title: AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli.
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.
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Vaishnav
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Michelle
authors.initials: M
authors.lastname: Mazei-Robison
authors.affiliation: Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee.
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Iñiguez
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Ables
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Vincent
authors.initials: V
authors.lastname: Vialou
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Olivier
authors.initials: O
authors.lastname: Berton
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Subroto
authors.initials: S
authors.lastname: Ghose
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Covington
authors.affiliation: Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wiley
authors.affiliation: Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee.
authors.forename: Ross P
authors.initials: RP
authors.lastname: Henderson
authors.affiliation: Harvard Medical School, McLean Hospital, Belmont, Massachusetts.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Eisch
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Tamminga
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.affiliation: Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bolaños
authors.affiliation: Departments of Psychiatry and Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: eric.nestler@utsouthwestern.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: 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*
chemical_list: D000928:Antidepressive Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt