title: Essential Role of Mesolimbic Brain-Derived Neurotrophic Factor in Chronic Social Stress-Induced Depressive Behaviors.
abstract: Previous work has shown that chronic social defeat stress (CSDS) induces increased phasic firing of ventral tegmental area (VTA) dopamine (DA) neurons that project to the nucleus accumbens (NAc) selectively in mice that are susceptible to the deleterious effects of the stress. In addition, acute optogenetic phasic stimulation of these neurons promotes susceptibility in animals exposed to acute defeat stress. These findings are paradoxical, as increased DA signaling in NAc normally promotes motivation and reward, and the influence of chronic phasic VTA firing in the face of chronic stress is unknown.
  
  
  
  We used CSDS with repeated optogenetic activation and pharmacologic manipulations of the mesolimbic VTA-NAc pathway to examine the role of brain-derived neurotrophic factor (BDNF) and DA signaling in depressive-like behaviors. We measured BDNF protein expression and DA release in this model.
  
  
  
  Pharmacologic blockade of BDNF-tyrosine receptor kinase B (TrkB) signaling, but not DA signaling, in NAc prevented CSDS-induced behavioral abnormalities. Chronic optogenetic phasic stimulation of the VTA-NAc circuit during CSDS exacerbated the defeat-induced behavioral symptoms, and these aggravated symptoms were also normalized by BDNF-TrkB blockade in NAc. The aggravated behavioral deficits induced by phasic stimulation of the VTA-NAc pathway were blocked as well by local knockdown of BDNF in VTA.
  
  
  
  These findings show that BDNF-TrkB signaling, rather than DA signaling, in the VTA-NAc circuit is crucial for facilitating depressive-like outcomes after CSDS and they establish BDNF-TrkB signaling as a pathologic mechanism during periods of chronic stress.
authors: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neural Development and Disease, Korea Brain Research Institute, Daegu, Republic of Korea.
authors: Ja
authors: J
authors: Wook Koo
authors: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Benoit
authors: B
authors: Labonté
authors: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Olivia
authors: O
authors: Engmann
authors: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: eric.nestler@mssm.edu.
authors: Erin S
authors: ES
authors: Calipari
authors: Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Barbara
authors: B
authors: Juarez
authors: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Zachary
authors: Z
authors: Lorsch
authors: Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Jessica J
authors: JJ
authors: Walsh
authors: Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Allyson K
authors: AK
authors: Friedman
authors: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors: Jordan T
authors: JT
authors: Yorgason
authors: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Ming-Hu
authors: MH
authors: Han
authors: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Eric J
authors: EJ
authors: Nestler
mesh_terms: D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003042:Cocaine / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003863:Depression / Q000503:physiopathology* / Q000523:psychology*; D004298:Dopamine / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D009434:Neural Pathways / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020813:Receptor, trkB; D012457:Salicylamides / Q000008:administration & dosage / Q000494:pharmacology; D012919:Social Behavior; D013315:Stress, Psychological / Q000503:physiopathology*; D017557:Ventral Tegmental Area / Q000502:physiology*
chemical_list: C559317:ANA 12 compound; D001381:Azepines; D001549:Benzamides; D001552:Benzazepines; D019208:Brain-Derived Neurotrophic Factor; C534628:SCH 23390; D012457:Salicylamides; C000621230:Ntrk2 protein, rat; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; D003042:Cocaine; C045989:eticlopride; D004298:Dopamine
keywords: BDNF; Chronic defeat stress; Dopamine; Nucleus accumbens; Social avoidance; Ventral tegmental area