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 postnatally. Cellular Mechanisms of Learning While we continue our long-standing research interest in synaptic plasticity, our laboratory is actively exploring new mechanisms of nervous system plasticity during learning that extend beyond the neuron doctrine. This includes neurons firing antidromically, and the release of neurotransmitters along axons. We are particularly interested in the involvement of glial cells in learning and cognition. Glia are brain cells that do not fire electrical impulses, but they communicate by releasing neurotransmitters. This enables glia to monitor and regulate synaptic transmission. Our research showing that myelination of axons by glia (oligodendrocytes and Schwann cells) is regulated by impulse activity, suggests a new form of nervous system plasticity and learning that would be particularly important in child development, because myelination proceeds through childhood and adolescence. The mechanisms we have identified suggest that environmental experience would alter myelin formation in an activity-dependent manner, thereby improving function based on experience. The laboratory has three broad areas of interest: 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 emphasis 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. Myelin Plasticity Myelin, the multilayered membrane of insulation wrapped around nerve fibers by glial cells (oligodendrocytes), is essential for nervous system function, increasing conduction velocity by at least 50 times. Myelination is an essential part of brain development. The processes controlling myelination of appropriate axons are not well understood. Myelination begins in late fetal life and continues through childhood and adolescence, but myelination of some brain regions is not completed until the early twenties. Our research shows that release of the neurotransmitter glutamate from vesicles along axons promotes the initial events in myelin induction. This includes stimulating the formation of cholesterol-rich signaling domains between oligodendrocytes and axons, and increasing the local synthesis of the major protein in the myelin sheath, myelin basic protein, through Fyn kinase dependent signaling. This axon-oligodendrocyte signaling would promote myelination of electrically active axons to regulate neural development and function according to environmental experience. The findings are also relevant to demyelinating disorders, such as multiple sclerosis, and remyelination after axon injury. We also find that other signaling molecules released from axons, notably ATP, act to stimulate differentiation of oligodendrocytes with increases myelination. In collaboration with colleagues in Italy, found that a new membrane receptor on oligodendrocyte progenitor cells, GPR-17, regulates oligodendrocyte differentiation. The release of neurotransmitters and other signaling molecules outside synapses has broad biological implications, particularly with regard to communication between axons and glia. We have identified a mechanism for nonsynaptic, nonvesicular release of the neurotransmitter ATP from axons through volume-activated anion channels (VAACs) that are activated by microscopic axon swelling during action potential firing. These studies combined imaging single photons to measure ATP release, together with imaging intrinsic optical signals, intracellular calcium, time-lapse video, and confocal microscopy. Microscopic axon swelling accompanying electrical depolarization of axons activates VAACs to release ATP. This nonvesicular, nonsynaptic communication could mediate various activity-dependent interactions between axons and nervous system cells in normal conditions, development, and disease. Synaptic Plasticity Learning and other cognitive tasks require integrating new experiences into context. Coherent high-frequency oscillations of electrical activity in CA1 hippocampal neurons (sharp-wave ripple complexes, SPW-Rs) functionally couple neurons into transient ensembles. This is thought to contribute to the formation of a schema, which is the combination of multimodal aspects of an experience in proper temporal sequence to form a coherent memory. These oscillations occur during slow-wave sleep or at rest. Neurons that participate in SPW-Rs are distinguished from adjacent nonparticipating neurons by firing action potentials that are initiated ectopically in the distal region of axons and propagate antidromically to the cell body. We find that facilitation of spontaneous SPW-Rs in hippocampal slices and electrical antidromic stimulation of axons evokes a cell-wide, long-lasting synaptic depression, which we term AP-LTD (action potential-induced long-term depression). This new form of synaptic plasticity is not dependent upon synaptic input or glutamate receptor activation, but rather requires L-type calcium channel activation and functional gap junctions. Rescaling synaptic weights through this mechanism of plasticity in subsets of neurons firing antidromically during SPW-Rs would contribute to memory consolidation by sharpening specificity of subsequent synaptic input and promoting incorporation of novel information. Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are coordinately regulated during homeostatic synaptic plasticity is unknown. Micro RNAs (miRNAs) exert regulatory control over mRNA stability and translation and they may contribute to local activity-dependent posttranscriptional control of synapse associated mRNAs. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of mRNAs that are rapidly destabilized after increasing impulse activity in hippocample neurons in culture, we identified a developmentally and activity-regulated miRNA (miR485) and found that it controls dendritic spine number and synapse formation in an activity dependent homeostatic manner. Many plasticity associated genes contain predicted miR-485 binding sites including the presynaptic protein SV2A. We found that miR-485 decreases SV2A abundance and negatively regulates dendritic spine density, postsynaptic density protein (PSD-95) clustering, surface expression of GluR2 and postsynaptic currents. These findings show that miRNAs participate in homeostatic synaptic plasticity with possible implications in neurological disorders such as Huntington and Alzheimer's disease, where miR-485 is dysregulated.

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Pourshafie, Naemeh; Lee, Philip R; Chen, Ke-Lian et al. (2016) MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy. Mol Ther 24:937-45
Ravin, Rea; Blank, Paul S; Busse, Brad et al. (2016) Blast shockwaves propagate Ca(2+) activity via purinergic astrocyte networks in human central nervous system cells. Sci Rep 6:25713
Filley, Christopher M; Fields, R Douglas (2016) White Matter and Cognition: Making the Connection. J Neurophysiol :jn.00221.2016
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
Nunez, Paul L; Srinivasan, Ramesh; Fields, R Douglas (2015) EEG functional connectivity, axon delays and white matter disease. Clin Neurophysiol 126:110-20
Fields, R Douglas (2015) A new mechanism of nervous system plasticity: activity-dependent myelination. Nat Rev Neurosci 16:756-67
Fields, R Douglas; Woo, Dong Ho; Basser, Peter J (2015) Glial Regulation of the Neuronal Connectome through Local and Long-Distant Communication. Neuron 86:374-86
Rinaldi, Carlo; Schmidt, Thomas; Situ, Alan J et al. (2015) Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia. JAMA Neurol 72:561-70
Wake, Hiroaki; Ortiz, Fernando C; Woo, Dong Ho et al. (2015) Nonsynaptic junctions on myelinating glia promote preferential myelination of electrically active axons. Nat Commun 6:7844
Fields, R Douglas (2014) NIH policy: mandate goes too far. Nature 510:340

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