We propose to study the neurobiological mechanisms of affective resilience to anxiety and stress, and to identify strategies for enhancing resilience specifically in highly vulnerable individuals. Our general hypothesis is that epigenetic mechanisms are critical predisposing factors that shape responsiveness to negative valence and impact vulnerability to chronic anxiety disorders. More specifically, we focus on the Fibroblast Growth Factor 2 (FGF2) which serves as a """"""""master molecular organizer"""""""" that is critical during development and continues to be active in shaping affective responsiveness throughout life. This proposal tests the hypothesis that FGF2 is an endogenous resilience molecule that is not only a target of epigenetic mechanisms but is itself a modifier of these mechanisms that, in turn, fine-tune affective responsiveness. The proposed series of studies relies on two lines of rats that we have genetically selected based on their propensity to explore a mildly stressful novel environment. Our breeding strategy over 40 generations has resulted in contrasting behavioral phenotypes that capture a stable bias towards """"""""negative valence responsiveness"""""""" versus """"""""positive valence responsiveness"""""""". In particular, bred Low-Responder rats (bLRs) exhibit greater basal anxiety and depression behaviors, greater fear conditioning, greater responsiveness to chronic and social defeat stress, lower levels of hippocampal FGF2 and a distinct epigenetic profile when compared to bred High Responders (bHRs) that are significantly more resilient. Thus bLRs are a model of vulnerability to negative affective disorders and a target for resilience enhancement.
Aim 1 uses direct administration of FGF2 to promote resilience during early life and in adolescence. It also investigates environmental complexity (EC) as a strategy for promoting resilience during adolescence. It studies the impact of these interventions on two """"""""molecular master organizer"""""""" genes in hippocampus- FGF2 itself, which reduces anxiety and the glucocorticoid receptor GR, which enhances anxiety behavior.
Aim 2 characterizes the basal epigenetic profiles associated with the bHR/bLR phenotypes and the impact of resilience induction on these profiles both at the global level and in association with FGF2 and GR promoters. These studies will be extended to anatomical analyses using a range of tools including Clarity.
Aim 3 addresses at a mechanistic level the functional bidirectional relationship between FGF2 and epigenetic mechanisms and their impact on resilience--- be it basal resilience (in bHRs) or induced (in bLRs). It uses virally-mediated, targeted RNA intervention strategies to knockdown either FGF2 or histone modifying enzymes in the hippocampus and determine whether they play an essential role in the induction of resilience. Together, these studies will provide a highly targeted approach to understanding and harnessing epigenetics as key factors in affect regulation.

Public Health Relevance

Chronic anxiety and vulnerability to stress can cause a great deal of damage, leading to severe clinical depression along with many other medical illnesses. We argue in this project that it is possible for vulnerable individuals to build up their emotional resilience, decrease their chronic anxiety and buffer their responses against psychosocial stress. We have discovered a molecule in the brain that naturally protects against anxiety and that is decreased in the brains of depressed humans. We have shown in our animal model of genetic vulnerability to anxiety that this same molecule is also low and that enhancing it shortly after birth can have lifelong protective effects against stress and anxiety responses. The current project studies the molecular mechanisms involved in the resilience induced by this natural brain factor. It examines whether these brain mechanisms can still be engaged in adolescence and produce lasting effects. It also asks whether an enriched environment that activates this brain factor can produce lifelong emotional resilience. These studies can lead to both new drugs and new behavioral strategies for enhancing emotional resilience.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Beckel-Mitchener, Andrea C
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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