CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits.
Here, we characterized behavioral abnormalities induced by prolonged social isolation in adult rodents. Social isolation induced both anxiety- and anhedonia-like symptoms and decreased cAMP response element-binding protein (CREB) activity in the nucleus accumbens shell (NAcSh). All of these abnormalities were reversed by chronic, but not acute, antidepressant treatment. However, although the anxiety phenotype and its reversal by antidepressant treatment were CREB-dependent, the anhedonia-like symptoms were not mediated by CREB in NAcSh. We found that decreased CREB activity in NAcSh correlated with increased expression of certain K(+) channels and reduced electrical excitability of NAcSh neurons, which was sufficient to induce anxiety-like behaviors and was reversed by chronic antidepressant treatment. Together, our results describe a model that distinguishes anxiety- and depression-like behavioral phenotypes, establish a selective role of decreased CREB activity in NAcSh in anxiety-like behavior, and provide a mechanism by which antidepressant treatment alleviates anxiety symptoms after social isolation.
Wallace
Deanna L
DL
Department of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9070, USA.
Han
Ming-Hu
MH
Graham
Danielle L
DL
Green
Thomas A
TA
Vialou
Vincent
V
Iñiguez
Sergio D
SD
Cao
Jun-Li
JL
Kirk
Anne
A
Chakravarty
Sumana
S
Kumar
Arvind
A
Krishnan
Vaishnav
V
Neve
Rachael L
RL
Cooper
Don C
DC
Bolaños
Carlos A
CA
Barrot
Michel
M
McClung
Colleen A
CA
Nestler
Eric J
EJ
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000342:Affective Symptoms / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D050882:CREB-Binding Protein / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D007099:Imipramine / Q000494:pharmacology; D007763:Lac Operon; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009714:Nucleus Accumbens / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012726:Sexual Behavior, Animal / Q000187:drug effects / Q000502:physiology; D012934:Social Isolation
D018759:Adrenergic Uptake Inhibitors; D015221:Potassium Channels; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C494365:Crebbp protein, rat; D007099:Imipramine