Stress-induced epigenetic regulation of transcription in neocortical excitatory neurons drives depression-like behavior

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Prolonged stress exposure is a major risk factor for the development of depression and comorbid anxiety. Efforts to understand how recurrent stress induces behavioral maladaptation have largely concentrated on the neuronal synapse with limited understanding of the underlying epigenetic mechanisms. Here, we performed complementary bulk nuclei- and single-nucleus transcriptome profiling and mapped fine-scale chromatin architecture in mice subjected to chronic unpredictable stress (CUS) to identify the cell type-specific epigenetic alterations that drive complex behavior. We find that neocortical excitatory neurons are particularly vulnerable to chronic stress and acquire signatures of transcription and chromatin configuration that denote reduced neuronal activity and expression of Yin Yang 1 (YY1). Selective ablation of YY1 in excitatory neurons of the prefrontal cortex (PFC) enhances stress sensitivity in mice, inducing depressive- and anxiety-related behaviors and deregulating the expression of stress-associated genes following an abbreviated stress exposure. Notably, we find that loss of YY1 in PFC excitatory neurons provokes more maladaptive behaviors in stressed females than males. These findings demonstrate how chronic stress provokes maladaptive behavior by epigenetically shaping excitatory neurons in the PFC, identifying a novel molecular target for therapeutic treatment of stress-related mood and anxiety disorders.</jats:p>

B cells and the stressed brain: emerging evidence of neuroimmune interactions in the context of psychosocial stress and major depression

“…Studies on the effects of stress exposure, and stress-associated hormonal signaling, on leukocyte adhesion mechanisms have yielded interesting observations (Ince et al, 2018). Following 12 days of chronic unpredictable stress, RNAseq data in prefrontal cortex revealed increased gene expression of Alcam in non-neuronal cell clusters as well as several types of inhibitory and excitatory neuronal populations (Kwon et al, 2022). Fifteen minutes of forced public speaking resulted in elevated LFA-1 on mixed lymphocytes, no impact to ICAM1 density, and a decrease in L-selectin on T cells (Goebel and Mills, 2000).…”

The dynamics of chromatin architecture in brain development and function

“…Gene expression changes have been reported in the neurons of sleep-deprived mice, but how these relate to chromatin organization and the underlying genetic factors remains to be investigated [46]. Studies on sex-specific effects of stress on the brain also show promising results [47]. For example, the fluctuating hormonal levels during the female oestrus cycle modify chromatin interactions between neuronal-specific genes and might help explain increased predisposition to anxiety and depression [48].…”