Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity.

The brain, endocrine, and immune systems are inextricably linked. Immunocompetent cells are located throughout virtually every organ of the body, including the brain and other endocrine tissues, and sophisticated interactions occur among these cells, via hormones, neurotransmitters, and soluble protein messengers called cytokines and chemokines (small chemotactic cytokines). These immune molecules have a powerful impact on neuroendocrine function, including behavior, during health as well as sickness.  Similarly, alterations in hormones, such as during stress, can powerfully impact immune function or reactivity.  These functional shifts are evolved, adaptive responses that organize changes in behavior and mobilize immune resources but can also lead to pathology or exacerbate disease if prolonged or exaggerated. However, the mechanisms by which such pathology develops, in particular the precipitation of mental health disorders, remain largely misunderstood. The developing brain is exquisitely sensitive to both endogenous and exogenous signals, and increasing evidence suggests the immune system has a critical role in brain development and associated behavioral outcomes for the life of the individual. There is now ample evidence that immune activation during prenatal or early postnatal development can have profound and long-lasting effects on the brain, and I believe the early-life immune history of an individual may indeed be critical to understanding the later-life risk or resilience of developing certain neuropsychiatric disorders.  

A particular focus of my research is on microglia, the primary immunocompetent cells of the CNS, which are involved in multiple aspects of brain development and function, including activity-dependent synaptic pruning and stripping, phagocytosis of apoptotic cells, and angiogenesis.  Cytokines such as tumor necrosis factor [TNF]a, interleukin [IL]-1b, and IL-6 are produced primarily by glia within the CNS and are implicated in the developing and adult brain in synaptic scaling, long-term potentiation, and neurogenesis.  Microglia originate early in the life of the fetus and are very long-lived, meaning they may have the capacity to reside in the brain for most of the life of the animal. Taken together, I have hypothesized that the developing brain is particularly sensitive to early-life immune activation and the associated risk of later-life neuropsychiatric disorders because (1)microglia are long-lived such that previously activated/functionally altered microglia (i.e. microglia exposed to an early-life immune challenge) may remain within the brain into adulthood, (2) immature microglia within the developing brain are functionally and/or immunologically different than microglia within the adult brain such that early-life immune activation can have greater consequences for neuroimmune function when compared to the adult brain, and (3) microglia and their inflammatory products are critical for normal cognitive function and behavior such that neuroimmune dysfunction results in mental health dysfunction.  

The simple goal of my research is thus to understand the important role of the immune system during brain development, and thereby the ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, mood and cognition.  In concert with this, I am interested in modeling current social and environmental issues (e.g. poverty, pollution, addiction) that impact the developing brain, and thereby how these factors may eventually be mitigated via careful scholarship, education, and engagement with trainees, collaborators, and members of society.