DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses.
In contrast with the many studies of stress effects on the brain, relatively little is known about the molecular mechanisms of resilience, the ability of some individuals to escape the deleterious effects of stress. We found that the transcription factor DeltaFosB mediates an essential mechanism of resilience in mice. Induction of DeltaFosB in the nucleus accumbens, an important brain reward-associated region, in response to chronic social defeat stress was both necessary and sufficient for resilience. DeltaFosB induction was also required for the standard antidepressant fluoxetine to reverse behavioral pathology induced by social defeat. DeltaFosB produced these effects through induction of the GluR2 AMPA glutamate receptor subunit, which decreased the responsiveness of nucleus accumbens neurons to glutamate, and through other synaptic proteins. Together, these findings establish a previously unknown molecular pathway underlying both resilience and antidepressant action.
Vialou
Vincent
V
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.
Robison
Alfred J
AJ
Laplant
Quincey C
QC
Covington
Herbert E
HE
Dietz
David M
DM
Ohnishi
Yoshinori N
YN
Mouzon
Ezekiell
E
Rush
Augustus J
AJ
Watts
Emily L
EL
Wallace
Deanna L
DL
Iñiguez
Sergio D
SD
Ohnishi
Yoko H
YH
Steiner
Michel A
MA
Warren
Brandon L
BL
Krishnan
Vaishnav
V
Bolaños
Carlos A
CA
Neve
Rachael L
RL
Ghose
Subroto
S
Berton
Olivier
O
Tamminga
Carol A
CA
Nestler
Eric J
EJ
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002908:Chronic Disease; D004291:Dominance-Subordination; D005473:Fluoxetine / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D055500:Resilience, Psychological; D012201:Reward; D015398:Signal Transduction; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism*; D016896:Treatment Outcome
D000928:Antidepressive Agents; C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D005473:Fluoxetine; D018698:Glutamic Acid
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