Regulation of BNST development by the adaptive immune system: implications for neurodevelopmental disorders

Defining the mechanisms that underlie brain development and function are vital for understanding the etiology of a broad range of neurodevelopmental (NDD) and psychiatric disorders, including autism, attention deficit disorder, bipolar disorder, and schizophrenia. Despite their distinct diagnoses, many of these disorders display similar behavioral phenotypes suggesting that transdiagnostic mechanisms may underlie their pathophysiology. We propose that one such mechanism is the development of the bed nucleus of the stria terminalis (BNST) via recruitment and activation of microglia by the immune system. The BNST is a complex, sexually dimorphic region intricately involved with fear and threat assessment, social behaviors, and reward processing. Notably, all of these behaviors are affected to varying degrees among NDDs and psychiatric disorders, suggesting that impaired development of the BNST and its neurocircuitry may play a significant role in their etiology. Despite its small size, the BNST is highly heterogenous, comprising several nuclei and multiple cell types which participate in both micro- and macrocircuits to modulate behavioral responses to the environment, including stress. Additionally, the BNST is one of the few brain regions that produces corticotropin releasing factor (CRF), a neuropeptide that is released in response to stress, as well as inflammation, two of the highest environmental risk factors for developing NDDs or psychiatric disorders. Microglia, considered the immune cells of the brain, play a significant role in neurodevelopment, particularly of sexually dimorphic regions, and are the primary effectors of systemic inflammation in the brain. While interactions between microglia and T cells, members of the adaptive immune system, have been described under pathological conditions, mounting evidence suggests they are required for homeostatic function and maturation of microglia as well. Our prior findings in immune deficient mice indicate that T cells are also required for normal behavioral responses to stress. Thus, we will determine if the adaptive immune system is necessary for normal BNST development by comparing immune deficient mice with littermates that received an adoptive transfer of lymphocytes from wild type mice as neonates. We will also determine if inflammation during early postnatal development is sufficient to alter BNST development. This proposal has been designed to utilize a combination of fundamental approaches to investigate the role of the adaptive immune system and inflammation in BNST neurocircuit development, and will include analysis of microglia, as well as behavior and circuit analyses. Elucidating whether the immune system recruits microglia to sculpt BNST neurocircuitry will profoundly shift our understanding of neuroimmune interactions in neurodevelopment and the role of inflammation in the pathophysiology of neurodevelopmental disorders. These studies will provide the foundation for future interrogations into the effects on BNST stress neurocircuits, and to evaluate neuroimmune interactions in specific BNST cell populations and neurocircuits, as well as other brain regions.