AKT Signaling within the Ventral Tegmental Area Regulates Cellular and Behavioral Responses to Stressful Stimuli

Vaishnav Krishnan, Ming Hu Han, Michelle Mazei-Robison, Sergio D. Iñiguez, Jessica L. Ables, Vincent Vialou, Olivier Berton, Subroto Ghose, Herbert E. Covington, Matthew D. Wiley, Ross P. Henderson, Rachael L. Neve, Amelia J. Eisch, Carol A. Tamminga, Scott J. Russo, Carlos A. Bolaños, Eric J. Nestler

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)691-700
Number of pages10
JournalBiological Psychiatry
Volume64
Issue number8
DOIs
StatePublished - Oct 15 2008

Keywords

  • Depression
  • PTSD
  • mesolimbic dopamine
  • resilience
  • social defeat
  • vulnerability

ASJC Scopus subject areas

  • Biological Psychiatry

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