Using experimental animal models to study stress coping and resilience Sarah Clinton, PhD Virginia Tech Spring 2017 Global Forum on Urban and Regional Resilience Seminar Series January 29, 2017

psychology resilience noun 1. the capacity to recover quickly from difficulties; toughness. 2. the ability of a substance or object to spring back into shape; elasticity. 3. the long term capacity of a system to deal with change and continue to develop. engineering Evolutionary biology

Stress & Resilience Across Scales Family Peers Community Global scale National scale Individual Brain Cells Molecules & Receptors

Broad questions in the field of stress neurobiology include: What factors influence how individuals cope with stress? Genetic predisposition Innate differences in brain circuits that govern reactivity to stress Environmental factors (familial relationships, cultural factors, prior stress/trauma) What factors determine whether an individual may be resilient (or vulnerable) to stress-induced illness? Through studying brain responses to stress, can we develop improved methods to prevent and treat stress-related illnesses such as depression, anxiety, and PTSD?

Neurobiology of Stress Physical and psychological stressors activate the Hypothalamic-Pituitary-Adrenal (HPA) Axis. Corticotropin Releasing Hormone (CRH) Adrenocorticotrophin releasing hormone Cortisol elicits a number of effects throughout the brain and body: Mobilizing energy stores Increasing arousal/vigilance Focusing attention Suppressing immune function Chronic stress/elevated cortisol can elicit adverse effects: Hypertension, cardiovascular disease Immunosuppression Insulin resistance Emotional disorders (anxiety, depression)

(e.g., active coping, passive coping) Individuals can exhibit differences in neural, physiological and behavioral response to stress Stress Coping (e.g., active coping, passive coping) Individuals can choose to cope with stress in different ways (for example, adopting a proactive or passive approach to dealing with stress). Maladaptive stress coping is associated with a variety of emotional disorders, including anxiety and depression. What factors influence how individuals cope with stress? What factors determine whether an individual may be resilient (or vulnerable) to stress?

Early life stress triggers adverse effects in the developing brain The Developing Human Brain

How do biological & environmental factors shape individuals’ vulnerability (or resilience) to stress? “Nature” “Nurture” Biological and early-life environmental factors can influence the developing brain, thereby ‘setting the stage’ for later stress vulnerability vs. resilience. Genetic Vulnerability (Genes, epigenetic programs, neurochemistry) Early Experiences (Rearing, stress, drugs) Stress Vulnerable / “At Risk” Maladaptive Stress Coping Examples of factors that may boost stress resilience to prevent emergence of stress-related illness. Exercise Antidepressants Psychotherapy Daily Stress Traumatic Event Emotional dysfunction

Rats (like humans) can exhibit distinct stress coping styles Stressor = Shock from electric probe Burying Probe with Bedding = Active Coping Freezing / Immobility = Passive Coping Active coping response = Bury shock probe with bedding Passive coping response = Freeze, immobile in corner Stress coping behavior task-Defensive Burying Active Coping Passive Coping Fight-or-flight Rat Coping Behavior in Defensive Burying Task Passive Coping Rat Active Coping Rat 5-HT = 5-hydroxytryptamine (serotonin) Freeze / hide

How do we examine neurobiological underpinnings of stress coping? Behavior Brain Circuits Molecular mechanisms can influence genes Genes GR TPH2, 5HT1a FGF2 DNA methylation microRNAs Histone modifications Experimental animal models offer a controlled system that allows scientists to dissect a number of complex biological and environmental factors that shape stress coping behavior, and perhaps stress resilience. How does early life stress influence an individual’s later stress coping ability? How do family / parental interactions shape an individuals’ later stress coping ability? If an individual exhibits maladaptive stress coping behavior, can new / better coping strategies be learned?

Studying molecules that influence stress coping and anxiety behavior – microRNA-101a MicroRNA miR-101a can regulate expression of many other genes. “Passive Coping” Rats show high levels of anxiety behavior and especially high levels of miR-101a in certain brain regions (compared to low anxiety/Active Coping Rats) Could this molecular difference drive their anxiety behavior differences? Cohen et al, Under Review 2017

Testing whether increasing miR-101a levels in the rat brain leads to increased anxiety We microinjected a virus to increase miR-101a levels in the amygdala, a part of the brain that controls fear and anxiety behavior. amygdala Elevated Plus Maze Anxious rats will avoid the open arms This new experiment suggests that experimentally increasing miR-101a levels in the amygdala pushes an ‘Active Coping Rat’ to behave more like an anxiety-prone ‘Passive Coper’. Cohen et al, Under Review 2017

The Amygdala & Stress Vulnerability (vs. Resilience) Another brain region – the prefrontal cortex (PFC) – can act as a BRAKE on the amygdala. It can help control emotional behavior, and can promote stress resilience When we are stressed, the amygdala can get out of control, over-activating emotional, behavioral, and physiological responses to a stressful situation.

HR/LR : Environmental Complexity (EC) Environmental factors can also shape the brain, stress coping style, and perhaps resilience Standard rat cage “Enriched Environment” at week 1 “Enriched Environment” at week 3 Most experimental rats live in fairly boring cages with food, water, bedding, and 1 ‘roommate’. In this experiment, rats raised under standard housing conditions were compared to rats raised for 3 weeks in an “enriched environment” that was increasingly filled with toys as well as multiple rats. Perez, J, et al. J. Neurosci., Under Revision Kerman, Clinton et al

Environmental factors can also shape the brain, stress coping style, and perhaps resilience Standard rat cage “Enriched Environment Rats that normally display a passive stress coping response will convert to a more “active stress coping” style when they are exposed to an enriched living environment. Kerman, Clinton et al

Stress & Resilience Across Scales Family Peers Community Global scale National scale Individual Brain Cells Molecules & Receptors The most detrimental stressors are uncontrollable, unpredictable and full of uncertainty. This is true at the individual level, but also holds true across scales, for instance: Financial insecurity / economic instability War, population displacement Disease outbreak Natural disasters Terrorism Climate change Although types of threats & stressors may vary across scales, they will essentially all activate the same fundamental “fear/stress” brain circuits.

Acknowledgements Grant Support: Clinton Lab Matthew Glover Chelsea McCoy Joshua Cohen (MD/PhD student @ UAB) Jonathan Huaman Hunter Moore Former members at UAB: Nateka Jackson Rebecca Simmons Phyllis Pugh Sara Anne Stringfellow Samantha Golf Mohamad Moughnyeh Anooshah Ejaz Ata Collaborators Jeremy Day (UAB) Elliot Lefkowitz (UAB) Farah Lubin (UAB) Grant Support: NIMH R01 MH105447-01 (SMC), NIMH K99/R00 MH085859-01A1 (SMC)