Specific Aims: Anxiety and depressive disorders are common, comorbid, and challenging to treat, ranking them among the greatest contributors to human suffering. An early-life extreme inhibited or anxious temperament, characterized by behavioral inhibition and extreme physiological responses to novel and/or potentially threatening contexts, is among the strongest predictors of the later development of anxiety and depressive disorders. Understanding the neurobiology of this early-life risk will identify treatment targets and provide a unique opportunity to develop scientifically founded behavioral and pharmacological interventions to treat and prevent stress-related psychopathology. Here, we propose a prospective longitudinal study in nonhuman primates (NHPs) to understand how inborn risk-factors and early-life inhibition lead to anxiety and maladaptive social behavior during adolescence and early adulthood. We will do this by leveraging the resources at the California National Primate Research Center (CNPRC), including previous early-life assessments of behavioral inhibition, a multi-generational family pedigree, and large outdoor housing, alongside cutting-edge tools and analysis techniques, including multimodal neuroimaging and neural network-based animal tracking and behavioral analyses. We will use a prospective longitudinal design, and select 176 NHPs (88 F) previously phenotyped for early-life inhibition (3-4 months old) from the CNPRC?s large, multi-generational family pedigree. To study the emergence of anxiety- and depression-like symptomatology, half of the NHPs will be adolescents and half will be young adults. We will perform in-lab behavioral and neuroimaging assessments, and longitudinal large-scale monitoring as animals navigate the entirety of their socio-geographic environment. First, we will examine how heritable-risk and early- life inhibition contribute to maladaptive socio-emotional behaviors in ecologically-valid contexts during adolescence and early adulthood (Aim 1). Starting in puberty, the risk for anxiety disorders is greater for girls than boys. Therefore, we also aim to demonstrate adolescent and young-adult sex differences in anxiety- and depression-like behaviors (Aim 2). To understand how these factors are mediated by alterations in relevant brain circuitry, including the extended amygdala, each animal will undergo multimodal structural and functional neuroimaging assessments. Using these data, we will test specific hypotheses regarding the extent to which extended amygdala circuits link early-life inhibition to the progression of anxiety- and depression-like behaviors (Aim 3). This combination of approaches promises to provide unprecedented insight into the neural substrates of maladaptive socio-emotional behavior during the transition to adulthood.
A key challenge for psychiatry and clinical psychology is to discover, understand, and ultimately treat the root causes of the most common mental illness, including anxiety and depressive disorders. This project will harness an innovative combination of longitudinal measures and state-of-the-art tools?including a multi-generational pedigree, brain imaging, and deep neural networks?to objectively identify and prioritize the pathways that contribute to maladaptive social behavior as individuals mature into adults. This proposal promises to identify new treatment targets for the prevention of stress-related psychopathology.
