Transcriptomic Evaluation of a Stress Vulnerability Network Using Single-Cell RNA Sequencing in Mouse Prefrontal...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Stress vulnerability is a key risk factor for mood disorders like major depressive disorder.
• Mechanisms underlying stress-induced depressive behaviors are known, but latent vulnerability mechanisms remain unclear.

Purpose of the Study:

• To identify cell types and transcriptomic differences associated with latent stress vulnerability.
• To investigate the molecular basis of brain states predisposing individuals to chronic stress damage.

Main Methods:

• Used in vivo neurophysiology in mice to measure brain network activity indicative of stress vulnerability.
• Combined neurophysiology with single-cell RNA sequencing of the prefrontal cortex to compare high and low vulnerability groups.

Main Results:

• Identified hundreds of differentially expressed genes across five cell types in high versus low stress vulnerability mice.
• GABAergic neuron gene expression and mitochondrial/metabolic pathways were key differentiators, particularly in inhibitory neurons.
• Vulnerability-associated genes overlapped significantly with genes linked to depression risk via GWAS and in patient postmortem brain tissue.

Conclusions:

• This study is the first to pinpoint specific cell types and genes involved in a latent brain state of stress vulnerability.
• Findings provide novel molecular targets for understanding and potentially treating stress-related mood disorders.