Summary
Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here we performed RNA-sequencing on 4 brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery.
This comprehensive picture of transcriptome-wide regulation in the brain's reward circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.
Background
Repeated exposure to cocaine or social stress leads to lasting structural and functional synaptic alterations in medium spiny neurons (MSNs) of nucleus accumbens (NAc). While cocaine- and stress-induced structural changes in dendritic spines have been well-documented, few studies have investigated functional consequences of cocaine and stress at the level of single spines.
Methods
We exposed mice to chronic cocaine or chronic social defeat stress (CSDS) and used two-photon laser scanning microscopy with glutamate photouncaging and whole-cell recording to examine synaptic strength at individual spines on two distinct types of NAc MSNs in acute slices following 24 hours of cocaine withdrawal and following CSDS.
Results
In animals treated with cocaine, average synaptic strength was reduced specifically at large mushroom spines of dopamine receptor type 1-expressing MSNs (D1-MSNs). In contrast, cocaine promoted a rightward shift in the distribution of synaptic weights toward larger synaptic responses in MSNs expressing dopamine receptor type 2 (D2-MSNs). Surprisingly, following CSDS, resilient animals displayed an upregulation of synaptic strength at large mushroom spines of D1-MSNs and a concomitant downregulation in D2-MSNs. Though susceptible mice did not exhibit a significant overall change in synaptic strength on D1 or D2-MSNs, we observed a slight leftward shift in cumulative distribution of large synaptic responses in both cell types.
Conclusions
This study provides the first functional cell type- and spine type-specific comparison of synaptic strength at a single spine level between cocaine- and stress-induced neuroadaptations and demonstrates that psychoactive drugs and stress trigger divergent changes in synaptic function in NAc.
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