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.