This proposal for a NIH Pathway to Independence Award (K99/R00) aims to elucidate neurodevelopmental underpinnings of emotional dysregulation and stress vulnerability which may play a role in the onset of anxiety and mood disorders. Innate differences in personality and emotional reactivity strongly shape how individuals respond to stress, and this biological endowment together with early-life experience can powerfully influence neural and emotional development. Understanding the neurobiological mechanisms whereby inborn and environmental factors interact to contribute to the onset of affective dysfunction in the developing brain is crucial for generating improved preventative treatments. Thus, the proposed studies will elucidate the ontogeny of neural circuits in an animal model of comorbid anxiety and depression to better understand how altered wiring during development may give rise to emotional dysfunction later in life. We recently developed selectively-bred rats exhibiting dramatic differences in emotional reactivity. High-Responder rats (HR) vigorously explore new environments, while Low-Responder rats (LR) are inhibited, showing much less novelty-induced activity, as well as exaggerated anxiety- and depressive- like behavior. We found that the LR- HR traits are heritable, present in early life, and likely linked to differential formation of hippocampal circuits. The current proposal aims to characterize the ontogeny of hippocampal circuits in LR vs. HR animals and determine how early-life factors may alter the trajectory of hippocampal development.
In Specific Aim 1 we will determine potential alterations of hippocampal gene expression, morphology and connectivity to define how these circuits unfold across development. Since LR/HR mothers exhibit distinct maternal styles, studies in Aim 2 will utilize a cross-fostering paradigm to determine how maternal care shapes LR-HR behavioral and neural differences. Finally, in Aim 3 we will manipulate hippocampal development via administration of the neurotrophic factor Fibroblast Growth Factor-2 (FGF2) to determine whether it can reshape LRs'neural emotional circuits and assuage the emergence of the anxious/depressive-like LR phenotype. Together these studies will identify neurodevelopmental mechanisms that may underlie key aspects of individual differences in emotionality and susceptibility to depression and anxiety. This may ultimately impact our understanding of the neurobiology of emotional disorders and how to develop improved treatments. The research and educational components of this K99/R00 application aim to provide necessary training for the applicant to become a successful independent investigator who can integrate molecular, neuroanatomical, and behavioral findings from animal studies, and effectively translate these results to improve our understanding of the pathophysiology of psychiatric disease.

Public Health Relevance

Inborn differences in personality and temperament strongly influence how individuals respond to stress and put some people at risk for developing emotional disorders such as depression and anxiety. This proposal uses an animal model of depression/anxiety to study how abnormal brain development may give rise to emotional dysfunction later in life. Ultimately this work hopes to improve our understanding of the neurobiology of emotional disorders and help to develop improved treatments.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Transition Award (R00)
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Study Section
Special Emphasis Panel (NSS)
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Panchision, David M
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University of Alabama Birmingham
Schools of Medicine
United States
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Clinton, Sarah M; Watson, Stanley J; Akil, Huda (2014) High novelty-seeking rats are resilient to negative physiological effects of the early life stress. Stress 17:97-107
Clinton, Sarah M; Glover, Matthew E; Maltare, Astha et al. (2013) Expression of klotho mRNA and protein in rat brain parenchyma from early postnatal development into adulthood. Brain Res 1527:1-14
Simmons, Rebecca K; Stringfellow, Sara A; Glover, Matthew E et al. (2013) DNA methylation markers in the postnatal developing rat brain. Brain Res 1533:26-36
Cummings, Jennifer A; Clinton, Sarah M; Perry, Adam N et al. (2013) Male rats that differ in novelty exploration demonstrate distinct patterns of sexual behavior. Behav Neurosci 127:47-58
Kerman, Ilan A; Clinton, Sarah M; Simpson, Danielle N et al. (2012) Inborn differences in environmental reactivity predict divergent diurnal behavioral, endocrine, and gene expression rhythms. Psychoneuroendocrinology 37:256-69
Clinton, Sarah M; Kerman, Ilan A; Orr, Hailey R et al. (2011) Pattern of forebrain activation in high novelty-seeking rats following aggressive encounter. Brain Res 1422:20-31
Clinton, Sarah M; Stead, John D H; Miller, Sue et al. (2011) Developmental underpinnings of differences in rodent novelty-seeking and emotional reactivity. Eur J Neurosci 34:994-1005
Kerman, Ilan A; Clinton, Sarah M; Bedrosian, Tracy A et al. (2011) High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups. Brain Res 1419:34-45