Induction of deltaFosB in the periaqueductal gray by stress promotes active coping responses.
We analyzed the influence of the transcription factor DeltaFosB on learned helplessness, an animal model of affective disorder wherein a subset of mice exposed to inescapable stress (IS) develop a deficit in escape behavior. Repeated IS induces DeltaFosB in the ventrolateral periaqueductal gray (vlPAG), and levels of the protein are highly predictive of an individual's subsequent behavorial deficit-with the strongest DeltaFosB induction observed in the most resilient animals. Induction of DeltaFosB by IS predominates in substance P-positive neurons in the vlPAG, and the substance P gene, a direct target for DeltaFosB, is downregulated upon DeltaFosB induction. Local overexpression of DeltaFosB in the vlPAG using viral-mediated gene transfer dramatically reduces depression-like behaviors and inhibits stress-induced release of substance P. These results indicate that IS-induced accumulation of DeltaFosB in the vlPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses.
Berton
Olivier
O
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Covington
Herbert E
HE
Ebner
Karl
K
Tsankova
Nadia M
NM
Carle
Tiffany L
TL
Ulery
Paula
P
Bhonsle
Akshay
A
Barrot
Michel
M
Krishnan
Vaishnav
V
Singewald
Georg M
GM
Singewald
Nicolas
N
Birnbaum
Shari
S
Neve
Rachael L
RL
Nestler
Eric J
EJ
D000222:Adaptation, Physiological; D000223:Adaptation, Psychological / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D004924:Escape Reaction / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006380:Helplessness, Learned; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D009714:Nucleus Accumbens / Q000378:metabolism; D010487:Periaqueductal Gray / Q000166:cytology / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism
C483819:Fosb protein, mouse; C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; D013373:Substance P