Extracellular signal-regulated kinase-2 within the ventral tegmental area regulates responses to stress.
Neurotrophic factors and their signaling pathways have been implicated in the neurobiological adaptations in response to stress and the regulation of mood-related behaviors. A candidate signaling molecule implicated in mediating these cellular responses is the extracellular signal-regulated kinase (ERK1/2), although its functional role in mood regulation remains to be fully elucidated. Here we show that acute (1 d) or chronic (4 weeks) exposure to unpredictable stress increases phosphorylation of ERK1/2 and of two downstream targets (ribosomal S6 kinase and mitogen- and stress-activated protein kinase 1) within the ventral tegmental area (VTA), an important substrate for motivated behavior and mood regulation. Using herpes simplex virus-mediated gene transfer to assess the functional significance of this ERK induction, we show that overexpressing ERK2 within the VTA increases susceptibility to stress as measured in the forced swim test, responses to unconditioned nociceptive stimuli, and elevated plus maze in Sprague Dawley male rats, and in the tail suspension test and chronic social defeat stress procedure in C57BL/6 male mice. In contrast, blocking ERK2 activity in the VTA produces stress-resistant behavioral responses in these same assays and also blocks a chronic stress-induced reduction in sucrose preference. The effects induced by ERK2 blockade were accompanied by decreases in the firing frequency of VTA dopamine neurons, an important electrophysiological hallmark of resilient-like behavior. Together, these results strongly implicate a role for ERK2 signaling in the VTA as a key modulator of responsiveness to stress and mood-related behaviors.
Department of Psychology, Florida State University, Tallahassee, Florida 32306-4301, USA.
Sergio D
SD
Iñiguez
Vincent
V
Vialou
Brandon L
BL
Warren
Jun-Li
JL
Cao
Lyonna F
LF
Alcantara
Lindsey C
LC
Davis
Zarko
Z
Manojlovic
Rachael L
RL
Neve
Scott J
SJ
Russo
Ming-Hu
MH
Han
Eric J
EJ
Nestler
Carlos A
CA
Bolaños-Guzmán
D000200:Action Potentials / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal / Q000502:physiology; D004291:Dominance-Subordination; D004597:Electroshock / Q000009:adverse effects; D004924:Escape Reaction / Q000502:physiology; D005518:Food Preferences / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D019417:Hindlimb Suspension / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity; D009474:Neurons / Q000502:physiology; D015514:Oncogene Proteins, Fusion; D010146:Pain / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor; D015398:Signal Transduction / Q000502:physiology; D018139:Simplexvirus / Q000502:physiology; D013315:Stress, Psychological / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013550:Swimming / Q000523:psychology; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000201:enzymology* / Q000473:pathology
C439709:FOP-FGFR1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D017468:Receptors, Fibroblast Growth Factor; D013549:Sweetening Agents; D049452:Green Fluorescent Proteins; D013395:Sucrose; D014446:Tyrosine 3-Monooxygenase; D019950:Mitogen-Activated Protein Kinase 1