early adolescence was sufficient for adult mice to show a marked vulnerability to nicotine. Brain-wide activity mapping showed that these mice had an enhanced response to an acute nicotine injection and widespread disruption of functional connectivity in comparison to controls, particularly within dopaminergic networks. Neurophysiological analysis further revealed that their ventral tegmental area (VTA) dopamine neurons show an immature basal plasticity signature and an adolescent-like imbalance in nicotine-induced activity between nucleus accumbens (NAc) and amygdala (AMG)-projecting pathways, known to respectively produce the reinforcing and anxiogenic effects of nicotine. The anxiogenic effect of nicotine is abolished in adult mice treated with nicotine in adolescence, strongly resembling the normal phenotype of young mice. Together these results suggest that nicotine exposure in adolescence somehow "froze" both their neural circuit and behavioral reaction to nicotine, carrying an adolescent-like vulnerability to the drug into adulthood. Finally, we are able to "thaw" the behavioral response to acute nicotine in adolescent-exposed mice by chemogenetically resetting the balance between the underlying NAc- and AMG-projecting dopamine circuits, restoring a mature anxiety-like response to acute nicotine. Together, our results highlight how diverse dopamine pathways can be impacted by experience in adolescence, and further suggest that the perseverance of a developmental imbalance between dopamine pathways may alter vulnerability profiles for later dopamine-dependent psychopathologies.

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bioRxiv2021

SWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress

Stress exposure is a cardinal risk factor for most psychiatric diseases. Preclinical and clinical studies point to changes in gene expression involving epigenetic modifications within mesocorticolimbic brain circuits. Brahma (BRM) and Brahma-Related-Gene-1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that repeated social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.

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bioRxiv2020

Gut microbial metabolite p-Cresol promotes autistic-like behaviors in mice through remodeling of the microbiota

BackgroundAutism Spectrum Disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis resulting in changes in microbiota composition as well as fecal, serum and urine levels of microbial metabolites. Yet, a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. ResultsMice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol levels compared to mice transplanted with the microbiota of control mice and identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. ConclusionsThe microbial metabolite p-Cresol induces ASD core behavioral symptoms in mice via a gut microbiota-dependent mechanism. Our study paves the way for therapeutic interventions targeting the microbiota to treat patients with ASD.

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