Nervous System Development and Plasticity

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Linked publications, trials & patents

Abstract

Our long-standing interest is in neural plasticity, but we are especially interested in the involvement of glial cells in nervous system development, learning & cognition. Glia are brain cells that do not fire electrical impulses, but they communicate by releasing neurotransmitters. This enables glia to monitor & regulate nervous system function. Myelinating glia (oligodendrocytes in the brain & Schwann cells in the body) form the electrical insulation on axons that greatly speeds impulse conduction velocity. Damage to myelin in multiple sclerosis, cerebral palsy, & other demyelinating disorders, causes severe nervous system impairment. Our research shows that myelination of axons is regulated by impulse activity and that even mature myelin can change structure in ways that alter the speed of neural impulse transmission. This represents a new form of nervous system plasticity & cellular mechanism of learning that would be particularly important in child development, because myelination proceeds through childhood & adolescence. Early life experience, both adverse & enriching, influences development of the brain in ways that can persist into adulthood. Rather than directly modifying synaptic transmission, activity-dependent myelination alters the speed & 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, information integration & synaptic plasticity, & in the coupling of brainwave oscillations. We have identified several molecular mechanisms for activity-dependent myelination & shown that electrically active axons are preferentially myelinated. The laboratory has four areas of current research interest 1. Determining how neurons & glia interact, communicate, & cooperate functionally. We are identifying how glia sense neural impulse activity & investigating the functional & developmental consequences. 2. A major emphasis of our research is in understanding how myelin is involved in learning, cognition, child development, & psychiatric disorders. We are determining how myelination is influenced by neural impulse activity and by sensory experience. 3. Functional experience influences nervous system development & plasticity by guiding appropriate changes in specific proteins & genes that regulate neural network formation & function. We are determining how different patterns of neural impulses regulate specific genes in neurons and glia controlling nervous system development & plasticity. 4. We are developing a novel nanocellulose material that can be used to capture and inactivate coronavirus to prevent infection. Our research goals advance 4 of the 6 NICHD research themes: 1. Understanding Early Human Development, 2. Setting the Foundation for a Healthy Pregnancy & Lifelong Wellness, 3. Identifying Sensitive Time Periods to Optimize Health Interventions, & 4. Improving Health During the Transition from Adolescence to Adulthood, and pursuing a novel approach to preventing infection by coronavirus, including SARS-Cov2. Myelin Plasticity Myelination is an essential part of brain development that begins in the second trimester & continues through adolescence, but myelination of some brain regions is not completed until the early twenties. The last part of the brain to complete myelination is the prefrontal cortex, the brain region responsible for impulse control & other executive functions. Environmental and other influences on myelination of the prefrontal cortex during adolescences contribute to neuropsychiatric concerns, including social interactions, decision making, anxiety disorders, & impulsivity. Many pediatric disorders, including cerebral palsy, dyslexia, language development, spasticity, & developmental delay are associated with disorders of myelin, in addition to well recognized demyelinating disorders, such as multiple sclerosis. Myelin Remodeling in Information Processing, Learning, and Plasticity The fundamental cellular mechanism of learning and plasticity is based on changes in strength of connections between neurons at synapses. While we study synaptic plasticity, our research has identified a new cellular mechanism of plasticity involving myelin plasticity. Synchronous neural impulse arrival at synaptic relay points in neural networks is critical for optimal information processing, and this is the fundamental basis for learning through strengthening and weakening synapses. By altering myelin sheath thickness and the structure of nodes of Ranvier, oligodendrocytes participate in learning and activity-dependent modification of neural networks. Our research shows that the neurotransmitter glutamate released from vesicles along axons initiates myelin formation. This signaling promotes myelination of electrically active axons to regulate neural development & function according to environmental experience. We also find that other signaling molecules released from axons, notably ATP, regulate development of myelinating glia. This nonsynaptic communication could mediate various activity-dependent interactions between axons & nervous system cells in normal conditions, development, & disease. Our recent research reveals that the structure of fully formed myelin can change to adjust conduction velocity to optimize neural circuit function. We find that glial cells called astrocytes, regulate changes in thickness of the myelin sheath and node of Ranvier structure by secreting molecules (thrombin protease inhibitors), that inhibit severing of the molecules that attach myelin to the axon (neurofascin 155). Myelin alterations through this mechanism in the optic nerve change the speed of impulse transmission, influence the timing of neural impulse arrival in visual cortex, and affect visual acuity. These findings are relevant to visual disorders resulting from abnormal visual experience (e.g., amblyopia), but more generally to information processing and plasticity in general. If optimizing synchrony of impulse arrival is how myelin contributes to nervous system plasticity, a major question in the field is how oligodendrocytes situated along axons, and far from synapses, could determine that neural impulses arrive with high synchrony. Using mathematical modeling, our most recent research indicates how this is possible. Unlike myelin forming cells in the peripheral nervous system, oligodendrocytes in the central nervous system where information and learning take place, have up to 50 long cellular processes, each of which wraps myelin around a different axon. According to our theory, an oligodendrocyte assess when a neural impulse arrives at each of its processes in contact with a different axon and compares its arrival with the arrival times of all axons within its domain. Myelin is then altered on each axon to minimize variation in timing of neural impulse arrival among all axons surveyed by an oligodendrocyte. This process continues in series through all oligodendrocytes along nerve fibers, which results in greatly increased synchrony of neural impulse arrival at the nerve terminal. Activity-Dependent Gene Regulation Using optogenetic stimulation in vivo & electrical stimulation in co-cultures, together with microarray and RNA sequencing, we are determining how gene networks & chromatin structure in neurons & glia are regulated by the pattern of neural impulse firing. Our studies show that specific patterns of action potentials regulate expression of thousands of genes in neurons and glia. COVID-19 We have developed a novel nanocellulose material that binds and inactivates coronavirus and HIV virus to prevent infection. The research involves cell culture, atomic force and confocal microscopy, and biochemical studies.