Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models.
Although it is a widely studied psychiatric syndrome, major depressive disorder remains a poorly understood illness, especially with regard to the disconnect between treatment initiation and the delayed onset of clinical improvement. We have recently validated chronic social defeat stress in mice as a model in which a depression-like phenotype is reversed by chronic, but not acute, antidepressant administration. Here, we use chromatin immunoprecipitation (ChIP)-chip assays--ChIP followed by genome wide promoter array analyses--to study the effects of chronic defeat stress on chromatin regulation in the mouse nucleus accumbens (NAc), a key brain reward region implicated in depression. Our results demonstrate that chronic defeat stress causes widespread and long-lasting changes in gene regulation, including alterations in repressive histone methylation and in phospho-CREB (cAMP response element-binding protein) binding, in the NAc. We then show similarities and differences in this regulation to that observed in another mouse model of depression, prolonged adult social isolation. In the social defeat model, we observed further that many of the stress-induced changes in gene expression are reversed by chronic imipramine treatment, and that resilient mice-those resistant to the deleterious effects of defeat stress-show patterns of chromatin regulation in the NAc that overlap dramatically with those seen with imipramine treatment. These findings provide new insight into the molecular basis of depression-like symptoms and the mechanisms by which antidepressants exert their delayed clinical efficacy. They also raise the novel idea that certain individuals resistant to stress may naturally mount antidepressant-like adaptations in response to chronic stress.
Wilkinson
Matthew B
MB
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
Xiao
Guanghua
G
Kumar
Arvind
A
LaPlant
Quincey
Q
Renthal
William
W
Sikder
Devanjan
D
Kodadek
Thomas J
TJ
Nestler
Eric J
EJ
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use*; D001522:Behavior, Animal; D050882:CREB-Binding Protein / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003863:Depression / Q000188:drug therapy* / Q000473:pathology*; D004195:Disease Models, Animal; D004291:Dominance-Subordination; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D055106:Genome-Wide Association Study / Q000379:methods; D006657:Histones / Q000378:metabolism; D007099:Imipramine / Q000627:therapeutic use*; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000648:ultrastructure*; D012934:Social Isolation
D000929:Antidepressive Agents, Tricyclic; D002843:Chromatin; D006657:Histones; D050882:CREB-Binding Protein; D007099:Imipramine