This proposal for a NIH Pathway to Independence Award (K99/R00) 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 will elucidate the ontogeny of neural circuits in a model of comorbid anxiety and depression to better understand how altered wiring during development may give rise to emotional dysfunction later in life. The project utilizes rats exhibiting dramatic differences in emotional reactivity ? those that either exhibit high levels of novelty-seeking behavior and those that are naturally inhibited, showing much less novelty-induced activity as well as exaggerated anxiety- and depressive- like behavior. These high versus low novelty-seeking traits appear to be 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 low vs. high novelty-seekers and determine how early-life factors may alter the trajectory of their 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 low/high novelty-seeking mothers exhibit distinct maternal styles, studies in Aim 2 will utilize a cross-fostering paradigm to determine how maternal care shapes low/high novelty-seekers? 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 low novelty-seekers'neural emotional circuits and assuage the emergence of their anxious/depressive-like 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.
PROJECT NARRATIVE 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.
