Post-Doctoral Fellow in Neurology, The Stevens Lab, Boston Children’s Hospital
1. What motivated you to come to Harvard Medical School?
I came to HMS initially for my graduate training in the Program in Neuroscience, and I was very fortunate to be mentored by Dr. Dennis Selkoe, a pioneer in many fundamental processes of Alzheimer’s disease pathogenesis. I had always been interested in studying mechanisms of neurodegeneration, in particular, in understanding how synapses that act as building blocks for brain function become dysfunctional. I learned that, in order to have a critical understanding of what goes awry in disease, one has to first understand how the brain is normally built and maintained to process and execute myriads of information. HMS has been an excellent training ground to further our understanding in both the basic and diseased aspects of neuroscience. So, for my postdoctoral work, I stayed at HMS and joined the laboratory of Dr. Beth Stevens, who is an expert in the study of how synapses, the connections between neurons, develop and degenerate.
2. What is your current area of research?
I study how microglia, the resident immune cells of the central nervous system, contribute to synapse loss in Alzheimer’s disease. Our hypothesis that microglia are critical in disease-related synapse elimination came from earlier work examining the normal synapse pruning that occurs during development to fine tune and sculpt the nervous system. The Stevens lab discovered that microglia help refine synapses for the proper wiring of the visual thalamus. We recently found that a key developmental pruning pathway involving microglia and a group of immune molecules called complement is aberrantly reactivated in a region-specific manner in very early disease stages in Alzheimer mouse models, and that blocking different stages of the complement pathway and microglial engulfment protects synapse loss. Now, I am studying what local cues may instruct microglia to prune, and whether microglia engulf intact synapses or whether they clean up synapses that have already degenerated (i.e. debris).
3. How does your research relate to diseases of the nervous system?
Loss of synaptic integrity is a hallmark of several neurodevelopmental and neurodegenerative diseases. In Alzheimer’s disease, synapse loss significantly correlates with cognitive decline and is thought to occur early in disease pathogenesis. However, mechanisms behind synapse loss and dysfunction have been unclear. Emerging research implicate microglia as a sculptor of the developing brain and a potential destroyer of synapses in early stages of brain disease. My recently published study was among the first of a series of studies that implicate microglia in synaptic pathology across various disease models. Moreover, we have data that suggest protecting synapses by perturbing an immune pathway may lead to a long-term rescue of cognitive impairment in an Alzheimer’s disease mouse model. These data altogether suggest that microglia may play a critical role in synapse homeostasis and plasticity in adult brains, and that disruptions of relevant pathways may contribute to neurologic diseases.
4. What has your Lefler fellowship allowed you to do as a scientist?
I obtained my Lefler fellowship in a very early stage of my postdoctoral research. The Committee was willing to take a risk with me, as I only had some preliminary data at hand at that point. With the Lefler fellowship, I was able to pursue an unchartered territory of testing the hypothesis of an immune-related mechanism of synapse loss in Alzheimer’s disease mouse models. My work altogether suggests a new role for microglia in synapse loss, that microglia can consume synapses in a region-specific manner at an early disease stage, before there is plaque-related neuroinflammation.
5. What are your research goals?
Recent data from both the developing and diseased brains highlight the importance of understanding microglia-synapse interaction in the healthy adult brain. However, we still know very little about whether microglia contribute to synapse homeostasis in the adult brain. In my laboratory, I would like to study whether microglia contribute to brain region-specific synapse maintenance and plasticity. In particular, I am interested in how higher cognitive functions impact microglial biology, and conversely, dissect molecular pathways by which microglia contribute to learning and memory, and to cognitive impairment. I am also interested in understanding whether differences among microglial cells contributes to region-specific vulnerability of synapse loss, a hallmark of many neurologic diseases.
6. What are your career goals?
I would like to establish an independent laboratory dedicated to studying microglia-neuron interactions in the adult brain. The goal of my laboratory will be to understand whether microglia contribute to learning and memory, and to cognitive impairment.
7. What do you think is the next frontier in brain research?
To understand on a functional level the heterogeneity of a given cell type (microglia, astrocytes, neurons, etc.) on a single cell basis, and how the different cell types within a brain region or circuit work together to maintain and execute specific function.