Extracellular Signal-Regulated Kinase-2 within the Ventral Tegmental Area Regulates Responses to Stress

Department of Psychology, Florida State University, Tallahassee, Florida 32306-4301, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2010; 30(22):7652-63. DOI: 10.1523/JNEUROSCI.0951-10.2010
Source: PubMed


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.

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Available from: Carlos A Bolaños, Mar 30, 2015
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    • "10 ) . Viral - mediated overexpression of the ERK2 isoform in rats was sufficient to increase anxiety on an elevated plus maze , and in mice resulted in enhanced susceptibility to social defeat stress . Blocking ERK2 activity was accompanied by reduced firing of VTA dopamine neurons , suggesting that ERK2 blockade may confer resiliency to stress ( Iniguez et al . , 2010 ) . PLCc1 in the VTA also has a prominent role in the regu - lation of anxiety - like behavior and sucrose preference ( Bolanos et al . , 2003 ) . Overexpression of PLCc1 produced two distinct behavioral phenotypes depending on the affected VTA subregion . PLCc1 overexpression in the rostral VTA increased reward preference for sucrose ,"
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