Research

Capturing oligodendrocyte plasticity with nascent proteome tagging

Spatiotemporal regulation of protein synthesis underlies neuronal plasticity in learning and memory. The development of spatiotemporal tools that enable real-time control of neuronal excitability and inhibition have led to deep mechanistic understanding of neuronal and synaptic plasticity. However, it is unclear what are the mechanisms that regulate activity-dependent oligodendrocyte plasticity. We have recently generated oligodendrocyte specific bio-orthogonal mice that allow us to track oligodendrocyte specific proteomes and secretomes with unprecedented temporal control. We aim to identify stage specific dynamic processes occurring in oligodendrocyte lineage cells during memory formation with the goal of identifying regulators of OL plasticity. This knowledge could be used to develop tools to directly manipulate oligodendrocyte lineage cells.

Oligodendrocyte SRF signaling in adult and aged mice

A fundamental property of the central nervous system is its ability to alter its structure and function in response to external life experience, thereby enabling learning and memory. SRF is an immediate early gene and a transcription factor expressed by oligodendrocytes and downregulated with aging in the mouse hippocampus. This raises many interesting questions such as what are the SRF targets in oligodendrocyte lineage cells in health and disease? Does SRF regulate OPC plasticity and adaptive myelination? Can SRF be targeted to rejuvenate oligodendrocytes in the aging brain?

Mechanisms of inefficient adaptive myelination with age

Despite high abundance of OPCs in the aged brain, OPC proliferation and differentiation is slow and inefficient. We recently found that exposure to young CSF or to the growth factor Fgf17 boosted OPC proliferation and myelination capacity with aging. However, the underlying cellular mechanisms of oligodendrocyte dysfunction with aging are mostly unknown. Combining labeling of proliferating cells with transcriptomics and proteomic profiling we aim to elucidate underlying mechanisms of failed oligodendrogenesis with aging and facilitate the discovery of novel strategies to rejuvenate oligodendrocytes to restore or maintain cognitive function with age.

Fgf17 function in the adult and aging brain

We recently discovered that the levels of growth factors in cerebrospinal fluid, such as Fgf17, impact oligodendrocyte growth and cognitive function. We are currently generating transgenic mice reporting the expression of Fgf17 and manipulating its levels to answer questions such as: which cells express Fgf17 in the adult and aging brain? Which cellular pathways regulate its secretion and how are they affected with age? What is the mode of action of Fgf17 signaling on oligodendrocytes and other neural cells?