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 postnatal life. Our long-standing research interest is in synaptic plasticity, but our laboratory is actively exploring new mechanisms of nervous system plasticity during learning that extend beyond the neuron doctrine. We are especially interested in the involvement of glial cells in learning and cognition; particularly myelinating glia. 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. Myelinating glia form the electrical insulation on axons that greatly speeds impulse conduction velocity. Damage to myelin in multiple sclerosis, cerebral palsy, and other demyelinating disorders, causes severe nervous system impairment. Our research shows that myelination of axons by glia (oligodendrocytes and Schwann cells) is regulated by impulse activity. These findings suggest a new form of nervous system plasticity and learning. Activity-dependent myelination would be particularly important in child development, because myelination proceeds through childhood and adolescence. Rather than directly modifying synaptic transmission, activity-dependent myelination alters the speed and timing of information transmitted between relay points in neural networks. The arrival time of neural impulses at relay points in neural networks is of fundamental importance in neural coding, neuronal integration and synaptic plasticity, and in the frequency and coupling of brain wave oscillations. Our research has identified several specific molecular mechanisms for activity-dependent myelination, and shown that electrically active axons are preferentially myelinated. Our studies are identifying how neurotransmitters are released along axons to communicate with glia, and we are exploring medical implications of axon communication with myelinating glia in research to investigate how myelin may be damaged due to pesticide exposure and in Gulf War Illness. In addition we are investigating how impulse activity that is transmitted in the reverse direction (from axons into the cell body, antidromically) alter synaptic strength. The laboratory has three general areas of interest 1. 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. 2. 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. 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 and LTD) 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, and it increases 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 formation. This includes stimulating the formation of a signaling complex between oligodendrocytes and axons, and increasing the local synthesis of the major protein in the myelin sheath, myelin basic protein. This axon-oligodendrocyte signaling promotes myelination of electrically active axons to regulate neural development and function according to environmental experience. We also find that other signaling molecules released from axons, notably ATP, act to stimulate differentiation of oligodendrocytes resulting in increased myelination. In collaboration with colleagues in Italy, found that a new membrane receptor on oligodendrocyte progenitor cells, GPR-17, regulates oligodendrocyte differentiation. Our most recent research resolves a long-standing question in the field by showing that neither myelination nor activity-dependent regulation of myelination require synapses between axons and myelinating glia (called NG2 or OPC cells). Instead, our results show that release of neurotransmitter along axons from vesicles and through ion channels is important in communicating electrical activity in axons to glia. The release of neurotransmitters and other signaling molecules outside synapses has broad biological implications, particularly with regard to communication between axons and glia. In addition to vesicular release of neurotransmitter along axons, we have shown that the neurotransmitter ATP is released along axons through volume-activated anion channels (VAACs) that are activated by microscopic axon swelling during action potential firing. These studies combine imaging single photons to measure ATP release, together with imaging intrinsic optical signals, intracellular calcium, time-lapse video, and confocal microscopy. This nonvesicular, nonsynaptic communication could mediate various activity-dependent interactions between axons and nervous system cells in normal conditions, development, and disease. White matter damage Myelin damage is associated with many medical conditions, including hypoxia/ischemia during birth, exposure to environmental toxins such as pesticides, autoimmune disorders such as multiple sclerosis, and other conditions. We are investigating the possible involvement of myelin disruption in these contexts and seeking to develop new biomarkers and treatments for these conditions. This research has resulted in a patent application filed this year for a novel treatment for demyelinating disorders. Activity-dependent gene regulation Using primary cell co-cultures of neurons and glia equipped with electrodes for chronic electrical stimulation, we are determining how gene networks in neurons and glia are regulated by the pattern of neural impulse firing by using microarrays and transcriptome sequencing (RNA-Seq) for analysis. In research funded by a Directors Investigator award jointly to Dr. David Clark, NICHD, and Dr. Fields, we are investigating chromatin structure remodeling using genome-wide nucleosome mapping in neurons and glia. Synaptic Plasticity Coherent high-frequency oscillations of electrical activity in CA1 hippocampal neurons (sharp-wave ripple complexes, SPW-Rs) couple neurons into transient functional ensembles during learning. We find that SPW-Rs and antidromic stimulation evoke a cell-wide, long-lasting synaptic depression, which we term AP-LTD (action potential-induced long-term depression). In research on homeostatic synaptic plasticity we have identified a developmentally and activity-regulated miRNA (miR485) that controls dendritic spine number and synapse formatio
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