Abstract
Although the synaptic alterations associated with the stress-related mood disorder major depression has been well-documented, the underlying transcriptional mechanisms remain poorly understood. Here, we perform complementary bulk nuclei- and single-nucleus transcriptome profiling and map locus-specific chromatin interactions in mouse neocortex to identify the cell type-specific transcriptional changes associated with stress-induced behavioral maladaptation. We find that cortical excitatory neurons, layer 2/3 neurons in particular, are vulnerable to chronic stress and acquire signatures of gene transcription and chromatin structure associated with reduced neuronal activity and expression of Yin Yang 1 (YY1). Selective ablation of YY1 in cortical excitatory neurons enhances stress sensitivity in both male and female mice and alters the expression of stress-associated genes following an abbreviated stress exposure. These findings demonstrate how chronic stress impacts transcription in cortical excitatory neurons and identify YY1 as a regulator of stress-induced maladaptive behavior in mice.
Highlights
The synaptic alterations associated with the stress-related mood disorder major depression has been well-documented, the underlying transcriptional mechanisms remain poorly understood
We found that chronic unpredictable stress (CUS) males consumed significantly less food than controls, even when food consumption was normalized to body weight to account for weight loss (P < 0.01; Fig. 1c)
By performing a battery of behavioral tests and genome-wide sequencing of nuclear RNA transcripts with cellular precision, we report a role for Yin Yang 1 (YY1) in mediating CUS-induced phenotypes in neocortical excitatory neurons
Summary
The synaptic alterations associated with the stress-related mood disorder major depression has been well-documented, the underlying transcriptional mechanisms remain poorly understood. A number of structural and functional changes in PFC pyramidal neurons—the primary glutamatergic excitatory cells in this brain region—have been reported in animals experiencing sustained stress or chronic glucocorticoid exposure[14,15,16,17,18], and decreased grey matter volume[19,20], synapse number[21], and altered glutamate levels[22,23] in the PFC have been reported in MDD patients These findings, taken together, have led to a glutamate hypothesis of depression, which theorizes that the disruption of glutamateexcitatory neurotransmission in the PFC leads to PFC hypoactivity, dysfunction, and impaired emotional regulation. To probe the molecular mechanisms in the PFC that drive behavioral maladaptation to chronic stress, we performed complementary bulk and single-cell sequencing of nuclear RNA transcripts and mapped activity-dependent changes in chromatin architecture at a defined locus This multipronged approach reveals key transcriptional regulators and gene-regulatory networks in neocortical excitatory neurons that are altered by chronic stress exposure. These findings provide insight into the molecular processes that transpire within the nuclei of neocortical excitatory neurons to drive maladaptive transcriptional and behavioral responses to chronic stress
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