R01MH125898

Sex and Circuit-Specific Determinants of Exercise-Induced Stress Resilience - Project Summary

Women are more susceptible than men to stress-related mood and anxiety disorders, underscoring the importance of identifying strategies to promote stress resistance in women. Exercise affords broad benefits to mental health in both sexes, but whether the degree of stress protection and underlying mechanisms differ between sexes is unknown.

We recently discovered that female rats are more responsive to the stress-buffering effects of exercise than males. It takes voluntary wheel running (VWR) half the time to enable protection against the depression- and anxiety-like effects of inescapable stress (IS) in female rats (3 wk) than it does in males (6 wk). Enhanced stress protection from exercise in females is an entirely unexplored resilience phenomenon.

The goal of this proposal is to examine the sex- and circuit-specific determinants of this process across multiple units of analysis (molecular, cellular, circuits, sex, and behavior). VWR prevents the behavioral sequelae of IS by constraining activation of serotoninergic (5HT) neurons in the dorsal raphe nucleus (DRN) during IS, but the mechanism by which exercise constrains DRN 5HT activity is unknown.

Our preliminary data provide strong evidence that stress resistance in both sexes arises from engagement of sensorimotor circuits (dorsolateral striatum; DLS) responsible for maintaining exercise. We have found that the DLS is positioned to inhibit DRN 5HT neurons through a direct GABAergic projection (DLS-DRN circuit), and 6 wk of VWR potentiates the activity of the DLS-DRN circuit during IS. Importantly, although the DLS is required to maintain VWR behavior in both sexes, the DLS governs VWR earlier in females (4 d) than in males (4 wk).

Dopamine (DA) in the DLS contributes to DLS-dependent behavior, and females are known to have heightened stimulus-evoked dopamine (DA) responses compared to males. This is likely the case with VWR, as just a few bouts of VWR activates D1 receptor-expressing neurons in the DLS of females, but not males. The rapid recruitment of the DLS during VWR in females could accelerate plasticity in the DLS-DRN circuit required for constraining stress-induced 5HT activity. Indeed, stress resistance from 3 wk of VWR in females depends on activity of the DLS-DRN circuit during IS.

These data suggest that once exercise becomes governed by the DLS, the DLS-DRN circuit now responds actively to future adversity, thereby inhibiting the DRN and enabling stress resistance. We hypothesize that DLS neural ensembles link exercise to stress resistance and are particularly responsive to exercise in females, due to heightened DA responses to exercise in females compared to males.

Intersectional genetic approaches that tag, record, and manipulate neural circuit activity during initial exercise and later stress will be used to:

1) Identify the role of the DLS in the development of exercise-induced stress resistance and accelerated stress resistance in females.
2) Determine the role of the DLS in the expression of exercise-induced stress resistance in both sexes.
3) Identify the role of DA in driving accelerated stress resistance from VWR in females and in determining whether an appetitive, sensorimotor experience enables stress resistance.

The Regents Of The University Of Colorado

THE MISSION OF THE NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH) IS TO TRANSFORM THE UNDERSTANDING AND TREATMENT OF MENTAL ILLNESSES THROUGH BASIC AND CLINICAL RESEARCH, PAVING THE WAY FOR PREVENTION, RECOVERY, AND CURE. IN MAY 2020, NIMH RELEASED ITS NEW STRATEGIC PLAN FOR RESEARCH. THE NEW STRATEGIC PLAN BUILDS ON THE SUCCESSES OF PREVIOUS NIMH STRATEGIC PLANS BY PROVIDING A FRAMEWORK FOR SCIENTIFIC RESEARCH AND EXPLORATION, AND ADDRESSING NEW CHALLENGES IN MENTAL HEALTH. THE NEW STRATEGIC PLAN OUTLINES FOUR HIGH-LEVEL GOALS: GOAL 1: DEFINE THE BRAIN MECHANISMS UNDERLYING COMPLEX BEHAVIORS GOAL 2: EXAMINE MENTAL ILLNESS TRAJECTORIES ACROSS THE LIFESPAN GOAL 3: STRIVE FOR PREVENTION AND CURES GOAL 4: STRENGTHEN THE PUBLIC HEALTH IMPACT OF NIMH-SUPPORTED RESEARCH THESE FOUR GOALS FORM A BROAD ROADMAP FOR THE INSTITUTE'S RESEARCH PRIORITIES OVER THE NEXT FIVE YEARS, BEGINNING WITH THE FUNDAMENTAL SCIENCE OF THE BRAIN AND BEHAVIOR, AND EXTENDING THROUGH EVIDENCE-BASED SERVICES THAT IMPROVE PUBLIC HEALTH OUTCOMES. THE INSTITUTE'S OVERALL FUNDING STRATEGY IS TO SUPPORT A BROAD SPECTRUM OF INVESTIGATOR-INITIATED RESEARCH IN FUNDAMENTAL SCIENCE, WITH INCREASING USE OF INSTITUTE-SOLICITED INITIATIVES FOR APPLIED RESEARCH WHERE PUBLIC HEALTH IMPACT IS A SHORT-TERM MEASURE OF SUCCESS. THE NEW STRATEGIC PLAN ALSO ADDRESSES A NUMBER OF CROSS-CUTTING THEMES THAT ARE RELEVANT TO ALL RESEARCH SUPPORTED BY NIMH, THESE THEMES HIGHLIGHT AREAS WHERE NIMH-FUNDED SCIENCE MAY HAVE THE GREATEST IMPACT, BRIDGE GAPS, AND OFFER NOVEL APPROACHES TO ACCELERATE ADVANCES IN MENTAL HEALTH RESEARCH. FOR EXAMPLE, NIMH VALUES A COMPREHENSIVE RESEARCH AGENDA THAT TAKES AN INCLUSIVE APPROACH THAT ENSURES RESEARCH INTERESTS ARE VARIED, MAINTAIN DIVERSE PARTICIPATION AND PARTNERSHIPS, AND ACHIEVE RESEARCH GOALS ACROSS MULTIPLE TIMEFRAMES. THIS INCLUDES DIVERSE METHODOLOGIES, TOOLS, AND MODELS, RESEARCH ADDRESSING COMPLEX BASIC, TRANSLATIONAL, AND APPLIED QUESTIONS, RESEARCH INCLUDING BOTH SEXES AND, AS APPROPRIATE, GENETIC BACKGROUND, AND, PARTICIPANTS FROM DIVERSE RACIAL AND ETHNIC BACKGROUNDS, AND ACROSS GENDER IDENTITIES, GEOGRAPHICAL CONTEXT, SOCIOECONOMIC STATUS, NEUROTYPE, AND AGE OFFERING THE BEST POSSIBLE REPRESENTATION, FOR THE BROADEST NUMBER OF INDIVIDUALS WHO MAY ULTIMATELY BENEFIT FROM THESE SCIENTIFIC ADVANCES. TO ACCOMPLISH THE GOALS OUTLINED IN THE NEW STRATEGIC PLAN, NIMH WILL SUPPORT RESEARCH THAT AIMS: TO CHARACTERIZE THE GENOMIC, MOLECULAR, CELLULAR, AND CIRCUIT COMPONENTS CONTRIBUTING TO BRAIN ORGANIZATION AND FUNCTION, TO IDENTIFY THE DEVELOPMENTAL, FUNCTIONAL, AND REGULATORY MECHANISMS RELEVANT TO COGNITIVE, AFFECTIVE, AND SOCIAL DOMAINS, ACROSS UNITS OF ANALYSIS, AND, TO GENERATE AND VALIDATE NOVEL TOOLS, TECHNIQUES, AND MEASURES TO QUANTIFY CHANGES IN THE ACTIVITY OF MOLECULES, CELLS, CIRCUITS, AND CONNECTOMES. TO DISCOVER GENE VARIANTS AND OTHER GENOMIC ELEMENTS THAT CONTRIBUTE TO THE DEVELOPMENT OF MENTAL ILLNESSES IN DIVERSE POPULATIONS, TO ADVANCE OUR UNDERSTANDING OF THE COMPLEX ETIOLOGY OF MENTAL ILLNESSES USING MOLECULAR EPIDEMIOLOGIC APPROACHES THAT INCORPORATE INDIVIDUAL GENETIC INFORMATION IN LARGE COHORTS, TO ELUCIDATE HOW HUMAN GENETIC VARIATION AFFECTS THE COORDINATION OF MOLECULAR, CELLULAR, AND PHYSIOLOGICAL NETWORKS SUPPORTING HIGHER-ORDER FUNCTIONS AND EMERGENT PROPERTIES OF NEUROBIOLOGICAL SYSTEMS, AND, TO DEVELOP NOVEL TOOLS AND TECHNIQUES FOR THE ANALYSIS OF LARGE-SCALE GENETIC, MULTI-OMIC DATA AS IT APPLIES TO MENTAL HEALTH. TO UTILIZE CONNECTOMIC APPROACHES TO IDENTIFY BRAIN NETWORKS AND CIRCUIT COMPONENTS THAT CONTRIBUTE TO VARIOUS ASPECTS OF MENTAL FUNCTION AND DYSFUNCTION, TO DETERMINE THROUGH BRAIN-WIDE ANALYSIS HOW CHANGES IN THE PHYSIOLOGICAL PROPERTIES OF MOLECULES, CELLS, AND CIRCUITS CONTRIBUTE TO MENTAL ILLNESSES, TO DEVELOP MOLECULAR, CELLULAR, AND CIRCUIT-LEVEL BIOMARKERS OF IMPAIRED NEURAL FUNCTION IN HUMANS, AND, TO DEVELOP INNOVATIVE TECHNOLOGIES, INCLUDING NEW IMAGING, COMPUTATIONAL, PHARMACOLOGICAL, AND GENETIC TOOLS TO INTERROGATE AND MODULATE CIRCUIT ACTIVITY AND STRUCTURE ALTERED IN MENTAL ILLNESSES. TO ELUCIDATE THE MECHANISMS CONTRIBUTING TO THE TRAJECTORIES OF BRAIN DEVELOPMENT AND BEHAVIOR, AND, TO CHARACTERIZE THE EMERGENCE AND PROGRESSION OF MENTAL ILLNESSES, AND IDENTIFYING SENSITIVE PERIODS FOR OPTIMAL INTERVENTION. TO DETERMINE EARLY RISK AND PROTECTIVE FACTORS, AND RELATED MECHANISMS, TO SERVE AS NOVEL INTERVENTION GROUPS, AND, TO DEVELOP RELIABLE AND ROBUST BIOMARKERS AND ASSESSMENT TOOLS TO PREDICT ILLNESS ONSET, COURSE, AND ACROSS DIVERSE POPULATIONS. TO DEVELOP NOVEL INTERVENTIONS USING A MECHANISM-INFORMED, EXPERIMENTAL THERAPEUTICS APPROACH, AND, TO DEVELOP AND IMPLEMENT MEASUREMENT STRATEGIES TO FACILITATE MECHANISM-BASED INTERVENTION DEVELOPMENT AND TESTING. TO INVESTIGATE PERSONALIZED INTERVENTION STRATEGIES ACROSS DISEASE PROGRESSION AND DEVELOPMENT, AND, TO DEVELOP AND REFINE COMPUTATIONAL APPROACHES AND RESEARCH DESIGNS THAT CAN BE USED TO INFORM AND TEST PERSONALIZED INTERVENTIONS. TO DEVELOP AND TEST APPROACHES FOR ADAPTING, COMBINING, AND SEQUENCING INTERVENTIONS TO ACHIEVE THE GREATEST IMPACT ON THE LIVES AND FUNCTIONING OF PERSONS SEEKING CARE, TO CONDUCT EFFICIENT PRAGMATIC TRIALS THAT EMPLOY NEW TOOLS TO RAPIDLY IDENTIFY, ENGAGE, ASSESS, AND FOLLOW PARTICIPANTS IN THE CONTEXT OF ROUTINE CARE, AND, TO ENHANCE THE PRACTICAL RELEVANCE OF EFFECTIVENESS RESEARCH VIA DEPLOYMENT-FOCUSED, HYBRID, EFFECTIVENESS-IMPLEMENTATION STUDIES. TO EMPLOY ASSESSMENT PLATFORMS WITHIN HEALTHCARE SYSTEMS TO ACCURATELY ASSESS THE DISTRIBUTION AND DETERMINANTS OF MENTAL ILLNESSES AND TO INFORM STRATEGIES FOR IMPROVED SERVICES, TO OPTIMIZE REAL-WORLD DATA COLLECTION SYSTEMS TO IDENTIFY STRATEGIES FOR IMPROVING ACCESS, QUALITY, EFFECTIVENESS, AND CONTINUITY OF MENTAL HEALTH SERVICES, AND, TO COMPARE ALTERNATIVE FINANCING MODELS TO PROMOTE EFFECTIVE AND EFFICIENT CARE FOR INDIVIDUALS WITH SERIOUS EMOTIONAL DISTURBANCES AND SERIOUS MENTAL ILLNESSES. TO STRENGTHEN PARTNERSHIPS WITH KEY STAKEHOLDERS TO DEVELOP AND VALIDATE STRATEGIES FOR IMPLEMENTING, SUSTAINING, AND CONTINUOUSLY IMPROVE EVIDENCE-BASED PRACTICES, TO BUILD MODELS TO SCALE-UP EVIDENCE-BASED PRACTICES FOR USE IN PUBLIC AND PRIVATE PRIMARY CARE, SPECIALTY CARE AND OTHER SETTINGS, AND, TO DEVELOP DECISION-SUPPORT TOOLS AND TECHNOLOGIES THAT INCREASE THE EFFECTIVENESS AND CONTINUOUS IMPROVEMENT OF MENTAL HEALTH INTERVENTIONS IN PUBLIC AND PRIVATE PRIMARY CARE, SPECIALTY CARE, AND OTHER SETTINGS. TO ADAPT, VALIDATE, AND SCALE-UP PROGRAMS CURRENTLY IN USE THAT IMPROVE MENTAL HEALTH SERVICES FOR UNDERSERVED POPULATIONS, TO DEVELOP AND VALIDATE SERVICE DELIVERY MODELS THAT PROVIDE EVIDENCE-BASED CARE FOR INDIVIDUALS THROUGHOUT THE COURSE OF MENTAL ILLNESS, TO DEVELOP AND VALIDATE SYSTEMS-LEVEL STRATEGIES USING TECHNOLOGY AND OTHER APPROACHES, TO IDENTIFY, SUPPORT, AND MONITOR THE EFFECTIVENESS OF EVIDENCE-BASED CARE THROUGHOUT THE COURSE OF ILLNESS, AND, TO DEVELOP AND VALIDATE DECISION-MAKING MODELS THAT BRIDGE MENTAL HEALTH, MEDICAL, AND OTHER CARE SETTINGS TO INTEGRATE THE APPROPRIATE CARE FOR PEOPLE WITH SERIOUS MENTAL ILLNESSES AND COMORBID MEDICAL CONDITIONS.

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

Colorado United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 397% from $604,642 to $3,003,577.