The degree of behavioral control that an organism (rodent to human) can exert over an adverse event is arguably the most potent variable yet discovered that modulates the behavioral and neurochemical impact of that event. When the organism does have an element of control, the behavioral and neurochemical sequelae of the adverse event are blunted or eliminated. Research over the past grant period has indicated that control does so by activating ventral medial prefrontal cortical (vmPFC) top-down inhibitory control over stress- responsive limbic and brainstem structures. That is, when control is present, activation of stress-activated structures that are the proximate mediators of the behavioral changes, such as the dorsal raphe nucleus (DRN) &amygdala, is potently reduced. Importantly, research over the last part of the previous grant period has demonstrated that the experience of control not only blunts the impact of the stressor being controlled, but also blunts the impact of stressors experienced much later (at least one month), that is, control produces future resilience in the face of adversity. Moreover, preliminary evidence indicates that this occurs because the experience of control induces long-lasting plasticity in the vmPFC so that subsequent adverse events that would not normally induce vmPFC top-down inhibitory control, such as uncontrollable aversive events, now do so. Thus, the present proposal focuses on the vmPFC &its role in resilience and vulnerability. The research explores whether a) the vmPFC ic critical because it is part of a corticostriatal circuit;b) control confers long- term protection agaimnst stress because it induces plasticity in the corticostriatal circuit, and c) other manipualtions whih protect against stress effects also activate the corticostriatal circuit.

Public Health Relevance

Exposure to major adverse events has profound effects on organismic functioning, &is an important etiological factor in the development of psychiatric disorders. However, there are large individual differences in the impact of such experiences, &so it is vital to understand factors that promote either vulnerability or resilience. Recent evidene suggests that experiencing behavioral control over adverse events produces resilience in the face of future adversity, and the proposed research explores the brain mechanisms that lead to resilience.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH050479-21
Application #
8547820
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Simmons, Janine M
Project Start
1993-04-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
21
Fiscal Year
2013
Total Cost
$357,925
Indirect Cost
$120,584
Name
University of Colorado at Boulder
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
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Christianson, John P; Drugan, Robert C; Flyer, Johanna G et al. (2013) Anxiogenic effects of brief swim stress are sensitive to stress history. Prog Neuropsychopharmacol Biol Psychiatry 44:17-22
Rozeske, Robert R; Der-Avakian, Andre; Watkins, Linda R et al. (2012) Activation of the medial prefrontal cortex by escapable stress is necessary for protection against subsequent inescapable stress-induced potentiation of morphine conditioned place preference. Eur J Neurosci 35:160-5
Rozeske, Robert R; Evans, Andrew K; Frank, Matthew G et al. (2011) Uncontrollable, but not controllable, stress desensitizes 5-HT1A receptors in the dorsal raphe nucleus. J Neurosci 31:14107-15
Christianson, John P; Jennings, Joshua H; Ragole, Thomas et al. (2011) Safety signals mitigate the consequences of uncontrollable stress via a circuit involving the sensory insular cortex and bed nucleus of the stria terminalis. Biol Psychiatry 70:458-64
Strong, P V; Christianson, J P; Loughridge, A B et al. (2011) 5-hydroxytryptamine 2C receptors in the dorsal striatum mediate stress-induced interference with negatively reinforced instrumental escape behavior. Neuroscience 197:132-44
Rozeske, Robert R; Greenwood, Benjamin N; Fleshner, Monika et al. (2011) Voluntary wheel running produces resistance to inescapable stress-induced potentiation of morphine conditioned place preference. Behav Brain Res 219:378-81
Christianson, John P; Ragole, Thomas; Amat, Jose et al. (2010) 5-hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress. Biol Psychiatry 67:339-45
Amat, J; Aleksejev, R M; Paul, E et al. (2010) Behavioral control over shock blocks behavioral and neurochemical effects of later social defeat. Neuroscience 165:1031-8
Thompson, Brittany M; Baratta, Michael V; Biedenkapp, Joseph C et al. (2010) Activation of the infralimbic cortex in a fear context enhances extinction learning. Learn Mem 17:591-9

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