Inhibition of TRPV4 rescues impaired excitability and social deficits in NAc-specific Shank3-deficient mice.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139683 | GEO | 2022/10/01
REPOSITORIES: GEO
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Project description:The functional complexity of nucleus accumbens (NAc) has been extensively characterized in recent years. However, the molecular and cellular heterogeneity beyond the established D1 and D2 medium spiny neuron (MSN) subtypes, which likely underlie its diverse functions, are not well understand. Here, we present the cell taxonomy of mouse NAc generated from single-cell transcriptomic profiling, which not only reveals a rich cellular heterogeneity within both NAc MSN and interneuron populations, but also identified tight correlation between the transcriptional feature and spatial distribution of NAc neuron subtypes, supporting the notion that functional heterogeneity of NAc sub-regions can arises from differential distribution of molecularly distinct neuronal populations. To further test this idea, we focused on a D1 MSN subtype identified from our analysis and demonstrated that these cells possess distinct anatomic location, neural connection and more importantly, behavioral function. Collectively, our work not only created comprehensive cell taxonomy of NAc, but also provided insights into how functional heterogeneity is embedded in this brain region.
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Project description:∆FosB, a transcription factor that accumulates in nucleus accumbens (NAc) after exposure to virtually every known rewarding substance, has been shown to directly control gene transcription and behavior downstream of both cocaine and opioid exposure but with potentially different roles in D1 and D2 medium spiny neurons (MSNs). To clarify MSN subtype-specific roles for ∆FosB, and investigate how these subtypes coordinate the actions of distinct classes of addictive drugs, we developed a CRISPR/Cas9-based epigenome editing tool to induce endogenous ∆FosB expression in vivo in the absence of drug exposure and performed RNA-sequencing on bulk male and female NAc tissue.
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Project description:Opioid abuse produces enduring associations between the drug euphoria and features of the drug-taking experience, and these powerful associations can trigger relapse in individuals recovering from opioid use disorder. We show here that the epigenetic enzyme, histone deacetylase 5 (HDAC5), functions in the nucleus accumbens (NAc) during active heroin use to limit future relapse-like behavior. Moreover, enhancing HDAC5 function in NAc dramatically suppresses context-associated and reinstated heroin seeking behaviors, but it does not impact sucrose seeking. We also find that HDAC5 functions within dopamine D1 receptor-expressing medium spiny neurons (MSNs) to suppress cue-induced heroin seeking, but within dopamine D2 receptor-expressing MSNs to suppress drug-primed heroin seeking. Using cell type-specific transcriptomics analysis, we found that HDAC5 reduces expression of numerous genes linked to ion transport, and it decreases intrinsic excitability of NAc MSNs, suggesting that HDAC5 limits relapse vulnerability by suppressing NAc MSN firing rates during active heroin use. We used microarrays to define genes differentially expressed in the presence or absence of AAV2-DIO-HDAC5-3SA in both D1 and D2 cell-types derived from Nucleus accumbens following vTRAP.
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Project description:Use of addictive substances often creates powerful and enduring associations with external cues that act as relapse triggers in individuals recovering from a substance use disorder (SUD). In the reward-associated brain region, the nucleus accumbens (NAc), drug use or drug-associated cue exposure activates a subset of D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs), which typically promotes drug seeking, and a smaller subset of D2 dopamine receptor-expressing MSNs (D2-MSNs), which typically opposes drug seeking. The activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), is activated in a small subset of NAc neurons during cocaine conditioning, and NAc NPAS4 is required for drug-context memories. Using a new Npas4-TRAP mouse combined with chemogenetics, we found that the during cocaine conditioning, the NPAS4-positive ensemble is required for drug-context associations. Single-cell transcriptomic analyses and in situ hybridization of NAc tissues from drug-conditioned mice revealed that NPAS4 is expressed predominantly in MSNs, and using cell type-specific molecular genetic approaches, we found that NPAS4 in D2-MSNs, but not D1-MSNs, was required for both drug-context associations and cue-reinstated cocaine seeking. Similarly, NPAS4 in NAc D2-MSNs, but not D1-MSNs, blocked cocaine experience-dependent strengthening of glutamatergic prefrontal cortical (PFC) inputs onto D2-MSNs. Analysis of differential gene expression in D2-MSNs revealed that NPAS4 and cocaine conditioning influence a gene expression program associated with synapses, dendrites, neuronal projections, dopamine, and cocaine. Together, our data reveal that NPAS4 functions during active cocaine use to maintain the imbalance of D1-MSN:D2-MSN activation and cue-induced drug seeking by suppressing excitatory drive onto relapse-opposing NAc D2-MSN circuits.
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Project description:Isolation of cell populations is untangling complex biological interactions, but studies comparing methodologies lack in vivo complexity and draw limited conclusions about the types of transcripts identified by each technique. Furthermore, few studies compare FACS-based techniques to ribosomal affinity purification, and none do so genome-wide. We addressed this gap by systematically comparing nuclear-FACS, whole cell-FACS, and RiboTag affinity purification in the context of D1 or D2 dopamine receptor-expressing medium spiny neuron (MSN) subtypes of the nucleus accumbens (NAc), a key brain reward region. We find that nuclear-FACS-seq generates a substantially longer list of differentially expressed genes between these cell types, and a significantly larger number of neuropsychiatric GWAS hits than the other two methods. RiboTag-seq has much lower coverage of the transcriptome than the other methods, but very efficiently distinguishes D1- and D2-MSNs. We also demonstrate differences between D1- and D2-MSNs with respect to RNA localization, suggesting fundamental cell type differences in mechanisms of transcriptional regulation and subcellular transport of RNAs. Together, these findings guide the field in selecting the RNAseq method that best suits the scientific questions under investigation.
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Project description:The striatum is the interface between dopamine reward signals and cortico-basal ganglia circuits that mediate diverse behavioral functions. Medium spiny neurons (MSNs) constitute the vast majority of striatal neurons and are traditionally classified as direct- or indirect-pathway neurons. However, that traditional model does not explain the anatomical and functional diversity of MSNs. Here, we defined molecularly distinct MSN types in the primate striatum, including (1) dorsal striatum MSN types associated with striosome and matrix compartments, (2) ventral striatum types associated with the nucleus accumbens shell and olfactory tubercle, and (3) an MSN-like type restricted to mu-opioid receptor rich islands in the ventral striatum. These results lay the foundation for achieving cell type-specific transgenesis in the primate striatum and provide a blueprint for investigating circuit-specific processing.
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Project description:Shank3 is a postsynaptic protein that complexes with group 1 metabotropic, AMPA-, and NMDA-type glutamate receptors. Mutations of Shank3 are causal for Phelan-McDermid syndrome (PMS) and associated autism phenotypes. Individuals with PMS often exhibit sensitivity to novelty or stress that can result in behavioral deterioration. Here we use a Shank3 mouse model with face-validity to PMS [Shank(3∆C/+)] and perform a transcriptomic analysis of principal neurons from neocortex of mice subjected to brief swim stress. Analysis reveals overrepresented pathways related to synapses accompanied by elevated expression of the immediate early gene Homer1a. In normal brain Homer1a is dynamically expressed in association with motivated behavior and mediates an essential step in sleep-related homeostatic down-scaling of synaptic proteins. This is consistent with observations that synaptic Shank3 expression requires Homer cross-linking, which is interrupted by Homer1a. Accentuated Homer 1a expression in Shank3(∆C/+) results in marked reductions of Shank3 expression, changes in synapse composition and NMDA-dependent synaptic plasticity, and disruption of social motivation. Deletion of Homer1a partially mitigates stress-induced phenotypes in Shank3(∆C/+) mice. Homer 1a is required for developmental plasticity, learning and memory, yet its enhanced expression in Shank3(∆C/+) may underlie a vulnerability of PMS patients that highlights the challenge of clinical management.
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