Although imperfect, the adult CNS (central nervous system) has the amazing ability to adapt to and compensate for deficits in neurologic function after CNS injury or neurodegenerative disease. While neurons and synaptic plasticity clearly contribute to this compensation, our laboratory is interested in understanding the contributions of the CNS immune system to this adaptation. Microglia, the only resident CNS immune cell, display astounding phenotypic plasticity, enabling them to respond and adapt to all aspects of CNS health and pathology. However, the cellular mechanisms enabling this plasticity over the course of chronic neuroinflammatory disease remain poorly understood. Although much research over the last 2 decades has been directed towards identifying exogenous molecules and pathways that attenuate the well-established pro-inflammatory/neurotoxic activities of microglia, little is known about endogenous cellular mechanisms used by microglia to self-regulate their transition to the reparative/neurosupportive phenotype during chronic disease, functions that would ultimately limit CNS damage and promote protection.

Thus, the overall goal of the research in our lab is to investigate the cellular and molecular mechanisms that regulate microglial phenotype and function as they contribute to CNS pathology and recovery in chronic neuroinflammatory disorders. To study microglial plasticity in chronic neuroinflammatory disease, one of our main research models is exposure to repetitive episodes of intermittent hypoxia (IH), a hallmark of sleep disordered breathing (e.g. sleep apnea). We have identified critical transitional periods in the microglial phenotype that occur between inflammatory and reparative/neurotrophic phenotypes over the course of intermittent hypoxia exposure. The specific timing of these effects and the elaborate shifts in classes of genes expressed at these times suggest that microglia utilize tightly regulated mechanisms to control their activities during CNS adaptation to chronic injury. Our recent evidence implicates a critical role for epigenetic processes (e.g. histone demethylation and microRNAs) in the mechanisms employed by microglia to initiate transitions between inflammatory and neurotrophic phenotypes. We are particularly interested in the signal transduction and gene transcriptional mechanisms used by microglia to enable these shifts in their function. These same epigenetic mechanisms underlie long-lasting alterations in adult microglial function that are initiated during fetal brain development as a consequence of in utero exposure to maternal IH.

We have developed powerful and novel flow cytometry and cell sorting tools with which to study specific microglial phenotypic populations in vivo, from which nucleic acids (DNA, mRNA and miRNAs) can be isolated for subsequent transcriptional regulation studies. These investigations are complemented by biochemical signaling studies in primary microglial cultures in wild type and transgenic mice to assess molecular/biochemical mechanisms of IH-induced signaling. Our recent work is aimed at defining microRNAs and histone modifications that contribute to microglial plasticity.

We also have projects designed to understand how neonatal development, aging and sex influences microglial regulatory processes. Age is a significant risk factor for many neurological disorders, many of which display sexual dimorphisms. Thus, we have studies focused on the differential responses of male and female microglia, and the role gonadal hormones play in their responses to inflammatory challenges. A current project involves looking at this question in a mouse model of Alzheimer’s disease, exposing them to chronic IH and assessing differences in microglial function and gene expression as well as cognitive and behavioral function.

Lastly, we have projects designed to understand the impact of microglial activities on neuronal function, and in particular, the ability of neurons to display plasticity. We are investigating the mechanisms whereby microglial inflammatory activities impair a form of spinal motor respiratory plasticity called phrenic motor facilitation, and how this differs between the sexes. Adult male offspring of mothers exposed in utero to maternal sleep disordered breathing have microglial-dependent neuroinflammation that impairs respiratory plasticity; but female offspring do not. Adult female offspring have normal neuroplasticity. We are testing the mechanisms whereby female offspring are protected from the gestational insults to which their male counterparts are predisposed.