Microglia States and Functions
As a postdoctoral fellow in the Stevens lab, Nicole has several areas of research that she is pursuing, with a broad focus on the role of glia in development, aging, and disease. Microglia contribute to developmental and disease-associated synaptic pruning. To better understand the underlying neuronal cues contributing to microglial synaptic recognition, we discovered that localized exposure of the ‘eat me’ signal phosphatidylserine occurs in a developmentally regulated manner. She is continuing to follow up on our initial findings, exploring upstream mechanisms of phosphatidylserine exposure and how neuronal activity affects this, and whether aberrant phosphatidylserine exposure contributes to neurodegeneration. In addition to studying the role of neuronal and microglial interactions involved in synaptic pruning, she is also interested in uncovering novel roles of glia and glial-derived factors across development and aging. The microglial-derived complement protein C1q has demonstrated roles in developmental and disease synaptic pruning, but was also found to have age-specific effects on synaptic plasticity and cognitive function. To better understand the potentially unique roles synaptic C1q may have, she conducted C1qIP/mass spec experiments to identify C1q protein interaction networks. From these experiments, she developed several hypotheses that she isactively exploring.
Nader is interested in understanding the links between microglial inflammation, endolysosomal dysfunction, and neurodegeneration using human stem cell models. He is developing new tools to characterize changes in the microglial proteome in order to define a new set of biomarkers for microglial disease states.
Neuroimmunology and Development
Adolescence, the transition from juvenile to adulthood, is a developmental period marked by a prolonged structural change in brain circuits that coincides with an increase in cognitive capacity, sensory seeking and risk-seeking behaviors. From humans to monkeys to rodents, there is evidence for a profound change across the adolescence window in prefrontal cortical structure, connectivity, and function. While inroads have been made to understand the developmental mechanisms that drive PFC maturation and how the PFC contributes to an array of cognitive tasks, the connection between the PFC's developmental changes and its impact on behavior remain unclear. Utilizing behavior, physiology and cognitive modeling, we will delineate the strategies and computations underlying risk-seeking behavior across developmental ages (adolescents vs adults), sex (male vs female) and species (mouse vs non-human primate, marmoset).
Yvanka de Soysa
Yvanka's postdoctoral work focuses on dissecting the regulation and function of a developmental microglial state that we call Axon Tract Microglia (ATM). This enigmatic state appears in the white matter tracts of the corpus callosum and cerebellum in just the first week of postnatal life in mice. Due to their unique spatiotemporally distinct window of emergence, ATM are a powerful in vivo model to interrogate how the intersection of developmental origin, intrinsic gene regulatory programs and local environmental cues regulates microglial state dynamics. One goal of her work is to understand how these factors contribute to ATM state identity. The white matter tracts, where ATM reside during their brief window of emergence, comprise millions of axons that transmit and coordinate signals between brain regions. These critical communication channels are commonly disrupted in neurodevelopmental disorders, such as autism spectrum disorder. The timing of ATM emergence in white matter tracts coincides with important developmental milestones of these structures, therefore a second goal of this work is to define the functional contributions of ATM to white matter tract development and determine whether ATM dysregulation contributes to neurodevelopmental disease.
Alec Walker and Helena Barr
It is increasingly recognized that neuroimmune communication in the central nervous system (CNS) influences brain development, homeostasis, and disease. Recent studies have revealed a diverse compartment of immune cells that reside in the choroid plexus, perivascular space, and meninges that compose the brain’s borders in the adult and degenerating brain. However, much less is known about how the brain border immune compartment develops. Through a combination of single cell RNA sequencing, flow cytometry, and imaging, we have generated and spatiotemporal map of immune cells at the borders of the brain and the stromal compartment that supports them, leading to several surprising observations indicating that the meninges composes a unique immune niche in early life. Further, how immune cells at the brain’s borders sense and appropriately respond to signals from healthy developing and adult CNS is poorly understood. One hypothesis is that brain border immune cells interface with the brain’s drainage system (e.g. glymphatic/lymphatic systems) to sample material that is draining from the brain parenchyma. We have identified transcriptionally distinct populations of brain border associated macrophages (BAMs) at different brain border interfaces that sample material draining from the brain and have developed transgenic tools to probe their potential roles in facilitating waste clearance from the brain and regulating brain-specific immunity in different disease contexts. Overall, we aim to build a more comprehensive picture of how neuroimmune signaling at the borders of the brain shapes healthy brain development and/or generation of immune privilege characteristic of the CNS.
Dan has been investigating the ways in which pathological interactions between neurons and glia result in the aberrant elimination of synaptic connections in Huntington’s disease. His work has specifically been focused on dissecting the signals involved in pathogenic cross-talk between components of the innate immune system and microglia as well as the mechanisms that lead to the loss of particular types of synaptic connections. His ongoing studies are currently aimed at determining the molecular and cellular mechanisms involved in driving the region-specific neurodegeneration observed in Huntington’s disease with a view to identifying those that could be targeted to reduce pathology and slow disease. He is also investigating of complement protein levels and pathway activation in biological fluids obtained from patients with neurodegenerative diseases to determine if changes in these metrics reflect aspects of clinical progression and can be used to predict disease stage.
Sam's projects center around understanding immune system dysfunction in Alzheimer’s disease and aging. He uses a revolutionary technique known as single cell sequencing (scRNA-seq) to understand the gene expression changes that occur during aging and disease in individual cells. This technique allows us to examine disease specific changes at unparalleled resolution and understand the complex cell-to-cell interactions that mediate disease pathogenesis. His projects involve both animal models and human subjects in an attempt to better bridge the gap between basic science and clinical translation.
Saša is currently a joint postdoctoral associate between the Stevens and Deverman labs at the Broad Institute, where she is developing novel viral tools to enable manipulation of gene expression in microglia, with a particular focus on AAV capsid engineering. She hopes to use these viral tools to address questions about microglia biology, especially their role in the progression of neurodegenerative diseases.
Using induced microglia differentiated from human stem cells, the Stevens lab aims to understand microglia states and their impact on microglia functions. Our projects focus on the development of new tools to better understand microglia functions, deep characterisation of microglia transcriptomic and proteomic profiles, and understanding the impact of schizophrenia and Alzheimer's disease risk genes on neuroimmune interactions.
Mike's work centers on building and applying novel technologies to understand brain cell biology, with a particular focus on glial cell-states in health and disease. To better understand how neuronal connectivity is dysregulated in CNS disease, we are developing a new approach to target mRNA barcodes to synaptic compartments for high-throughput connectomics. Our long-term goal is to enable simultaneous acquisition of synaptic connectivity with single-cell transcriptomics data. He is also applying unbiased single-cell and spatial transcriptomics to models of brain damage and repair to understand the constellation of glial cell-states that orchestrate brain repair.
Alec Walker and Lasse Dissing-Olesen
We have developed a high throughput approach for unbiased quantification of in vivo engulfment at single cell resolution. We call this method FEAST (Flow cytometric Engulfment Assay of Synaptic Terminals). FEAST has enabled us to examine engulfment in thousands of microglia in a single experiment and, thus, to ask exploratory questions across diverse paradigms including whether microglial engulfment of synaptic material is affected by alterations in peripheral immune signaling, environmental stressors, diet, host metabolism, circadian clock and sleep/wake cycles, and disease-relevant genetic modulations. Another benefit of FEAST is its broad application as it can be utilized to interrogate engulfment by tissue resident macrophages in different nervous systems and model organisms.
Microglia have been implicated in a wide range of neurodegenerative diseases. Genetics is a powerful tool for elucidating disease mechanism and identifying potential drug targets in this crucial cell type. For example, genome-wide association studies of patients and healthy controls point to risk genes, whereas specific rare mutations have been suggested to confer protection against disease. Inspired by there naturally-occurring guideposts, I am interested in performing genome-wide screens to better understand how microglia function in response to disease challenges. The overarching goal of these experiments is to better understand basic microglia biology and also to search for future therapeutic avenues.