Behavior, BDNF and epigenetic mechanisms in response to social isolation and social support in middle aged rats exposed to chronic stress

Social deprivation can be stressful for group-living mammals. On the other hand, an amazing response of these animals to stress is seeking social contact to give and receive joint protection in threatening situations. We explored the effects of social isolation and social support on epigenetic and behavioral responses to chronic stress. More specifically, we investigated the behavioral responses, corticosterone levels, BDNF gene expression, and markers of hippocampal epigenetic alterations (levels of H3K9 acetylation and methylation, H3K27 methylation, HDAC5, DNMT1, and DNMT3a gene expressions) in middle-aged adult rats maintained in different housing conditions (isolation or accompanied housing) and exposed to the chronic unpredictable stress protocol (CUS). Isolation was associated with decreased basal levels of corticosterone, impaired long-term memory, and decreased expression of the BDNF gene, besides altering the balance of H3K9 from acetylation to methylation and increasing the DNMT1 gene expression. The CUS protocol decreased H3K9 acetylation, besides increasing H3K27 methylation and DNMT1 gene expression, but had no significant effects on memory and BDNF gene expression. Interestingly, the effects of CUS on corticosterone and HDAC5 gene expression were seen only in isolated animals, whereas the effects of CUS on DNMT1 gene expression were more pronounced in isolated than accompanied animals. In conclusion, social isolation in middle age showed broader effects than chronic un-predictable stress on behavioral and epigenetic alterations potentially associated with decreased BDNF expres-sion. Moreover, social support prevented the adverse effects of CUS on HPA axis functioning, HDAC5, and DNMT1 gene expressions.

Automated summary

Social deprivation can cause stress in group-living mammals, but they have an amazing response of seeking social contact as a form of protection. This study explored the effects of social isolation and support on behavioral and epigenetic responses to chronic stress in middle-aged adult rats. The results showed that isolation led to decreased corticosterone levels, impaired long-term memory, and decreased BDNF gene expression, along with altered epigenetic markers. The chronic unpredictable stress protocol had different effects, mainly on epigenetic alterations, but social support prevented the adverse effects on HPA axis functioning and gene expressions.