AKT Signaling within the Ventral Tegmental Area Regulates Cellular and Behavioral Responses to Stressful Stimuli
Received 15 April 2008; received in revised form 2 June 2008; accepted 2 June 2008. published online 21 July 2008.
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.
aDepartments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas
bDepartment of Psychology and Program in Neuroscience, Florida State University, Tallahassee
cHarvard Medical School, McLean Hospital, Belmont, Massachusetts
Address reprint requests to Eric J. Nestler, M.D., Ph.D., Departments of Psychiatry and Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390
ABSTRACT