Exposure to stressful events can precipitate and/or exacerbate various types of affective disorders such as depression and anxiety. Physical activity increases stress resistance and reduces depression and anxiety. For example, voluntary freewheel running increases stress resistance and conveys antidepressant/anxiolytic effects in various animal models of affective dysregulation, including """"""""learned helplessness"""""""" (LH). LH is an acute behavioral state produced after exposure to uncontrollable, but not controllable, stress. Evidence suggests that LH is due to activation of a neural circuit that produces intense stimulation of serotonin (5HT) neurons of the dorsal raphe nucleus (DRN). This intense 5HT drive results in sensitization of the DRN 5HT system. The neurobiological mechanisms for the protective effect of physical activity on LH remain unknown. Results from our preliminary studies suggest that physical activity (voluntary freewheel running) prevents LH by changing the DRN 5HT response to uncontrollable stress. In the DRN, rats that voluntary freewheel run compared to sedentary (standard housing) controls have an increase in 5HT/1A somatodendritic autoreceptor expression (mRNA & protein), a decrease in 5HT/1B axonal autoreceptor mRNA, and a decrease in serortonin transporter expression (SERT, mRNA & protein). Freewheel running also conveys resistance to stress-induced decreases in DRN 5HT/1A protein expression and results in an attenuation of DRN 5HT neural responses (cFos expression) to uncontrollable stress. The reduction in stress-induced cFos expression is mirrored in a subset of areas that interact with the DRN and are involved with LH, namely the bed nucleus of the stria terminalis (BNST), the locus coeruleus (LC)-A5, and the amygdala (AMG). The changes in neural responses to stress are more robust after 6wks than after 3wks of freewheel running, and 6wks of freewheel running prevents LH behaviors (escape deficit & exaggerated freezing) after uncontrollable stress. The current proposal will test the hypothesis that the protective effect of physical activity on the development of learned helplessness is due to modulation of the DRN 5HT response. Both intra-DRN alterations and modulation of stress-induced interactions of the DRN with the AMG, BNST and LC-A5 could contribute to this effect. Together, these changes may prevent the intense DRN 5HT activation during uncontrollable stress, and/or the subsequent development & expression of LH.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Vicentic, Aleksandra
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado at Boulder
Schools of Arts and Sciences
United States
Zip Code
Lloyd, Brian A; Hake, Holly S; Ishiwata, Takayuki et al. (2017) Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior. Behav Brain Res 323:56-67
Herrera, Jonathan J; Fedynska, Sofiya; Ghasem, Parsa R et al. (2016) Neurochemical and behavioural indices of exercise reward are independent of exercise controllability. Eur J Neurosci 43:1190-202
Thompson, Robert S; Roller, Rachel; Greenwood, Benjamin N et al. (2016) Wheel running improves REM sleep and attenuates stress-induced flattening of diurnal rhythms in F344 rats. Stress 19:312-24
Mika, Agnieszka; Fleshner, Monika (2016) Early-life exercise may promote lasting brain and metabolic health through gut bacterial metabolites. Immunol Cell Biol 94:151-7
Clark, Peter J; Amat, Jose; McConnell, Sara O et al. (2015) Running Reduces Uncontrollable Stress-Evoked Serotonin and Potentiates Stress-Evoked Dopamine Concentrations in the Rat Dorsal Striatum. PLoS One 10:e0141898
Mika, Agnieszka; Van Treuren, Will; González, Antonio et al. (2015) Exercise is More Effective at Altering Gut Microbial Composition and Producing Stable Changes in Lean Mass in Juvenile versus Adult Male F344 Rats. PLoS One 10:e0125889
Mika, Agnieszka; Bouchet, Courtney A; Bunker, Preston et al. (2015) Voluntary exercise during extinction of auditory fear conditioning reduces the relapse of fear associated with potentiated activity of striatal direct pathway neurons. Neurobiol Learn Mem 125:224-35
Clark, Peter J; Ghasem, Parsa R; Mika, Agnieszka et al. (2014) Wheel running alters patterns of uncontrollable stress-induced cfos mRNA expression in rat dorsal striatum direct and indirect pathways: A possible role for plasticity in adenosine receptors. Behav Brain Res 272:252-63
Loughridge, Alice B; Greenwood, Benjamin N; Day, Heidi E W et al. (2013) Microarray analyses reveal novel targets of exercise-induced stress resistance in the dorsal raphe nucleus. Front Behav Neurosci 7:37
Greenwood, Benjamin N; Spence, Katie G; Crevling, Danielle M et al. (2013) Exercise-induced stress resistance is independent of exercise controllability and the medial prefrontal cortex. Eur J Neurosci 37:469-78

Showing the most recent 10 out of 25 publications