Research in the Section on Nervous System Development and Plasticity, is concerned with understanding the molecular 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 patterns of neural impulses regulate specific genes controlling development and plasticity of the nervous system.? ? 2. Investigating how neurons and non-neuronal cells (glia) interact, communicate, and cooperate functionally. This includes not only glia interactions at the synapse, but also the less-well understood communication in non-synaptic regions between the axon and myelinating glia.? ? 3. Determining how gene expression necessary for the conversion of e-LTP to l-LTP (a cellular model for conversion of short-term to long-term memory) is controlled. ? ? 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. ? 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 explored various 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.

Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2007
Total Cost
$825,395
Indirect Cost
City
State
Country
United States
Zip Code
Bukalo, Olena; Lee, Philip R; Fields, R Douglas (2016) BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus. Neurosci Lett 635:97-102
Lee, Philip R; Fields, R Douglas (2009) Regulation of myelin genes implicated in psychiatric disorders by functional activity in axons. Front Neuroanat 3:4
Fields, R Douglas (2008) Oligodendrocytes changing the rules: action potentials in glia and oligodendrocytes controlling action potentials. Neuroscientist 14:540-3
Fields, R Douglas (2008) White matter in learning, cognition and psychiatric disorders. Trends Neurosci 31:361-70
Fields, R Douglas (2008) White matter matters. Sci Am 298:42-9
Jia, Min; Li, Min-Xu; Fields, R Douglas et al. (2007) Extracellular ATP in activity-dependent remodeling of the neuromuscular junction. Dev Neurobiol 67:924-32
Fields, R Douglas; Fields, Kyle D; Fields, Melanie C (2007) Semiconductor gel in shark sense organs? Neurosci Lett 426:166-70
Stevens, Beth (2006) Cross-talk between growth factor and purinergic signalling regulates Schwann cell proliferation. Novartis Found Symp 276:162-75; discussion 175-80, 233-
Fields, R Douglas; Burnstock, Geoffrey (2006) Purinergic signalling in neuron-glia interactions. Nat Rev Neurosci 7:423-36
Lee, Philip R; Cohen, Jonathan E; Fields, R Douglas (2006) Immune system evasion by peripheral nerve sheath tumor. Neurosci Lett 397:126-9

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