Biology subjects

Salery, M.

Publications and source records attributed to Salery, M..

6 recordsLinked to original sources

bioRxiv2024

Sex-Specific Regulation of Stress Susceptibility by the Astrocytic Gene Htra1

Major depressive disorder (MDD) is linked to impaired structural and synaptic plasticity in limbic brain regions. Astrocytes, which regulate synapses and are influenced by chronic stress, likely contribute to these changes. We analyzed astrocyte gene profiles in the nucleus accumbens (NAc) of humans with MDD and mice exposed to chronic stress. Htra1, which encodes an astrocyte-secreted protease targeting the extracellular matrix (ECM), was significantly downregulated in the NAc of males but upregulated in females in both species. Manipulating Htra1 in mouse NAc astrocytes bidirectionally controlled stress susceptibility in a sex-specific manner. Such Htra1manipulations also altered neuronal signaling and ECM structural integrity in NAc. These findings highlight astroglia and the brains ECM as key mediators of sex-specific stress vulnerability, offering new approaches for MDD therapies.

neuroscience↗

bioRxiv2023

Transcriptional correlates of cocaine-associated learning in striatal ARC ensembles.

Learned associations between the rewarding effects of drugs and the context in which they are experienced underlie context-induced relapse. Previous work demonstrates the importance of sparse neuronal populations - called neuronal ensembles - in associative learning and cocaine seeking, but it remains unknown whether the encoding vs. retrieval of cocaine-associated memories involves similar or distinct mechanisms of ensemble activation and reactivation in nucleus accumbens (NAc). We use ArcCreERT2 mice to establish that mostly distinct NAc ensembles are recruited by initial vs. repeated exposures to cocaine, which are then differentially reactivated and exert distinct effects during cocaine-related memory retrieval. Single-nuclei RNA-sequencing of these ensembles demonstrates predominant recruitment of D1 medium spiny neurons and identifies transcriptional properties that are selective to cocaine-recruited NAc neurons and could explain distinct excitability features. These findings fundamentally advance our understanding of how cocaine drives pathological memory formation during repeated exposures.

neuroscience↗

bioRxiv2023

Dopaminoceptive D1 and D2 neurons in ventral hippocampus arbitrate approach and avoidance in anxiety

The hippocampus 1-7, as well as dopamine circuits 8-11, coordinate decision-making in anxiety-eliciting situations. Yet, little is known about how dopamine modulates hippocampal representations of emotionally-salient stimuli to inform appropriate resolution of approach versus avoidance conflicts. We here study dopaminoceptive neurons in mouse ventral hippocampus (vHipp), molecularly distinguished by their expression of dopamine D1 or D2 receptors. We show that these neurons are transcriptionally distinct and topographically organized across vHipp subfields and cell types. In the ventral subiculum where they are enriched, both D1 and D2 neurons are recruited during anxiogenic exploration, yet with distinct profiles related to investigation and behavioral selection. In turn, they mediate opposite approach/avoidance responses, and are differentially modulated by dopaminergic transmission in that region. Together, these results suggest that vHipp dopamine dynamics gate exploratory behaviors under contextual uncertainty, implicating dopaminoception in the complex computation engaged in vHipp to govern emotional states.

neuroscience↗

bioRxiv2022

Transcriptional control of nucleus accumbens neuronal excitability by Retinoid X Receptor Alpha tunes sensitivity to drug rewards

The complex nature of the transcriptional networks underlying addictive behaviors suggests intricate cooperation between diverse gene regulation mechanisms that go beyond canonical activity-dependent pathways. Here we implicate in this process a novel nuclear receptor transcription factor, Retinoid X Receptor Alpha (RXR), which we identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that, while its own expression remains unaltered after cocaine exposure, RXR controls plasticity- and addiction-relevant transcriptional programs in both dopamine receptor D1- and D2-expressing medium spiny neurons, which in turn modulate intrinsic excitability and synaptic activity of these NAc cell types. Behaviorally, bidirectional viral and pharmacological manipulation of RXR regulates drug reward sensitivity in both non-operant and operant paradigms. Together, this study demonstrates a key role for NAc RXR in promoting drug addiction, and paves the way for future studies of rexinoid signaling in psychiatric disease states.

neuroscience↗

bioRxiv2021

The Long Noncoding RNA FEDORA is a Cell-Type- and Sex-Specific Regulator of Depression

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify dramatic baseline sex differences in expression of long noncoding RNAs (lncRNAs) in human postmortem brain tissue that are profoundly lost in depression. One such lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and upregulated in several cortical regions of depressed females but not males. We found that virally-expressing FEDORA selectively either in neurons or in oligodendrocytes of prefrontal cortex promoted depression-like behavioral abnormalities in female mice only, changes associated with cell-type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic significance for depressed women. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

neuroscience↗

bioRxiv2018

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.

neuroscience↗