Social defeat induces changes in histone acetylation and expression of histone modifying enzymes in the ventral hippocampus, prefrontal cortex, and dorsal raphe nucleus

Abstract

Chronic exposure to stress is associated with a number of psychiatric disorders, but little is known about the epigenetic mechanisms that underlie the stress response or resilience to chronic stress. We investigated histone acetylation in seven different brain regions of rats exposed to chronic social defeat stress: the dorsal hippocampus (dHPC), ventral hippocampus (vHPC), medial prefrontal cortex (mPFC), basolateral amygdala (BLA), locus coeruleus (LC), paraventricular thalamus (PVT), and dorsal raphe (DR) nucleus. This stress paradigm was unique in that it allowed rats to display resilience in the form of an active coping mechanism. We found that there was an increase in acetylation of H3K9/14 (H3K9/14ac) and bulk acetylation of H4K5,8,12,16 (H4K5,8,12,16ac) in the DR nucleus of rats that were less resilient. Less resilient rats also displayed increased levels of H3K18 acetylation (H3K18ac) in the mPFC when compared to non-stressed controls. In the vHPC, there was an increase in H3K18ac and H4K12 (H4K12ac) in rats that were less resilient when compared to non-stressed control rats. In addition, there was a decrease in levels of H4K8 acetylation (H4K8ac) in both resilient and non-resilient rats as compared to controls. We assessed expression of histone modifying enzymes in the vHPC and the mPFC using quantitative real-time polymerase chain reaction (PCR) and found changes in expression of a number of targets. These included changes in Sirt1 and Sirt2 in the vHPC and changes in Kat5 in the mPFC. Overall, these results suggest that changes in histone acetylation and expression of histone modifying enzymes in these regions correlate with the behavioral response to stress in socially defeated rats.