Monika R Fleshner
University Of Colorado At Boulder
Project start date: 2003-06-01
Project end date: 2015-01-31
Sponsored Links Excellgen http://Excellgen.com
The Neurobiology Of The Stress Resistant Brain
Monika R Fleshner, Associate Professor
Integrative Physiologyuniversity Of Colorado At Boulder
572 Ucb
boulder, Co 80309
Grant 5R01MH068283-05 from National Institute Of Mental Health IRG: NMB
Abstract: 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
Keywords: aerobic exercise, behavior therapy, fear, learned helplessness, nonhuman therapy evaluation, physiologic stressor amygdala, dorsal raphe nucleus, escape reaction, locus coeruleus, messenger RNA, neural transmission, receptor expression, serotonin receptor, serotonin transporter, thalamus behavior test, behavioral /social science research tag, densitometry, electrode, horseradish peroxidase, immunocytochemistry, laboratory rat, microdialysis, nontherapeutic iontophoresis, video recording system
Project start date: 2004-03-01
Project end date: 2009-08-28
5R01MH068283-05 (2008): $316007
5R01MH068283-04 (2007): $315836
5R01MH068283-03 (2006): $323177
5R01MH068283-02 (2005): $323182
Grants awarded to Monika R Fleshner
THE NEUROBIOLOGY OF THE STRESS RESISTANT BRAIN
Monika R Fleshner, Associate Professor
University Of Colorado At Boulder, 572 Ucb, Boulder, Co 80309
Grant 2R01MH068283-06A1 from National Institute Of Mental Health
Abstract: Identification of means to prevent stress-related psychiatric disorders such as depression & anxiety is of primary importance. One manipulation with established stress resilient effects is exercise. We have observed that rats allowed access to running wheels are protected against the depression- & anxiety-like consequences of uncontrollable stress, or learned helplessness (LH). Growing evidence indicates that LH behaviors are produced by hyperactivation & sensitization of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). Hyperactivation of DRN 5-HT neurons during stress could lead to later sensitization of these neurons by desensitizing 5-HT1A inhibitory autoreceptors in the DRN. Results from our prior work & preliminary studies suggest that wheel running prevents LH by constraining the activity of DRN 5-HT neurons during stressor exposure & preventing the desensitization of 5-HT1A autoreceptors. Constraint over 5-HT neural activity could be an adaptive feature of the stress response that is dysregulated in stress-related psychiatric disorders but facilitated by prior voluntary exercise. Understanding how the experience of exercise is communicated to the DRN to result in stress resilience is a primary goal of this project that has clear clinical implications for the prevention of stress-related disorders. Exercise is a unique behavioral manipulation that will likely recruit neurocircuits that together result in unique adaptations in the brain. To facilitate identification of these neurocircuits, we propose an innovative approach of controllable / yoked uncontrollable wheel running. Although voluntary wheel running is associated with stress resilience, forced exercise often fails to produce stress protective effects despite considerable fitness benefits. These data suggest that activity or fitness per se is not sufficient to produce stress resilience. Instead, exercise plus the psychological variable of "perceived control" may be critical. This is an important distinction because it implies involvement of distinct neural substrates involved in the perception of control (such as the medial prefrontal cortex; mPFC), vs. those simply recruited by physical activity per se (such as the noradrenergic system), in the stress resilience produced by exercise. Indeed, we have observed that voluntary exercise recruits both of these systems; repeated activation of which could contribute to the increase in DRN 5- HT1A autoreceptors by inhibiting the activity of the 5-HT1A gene repressor Freud-1. The current project tests the hypotheses that 1) wheel running prevents LH by preventing DRN 5-HT1A autoreceptor desensitization &/or increasing mPFC-inhibition of the DRN during stress, 2) the effects of wheel running on behavior & 5-HT1A autoreceptors are dependent on exercise controllability, & 3) repeated activation of the mPFC &/or DRN 11- ADRs contribute to the increase in 5-HT1A autoreceptors & the protective effect of wheel running against LH. The goal of the current proposal is to identify how the experience of exercise is communicated to the central serotonergic system to result in resilience against stress- induced anxiety, focusing specifically on central circuits converging on the 5-HT1A autoreceptor. The results of this work will improve our basic understanding of the effects of stressor exposure and exercise on serotonin systems, and could lead to novel approaches for the prevention or treatment of stress-related psychiatric disorders
Keywords: 3-(2-Aminoethyl)-1H-indol-5-ol; 5-HT; 5-Hydroxytryptamine; 5HT; Anti-Anxiety Agents; Anti-Anxiety Drugs; Antidepressant Agent; Antidepressant Drugs; Antidepressants; Antidepressive Agents; Anxiety; Anxiolytic Agents; Anxiolytics; Autoreceptors; Behavior; Behavior Control; Behavioral; Behavioral Manipulation; Brain; Clinical; Common Rat Strains; DRN; Data; Depression; Development; Encephalon; Encephalons; Enteramine; Exercise; Exercise, Physical; Genes; Goals; Hippophaine; Housing; Human; Human, General; Lead; Learned Helplessness; Locus Coeruleus; Mammals, Rats; Man (Taxonomy); Man, Modern; Medial; Mental Depression; Mental disorders; Mental health disorders; Nerve Cells; Nerve Unit; Nervous; Nervous System, Brain; Neural Cell; Neurobiology; Neurocyte; Neurons; Nucleus Pigmentosus Pontis; Pb element; Perception; Physical activity; Prefrontal Cortex; Prevention; Proteins; Psychiatric Disease; Psychiatric Disorder; Rat; Rat Strains; Rattus; Recruitment Activity; Resistance; Role; Running; Serotonin; Stress; Structure of locus ceruleus; System; System, LOINC Axis 4; Testing; Tranquilizing Agents, Minor; Unspecified Mental Disorder; Work; antianxiety agent; behavior test; behavioral control; behavioral test; biological adaptation to stress; blue nucleus; density; desensitization; design; designing; dorsal raphe nucleus; experience; fitness; gene product; heavy metal Pb; heavy metal lead; improved; innovate; innovation; innovative; locus ceruleus structure; mRNA Expression; mental illness; neural; neurobiological; neuronal; new approaches; noradrenergic; novel approaches; novel strategies; novel strategy; prevent; preventing; protective effect; psychologic; psychological; psychological disorder; public health relevance; reaction; crisis; recruit; relating to nervous system; resilience; resistant; social role; stress related disorder; stress resilience; stress response; stress; reaction; stressor
Relevance: The goal of the current proposal is to identify how the experience of exercise is communicated to the central serotonergic system to result in resilience against stress- induced anxiety, focusing specifically on central circuits converging on the 5-HT1A autoreceptor. The results of this work will improve our basic understanding of the effects of stressor exposure and exercise on serotonin systems, and could lead to novel approaches for the prevention or treatment of stress-related psychiatric disorders
Project start date: 2003-06-01
Project end date: 2015-03-31
Budget start date: 24-JUN-2010
Budget end date: 31-MAR-2011
PFA/PA: PA-07-070
2R01MH068283-06A1 (2010): $336851
1R01MH068283-01A1 (2004): $320495
Stress, Heat-Shock Proteins, And Innate Immunity
Monika R Fleshner, Associate Professor
University Of Colorado At Boulder 572 Ucb Boulder, Co 80309
Grant 5R01AI057797-04 from National Institute Of Allergy And Infectious Diseases IRG: MESH
Abstract: Exposure to an acute (<4 hrs) mental or physical stressor stimulates a cascade of behavioral and physiological responses that function to facilitate fight/flight responses and improve an organism s chances of survival. At the cellular level, one important and highly conserved response to stress is stimulation of heat shock proteins, specifically heat-shock protein 72 (Hsp 72). Although the mechanisms of induction and functions of intracellular Hsp72 have been thoroughly studied, only recently has it been discovered that extracellular Hsp72 (crisp72) can be rapidly released into the blood in high concentrations after exposure to either mental or physical stressors. The release of eHsp72 appears to be a highly conserved response across species and stressors, leading us to propose that crisp72 release may be a previously unrecognized feature of the acute stress response. The gender, species and stressor generalizability, cellular source(s), signal(s) and function(s) of extracellular Hsp72 released after acute stressor exposure remain largely unexplored. We present preliminary data that concentrations of crisp72 increase in the blood of males and females, and rodents and humans after exposure to a variety of stressors, i.e., conditioned contextual fear, predatory stress, tailshock stress, restraint stress, exhaustive exercise stress, and handshock stress (humans). In addition, we have evidence that eHsp72 is rapidly (<15min) released via an a1-adrenergic receptor mediated mechanism from brown adipose tissue (BAT) because a1-adrenergic blockade (prazosin) prevents stress-induced increases of eHsp72 in the blood; and an adrenergic agonist (NE) releases crisp72 from BAT. Furthermore, we report that crisp72 in vitro stimulates NO and inflammatory cytokines from innate immune cells, and this effect is potentiatied in the presence of LPS. Finally, crisp72 at the site of bacterial challenge facilitates inflammation recovery, and both blockade of stress-induced crisp72 release (prazosin) and immunoneutralization of crisp72 at the site of inflammation, prevents the positive effects of stress. We propose, therefore, that crisp72 released after exposure to acute stress may function as an endogenous "danger signal" for the immune system. Hence, in presence of bacterial challenge, eHsp72 potentiates macrophage/neutrophil release of nitric oxide (NO) and inflammatory cytokines resulting in facilitated killing and recovery from in vivo bacterial challenge. We hypothesize, therefore, that exposure to an acute stressor stimulates the release of crisp72 into the blood via an alpha1-adrenergic receptor-mediated mechanism from brown adipose tissue and elevated crisp72 functions to facilitate innate immunity in the presence of bacterial challenge (Escherichia coli).
Keywords: extracellular, heat shock protein, immunity, protein biosynthesis, protein structure function, stress, Escherichia coli, adrenergic receptor, brown fat, conditioning, cytokine, estrus, fear, gender difference, hormone regulation /control mechanism, inflammation, macrophage, neutrophil, nitric oxide, stressor, baboon, laboratory rat
Project start date: 2004-06-01
Project end date: 2009-05-31
5R01AI057797-04 (2007): $315512
5R01AI057797-03 (2006): $349419
5R01AI057797-02 (2005): $357807
1R01AI057797-01A1 (2004): $361619
5R01AI057797-05 (2008): $0
EXERCISE, STRESS AND IMMUNITY--PHYSIOLOGICAL MECHANISMS
Monika R Fleshner, Associate Professor
University Of Colorado At Boulder 572 Ucb Boulder, Co 80309
Grant 5R01AI048555-04 from National Institute Of Allergy And Infectious Diseases IRG: RAP
Abstract: Applicant s ) The literature indicate that physically active organisms are less susceptible to the deleterious consequences of stress on illness and immune function. Using an established animal model of stress, my laboratory has investigated the effect of acute stressor exposure on the development of a specific antibody response to a benign protein, keyhole limpet hemocyanin (KLH) in physically active versus sedentary rats. Measurement of specific antibody levels in the blood after challenge with KLH provides an excellent measure of the in vivo immune response, and a reduction in the specific antibody response to a bacteria, virus or soluble toxin, could render the organism more susceptible to disease caused by that pathogen. Sedentary rats that are immunized with KLH, and exposed to a single session of tail shock stress, have a reduction in the antibody response to KLH (anti-KLH Ig). In contrast, rats that are allowed to live with a running wheel before exposure to an acute stressor, do not suffer the immunologically deleterious consequences of stress. The central theme of this proposal is to determine the immune-neuroendocrine-brain mechanism(s) of the stress-buffering effect of physical activity. Preliminary data suggest that physical activity modulates the brain and neuroendocrine responses to stressor exposure. Compared to sedentary stressed rats, physically active rats exposed to tail shock stress have a smaller increase in c-Fos immunoreactivity (neuronal activation marker) in several stress reactive brain areas that are important for activation of sympathetic descending pathways. These changes may be responsible for the reduction in stress-induced sympathetic nervous system output (plasma and splenic norepinephrine (NE)) found in physically active versus sedentary animals. Importantly, there is evidence that exposure to stress levels of NE elevates nitric oxide (NO) which leads to a reduction in anti-KLH Ig. Blockade of stress-induced sympathetic output prevents these effects. It is reasonable to hypothesize, therefore, that physically active rats are resistant to the negative effects of stress on immune function because they have a reduction in sympathetic nervous system output leading to a reduction in immunosuppressive NO, and prevention of suppressed anti-KLH Ig.
Keywords: antibody formation, exercise, immunosuppression, psychological stressor, catecholamine, ganglionic blocking agent, gene expression, hemocyanin, immunopharmacology, interferon gamma, interleukin 2, interleukin 4, neuronal transport, neutralizing antibody, nitric oxide, norepinephrine, protooncogene, sympathetic nervous system, zymosan, denervation, electrostimulus, immunocytochemistry, laboratory rat
Project start date: 2000-12-15
Project end date: 2004-11-30
5R01AI048555-04 (2004): $289209
5R01AI048555-03 (2003): $301266
5R01AI048555-02 (2002): $332357
Sponsored Links Excellgen http://Excellgen.com
1R01AI048555-01 (2001): $332744
EXERCISE PREVENTS THE IMMUNOSUPPRESSIVE EFFECT OF STRESS
Monika R Fleshner, Associate Professor
Integrative Physiologyuniversity Of Colorado At Boulder
572 Ucb
boulder, Co 80309
Grant 5R03AI045576-02 from National Institute Of Allergy And Infectious Diseases IRG: RAP
Abstract: Adapted from ´s ) Exposure to acute or chronic stress (mental or physical) is associated with an increase in disease susceptibility and severity. Evidence suggests that stress alters disease processes by modulating the immune system. Given the health problems associated with repeated acute and chronic stressor exposure, it is important to develop treatments which could prevent the immunologically deleterious consequences of stressor exposure. A simple pharmacological approach is currently unrealistic because the complex neurohormonal mediators of stress-induced changes in immune function are not understood. Another approach would be to develop a behavioral intervention that would buffer the deleterious consequences of stress, and thereby contribute to an overall improvement in health. Preliminary data from ´s laboratory suggest that regular, moderate, physical activity is a successful intervention capable of having such an effect. Regular, moderate exercise is associated with improved overall health. The health benefits of physical exercise are both direct and indirect. Regular, moderate exercise, for example, is associated with a decrease in coronary heart disease and high blood pressure, probably due to direct improvements in cardiovascular function. In addition to a reduction in heart disease, regular, moderate exercise is also associated with a decrease in bacterial and viral illness, which could be due to the indirect health benefits of exercise, i.e., stress reduction. Thus, it is possible that the reported reduction in infectious disease associated with exercise is due to the prevention of stress-induced suppression of the immune system. Using a well established animal model of stress, investigated the effect of acute stressor exposure on the development of a specific antibody response to a benign protein, keyhole limpet hemocyanin (KLH). Measurement of specific antibody levels in the blood after challenge with KLH provides and excellent measure of the in vivo immune response and the cellular mechanisms are well understood. Thus, using this well characterized stress and immunity paradigm, presents evidence that regular, moderate, exercise can prevent the effect of stress on anti-KLH antibody. The goal of this research proposal, therefore, is to better characterize the protective effect of regular, moderate physical activity on the detrimental immunological consequences of acute stressor exposure
Keywords: disease /disorder prevention /control, exercise, immunosuppression, psychoneuroimmunology, stress antibody formation laboratory rat
Project start date: 1999-09-30
Project end date: 2001-09-29
5R03AI045576-02 (2000): $71548