Serum response factor promotes resilience to chronic social stress through the induction of DeltaFosB.
The molecular mechanisms underlying stress- and drug-induced neuronal adaptations are incompletely understood. One molecule implicated in such adaptations is ΔFosB, a transcription factor that accumulates in the rodent nucleus accumbens (NAc), a key brain reward region, in response to either chronic stress or repeated exposure to drugs of abuse. The upstream transcriptional mechanisms controlling ΔFosB induction by these environmental stimuli remain elusive. Here, we identify the activity-dependent transcription factor, serum response factor (SRF), as a novel upstream mediator of stress-, but not cocaine-, induced ΔFosB. SRF is downregulated in NAc of both depressed human patients and in mice chronically exposed to social defeat stress. This downregulation of SRF is absent in resilient animals. Through the use of inducible mutagenesis, we show that stress-mediated induction of ΔFosB, which occurs predominantly in resilient mice, is dependent on SRF expression in this brain region. Furthermore, NAc-specific genetic deletion of SRF promotes a variety of prodepressant- and proanxiety-like phenotypes and renders animals more sensitive to the deleterious effects of chronic stress. In contrast, we demonstrate that SRF does not play a role in ΔFosB accumulation in NAc in response to chronic cocaine exposure. Furthermore, NAc-specific knock-out of SRF has no effect on cocaine-induced behaviors, indicating that chronic social defeat stress and repeated cocaine exposure regulate ΔFosB accumulation and behavioral sensitivity through independent mechanisms.
Vialou
Vincent
V
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
Maze
Ian
I
Renthal
William
W
LaPlant
Quincey C
QC
Watts
Emily L
EL
Mouzon
Ezekiell
E
Ghose
Subroto
S
Tamminga
Carol A
CA
Nestler
Eric J
EJ
D000328:Adult; D000368:Aged; D000818:Animals; D000928:Antidepressive Agents / Q000097:blood; D001007:Anxiety / Q000378:metabolism / Q000523:psychology; D015153:Blotting, Western; D003042:Cocaine / Q000494:pharmacology; D003863:Depression / Q000378:metabolism / Q000523:psychology; D005260:Female; D006380:Helplessness, Learned; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D055500:Resilience, Psychological / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026362:Serum Response Factor / Q000235:genetics / Q000502:physiology*; D012919:Social Behavior; D012931:Social Environment; D013315:Stress, Psychological / Q000523:psychology*
D000928:Antidepressive Agents; C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D026362:Serum Response Factor; D003042:Cocaine