Regulation of Brain-Derived Neurotrophic Factor in Microglia

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One of the most significant advances in neuroscience research is the realization that neurons are not the only cell type involved in signalling in the central nervous system (CNS). My research focuses on the fundamental biology of how signals are modulated by an understudied class of cells known as microglia, which are resident immune cells in the CNS. The complex interplay between microglia and neurons is increasingly recognized as being essential for shaping and regulating CNS functions. A key signaling molecule released from microglia is brain-derived neurotrophic factor (BDNF), which in the spinal cord is a substance that alters nerve communication. That BDNF released from microglia fundamentally enhances the ability of neurons to transmit peripheral nerve stimuli such as pain is striking, and makes studying the cellular processes that regulate BDNF a pressing issue for understanding the basic human and animal biology of sensory processing. To date, the mechanisms regulating BDNF in microglia are poorly understood; thus, the proposed research program will closely examine key processes in the production of BDNF, the dynamics of BDNF release and the machinery that drives this release in microglia. To dissect the complex intracellular processes, an experimental approach that integrates biochemical, molecular, and imaging approaches will be used in primary and cell line microglia culture systems. The findings of this research have direct functional implications for microglia-neuron communication, and will form a conceptual framework for broader understanding of microglia signalling throughout the CNS. The potential impact is expected to extend beyond sensory biology as microglia are increasingly implicated in diverse processes involved in the programming and wiring of circuits in the brain and spinal cord. In addition, the proposed studies will form an essential part of my overall research program to understand normal and altered microglia biology, as well as to cultivate the training of highly qualified individuals for careers in academia, government and industry.