Developmental Programming of the Human Hypothalamus and its Role in Motivated Behaviors

ABSTRACT This application, submitted in response to NIH PAR-19-162 “Accelerating the Pace of Child Health Research Using Existing Data from the Adolescent Brain Cognitive Development (ABCD) Study”, aims to probe the devel- opmental origins of mental illness, a current public health crisis. This proposal will focus on the developing hy- pothalamus, a historically understudied region of the brain responsible for integrating the brain and bodily states. Specifically, this proposal will test the hypothesis that the structure and connectivity of the hypothalamus is im- pacted by early life adversity, and contributes to maladaptive brain function and behaviors underlying mental illness. The hypothesis is tested via three independent and innovative aims capitalizing on large-scale archival datasets from representative samples of ~11,000 adolescents from the Adolescent Brain Cognitive Development (ABCD, 9-15 years old) study and up to 7,500 children from the HEALthy Brain and Child Development (HBCD, 0-4 years old) study. Specifically, Aim 1 will develop normative MRI-based measures of hypothalamic size and shape, and structural and functional connectivity from birth until adulthood using two additional large-scale ar- chival datasets from the Human Connectome Project (HCP-Development, n~1,300, 5-21 years old; HCP-Young Adult, n~1,200, 22-35 years old) and cutting edge analytical methods. Aim 2 will assess the impact of early life adversity (e.g., economic hardship and adverse childhood experiences) on the structure and function of the developing hypothalamus. Aim 3 will elucidate the contribution of the structure and function of the developing hypothalamus to the motivated behaviors (i.e., reward and inhibition) emerging during adolescence that typically underly complex disorders and mental illness. Collectively, this proposal will capitalize on large-scale archival datasets from representative samples to discover understudied brain-body connections and potentially provide the basis for the subsequent development of strategies and policies aimed at mitigating the risk for mental health disorders.