Research in the Section on Nervous System Development and Plasticity, is concerned with understanding the molecular and cellular mechanisms by which functional activity in the brain regulates development of the nervous system during late stages of fetal development and early postnatal life. This work has three main areas of emphasis: 1. Determining how different patterns of neural impulses regulate specific genes controlling development and plasticity of the nervous system. This includes effects of impulse activity on neurons and glia and the molecular signaling pathways regulating gene expression in these cells in response to neural impulses. 2. Investigating how neurons and non-neuronal cells (glia) interact, communicate, and cooperate functionally. A major emphesis of this current research is in understanding how myelin (white matter in the brain) is involved in learning, cognition, child development, and psychiatric disorders. This research is exploring how glia sense neural impulse activity at synapses and non-synaptic regions, and the functional and developmental consequences of activity-dependent regulation of neurons and glia. 3. Determining the molecular mechanisms converting short-term memory into long-term memory, and in particular, how gene expression necessary for long-term memory is controlled. Cellular, molecular, and electrophysiological studies on synaptic plasticity (LTP) in hippocampal brain slice are used. Major recent achievements include showing that myelination is regulated by electrical activity. We have identified three general mechanisms for activity-dependent myelination: (1) regulation of cell adhesion molecules on axons affecting myelination;(2) release of ATP and adenosine from axons regulating development and myelination by Schwann cells and oligodendrocytes;(3) release the cytokine leukemia inhibitory factor (LIF) from astrocytes in response to ATP liberated by axons firing action potentials. LIF then stimulates myelination by mature oligodendrocytes. New researach has identified how neurotransmitters are released from axons firing action potentials without synaptic vesicles, and identified a microRNA that regulates synaptic development in a homeostatic manner according to functional activity. Other achievements include identifying changes in gene expression associated with conversion of e-LTP to l-LTP, a cellular model for conversion of short-term to long term memory. We have explored the intracellular signaling pathways involved in this model of synaptic plasticity and shown the importance of action potentials (in contrast to synaptic potentials) in activating gene transcription necessary for long-term changes in synaptic strength. We have shown that gene expression in neurons is regulated by specific patterns of neural impulses, and identified the intracellular signaling mechanisms regulating gene expression by the pattern of neural impulse firing. We have identified and explored several different modes of activity-dependent interactions between neurons and glia, including how myelination in the PNS and CNS is regulated by axonal firing. The axon-glial signals regulating gene transcription in astrocytes, oligodendrocytes, and Schwann cells in response to impulse activity are being identified. Our work shows that purinergic signaling (via ATP and adenosine release from axons) is a major mechanism of activity-dependent communication between axons and glia, but several other modes of activity-dependent neuron-glia communication have also been identified and are under investigation. The relevance of this neuron-glial communication to synaptogenesis and synapse elimination were shown in hippocampal cultures, and the involvement of ATP release in stabilization and elimination of neuromuscular junctions has been shown.
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