title: Activation of a Habenulo-Raphe Circuit Is Critical for the Behavioral and Neurochemical Consequences of Uncontrollable Stress in the Male Rat.
abstract: Exposure to uncontrollable stress [inescapable tailshock (IS)] produces behavioral changes that do not occur if the stressor is controllable [escapable tailshock (ES)] an outcome that is mediated by greater IS-induced dorsal raphe nucleus (DRN) serotonin [5-hydroxytryptamine (5-HT)] activation. It has been proposed that this differential activation occurs because the presence of control leads to top-down inhibition of the DRN from medial prefrontal cortex (mPFC), not because uncontrollability produces greater excitatory input. Although mPFC inhibitory regulation over DRN 5-HT activation has received considerable attention, the relevant excitatory inputs that drive DRN 5-HT during stress have not. The lateral habenula (LHb) provides a major excitatory input to the DRN, but very little is known about the role of the LHb in regulating DRN-dependent behaviors. Here, optogenetic silencing of the LHb during IS blocked the typical anxiety-like behaviors produced by IS in male rats. Moreover, LHb silencing blocked the increase in extracellular basolateral amygdala 5-HT during IS and, surprisingly, during behavioral testing the following day. We also provide evidence that LHb-DRN pathway activation is not sensitive to the dimension of behavioral control. Overall, these experiments highlight a critical role for LHb in driving DRN activation and 5-HT release into downstream circuits that mediate anxiety-like behavioral outcomes of IS and further support the idea that behavioral control does not modulate excitatory inputs to the DRN.
authors: Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado 80309; Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado 80309.
authors: Samuel D
authors: 0000-0003-1279-0874
authors: SD
authors: Dolzani
authors: Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309.
authors: Michael V
authors: MV
authors: Baratta
authors: Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309.
authors: Jose
authors: J
authors: Amat
authors: Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309.
authors: Kara L
authors: 0000-0001-6194-4935
authors: KL
authors: Agster
authors: Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309.
authors: Michael P
authors: 0000-0002-0491-880X
authors: MP
authors: Saddoris
authors: Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309.
authors: Linda R
authors: LR
authors: Watkins
authors: Department of Psychology and Neuroscience and the Center for Neuroscience, University of Colorado Boulder , Boulder, Colorado 80309.
authors: Steven F
authors: 0000-0002-3370-6160
authors: SF
authors: Maier
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism; D066272:Basolateral Nuclear Complex / Q000378:metabolism; D065847:Dorsal Raphe Nucleus / Q000378:metabolism*; D004597:Electroshock; D019262:Habenula / Q000378:metabolism*; D008297:Male; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D062308:Optogenetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D012919:Social Behavior; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D012701:Serotonin
keywords: amygdala; habenula; optogenetics; raphe; serotonin; stress 