This proposal for a NIH Pathway to Independence Award (ROO component) aims to elucidate neurodevelopmental underpinnings of emotional dysregulation 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 use a novel animal model of depression and anxiety to elucidate the ontogeny of emotional neural circuits to better understand how altered wiring during development may give rise to emotional dysfunction later in life. Preliminary work revealed that anxiety- and depression-prone Low Novelty Reactive (LR) rats exhibit marked differences in the developing hippocampus compared to High Novelty Reactive (HR) animals.
The Specific Aims of this project are examining: 1) the ontogeny of hippocampal circuits in baseline LR versus HR animals;2) how their behavior and underlying neural circuits are modulated by environmental factors such as maternal care; and 3) how early life manipulation of hippocampal circuitry (via exposure to the growth factor FGF2) impacts brain development and later emotional behavior. The overarching goal of the proposed research is to identify neurodevelopmental mechanisms that may underlie key aspects of individual differences in emotionality and susceptibility to depression and anxiety.

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)
Program Officer
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