In humans and nonhuman primates, anxious temperament (AT) is a trait-like phenotype that is evident early in life and characterized by increased behavioral and physiological reactivity to mildly threatening stimuli. In children AT is key risk factor for the later development of anxiety disorders, depression and comorbid substance abuse. Our prior work provides initial validation for an anxious endophenotype in young primates. Monkeys with higher levels of AT are similar to behaviorally inhibited children;both show excess freezing, reduced affiliative vocalizations, and elevated cortisol in the face of mild threat. Because of similarities in brain structure and social behavior, the rhesus monkey represents the ideal animal model for understanding the biological underpinnings of AT. In terms of brain mechanisms, indirect evidence implicates increased central nucleus of the amygdala (CeA) activity and corticotropin-releasing hormone (CRH) system activity as factors underlying the risk to develop anxiety and depressive disorders. Additionally, recent evidence implicates decreased neuroplasticity in the pathogenesis of these disorders. Relevant to this, we have amassed evidence that activity of the neurotrophin 3 (NTF3)/neurotrophic tyrosine kinase receptor type 3 (NTRK3) neuroplasticity system in the CeA is inversely related to individual differences in AT.
The aim of the proposed work is to perform studies in young rhesus monkeys to test the neurodevelopmental consequences of manipulations that increase or decrease risk for developing anxiety and depressive disorders. Accordingly, to increase vulnerability we will use a viral vector to chronically increase CRH expression in CeA. To decrease vulnerability, we will use a similar vector to chronically increase expression of NTF3 in CeA. This work will test the hypothesis that chronic overactivity of these systems will fundamentally alter the developmental trajectory of the neural circuit underlying AT. Monkeys will receive vectors at 2 years of age and will be longitudinally studied across the transition to adolescence until 4.5 years of age by repeatedly assessing in vivo imaging measures of brain structure and function, anxiety-related behaviors, pituitary-adrenal activity, and cerebrospinal fluid (CSF) CRH and NTF3 measures. The use of nonhuman primates, paired with advanced brain imaging measures, provides a unique opportunity to better understand prefrontal-amygdala interactions. Additional emphasis will be focused on hippocampal volumetric and morphometric measures and influences on the serotonin system indexed by serotonin 1A (5HT1A) binding, measured with in vivo positron emission tomography (PET) of dorsal raphe and hippocampus. Following 2 years of CRH or NTF3 overexpression, monkeys will be sacrificed to assess molecular markers of neuroplasticity, serotonin function, and hippocampal neurogenesis. Elucidating the mechanisms that underlie the regulation of chronic anxiety in primates promises to provide crucial insights into the mechanisms underlying the pathophysiology of human anxiety and depressive disorders.

Public Health Relevance

Childhood anxiety and depression are common and frequently are the forerunners of adult affective and anxiety disorders. The proposed experiments will identify the roles of stress- related and neuroplasticity-related systems within the amygdala as developmental mechanisms that may increase or decrease, respectively, the childhood risk to develop anxiety and depression. The studies will use state of the art molecular methods in a well established nonhuman primate model to provide new insights into brain mechanisms mediating the susceptiblity to develop these psychiatric disorders.

National Institute of Health (NIH)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Simmons, Janine M
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University of Wisconsin Madison
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