1. 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

2. 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 the long term capacity of a system to deal with change and continue to develop.
engineering
Evolutionary biology

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

4. 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?

5. 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)

6. (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?

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

8. 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

9. 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

10. 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?

11. 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

12. 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

13. 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.

14. 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

15. 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

16. 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.

17. Acknowledgements Grant Support: Clinton Lab Matthew Glover
Chelsea McCoy
Joshua Cohen (MD/PhD 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 MH (SMC), NIMH K99/R00 MH A1 (SMC)