AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli.
BACKGROUND
The neurobiological mechanisms by which only a minority of stress-exposed individuals develop psychiatric diseases remain largely unknown. Recent evidence suggests that dopaminergic neurons of the ventral tegmental area (VTA) play a key role in the manifestation of stress vulnerability.


METHODS
Using a social defeat paradigm, we segregated susceptible mice (socially avoidant) from unsusceptible mice (socially interactive) and examined VTA punches for changes in neurotrophic signaling. Employing a series of viral vectors, we sought to causally implicate these neurotrophic changes in the development of avoidance behavior.


RESULTS
Susceptibility to social defeat was associated with a significant reduction in levels of active/phosphorylated AKT (thymoma viral proto-oncogene) within the VTA, whereas chronic antidepressant treatment (in mice and humans) increased active AKT levels. This defeat-induced reduction in AKT activation in susceptible mice was both necessary and sufficient to recapitulate depressive behaviors associated with susceptibility. Pharmacologic reductions in AKT activity also significantly raised the firing frequency of VTA dopamine neurons, an important electrophysiologic hallmark of the susceptible phenotype.


CONCLUSIONS
These studies highlight a crucial role for decreases in VTA AKT signaling as a key mediator of the maladaptive cellular and behavioral response to chronic stress.
Krishnan
Vaishnav
V
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Han
Ming-Hu
MH
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Mazei-Robison
Michelle
M
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Iñiguez
Sergio D
SD
Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee.
Ables
Jessica L
JL
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Vialou
Vincent
V
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Berton
Olivier
O
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Ghose
Subroto
S
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Covington
Herbert E
HE
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Wiley
Matthew D
MD
Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee.
Henderson
Ross P
RP
Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee.
Neve
Rachael L
RL
Harvard Medical School, McLean Hospital, Belmont, Massachusetts.
Eisch
Amelia J
AJ
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Tamminga
Carol A
CA
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Russo
Scott J
SJ
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
Bolaños
Carlos A
CA
Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee.
Nestler
Eric J
EJ
Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: eric.nestler@utsouthwestern.edu.
D000223:Adaptation, Psychological / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001362:Avoidance Learning / Q000502:physiology*; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004291:Dominance-Subordination; D015536:Down-Regulation; D004924:Escape Reaction / Q000502:physiology; D006801:Humans; D046353:Immobility Response, Tonic / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012919:Social Behavior; D018709:Statistics, Nonparametric; D013315:Stress, Psychological / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000378:metabolism*
D000928:Antidepressive Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt