Document text
Principal Investigator: RICHARD DOUGLAS FIELDS
Organization: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
Fiscal Year: 2021
Award: $1,436,963
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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. This suggests 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. A major emphasis is in understanding how myelin is involved in learning, cognition, child development, & psychiatric disorders. We are determining how glia sense neural impulse activity & investigating the functional & developmental consequences.
2. We are also investigating how myelination in the peripheral nervous system (PNS) is influenced by neural impulse activity. Far less is known about PNS myelination, but normal child development & recovery from nerve injury & disease require appropriate myelination.
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 controlling development & plasticity of the nervous system.
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.
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.
Myelin Remodeling
Our most recent research reveals that the structure of fully-formed myelin can change to adjust conduction velocity to optimize neural circuit function. Previously, it was assumed that myelin could not be altered, except by damage, but our research finds that myelin thickness & the node of Ranvier can be remodeled by a treadmilling process in which the outer layer of myelin wrapping is removed to thin the myelin sheath & slow conduction velocity, & new myelin is added beneath the overlaying layers to thicken the sheath. We find that glial cells called astrocytes, regulate the detachment of this outer layer of myelin from the axon by secreting molecules (thrombin protease inhibitors), that inhibit severing of the molecules that attach myelin to the axon (neurofascin 155).
White Matter Damage
Myelin damage is associated with many medical conditions, including hypoxia/ischemia during birth leading to cerebral palsy, exposure to environmental toxins such as pesticides, autoimmune disorders such as multiple sclerosis, & other conditions. We are investigating the possible involvement of myelin disruption in these contexts.
PNS Myelination
Myelin is formed in the PNS by Schwann cells, which are a different type of cells from oligodendrocytes which form myelin in the CNS. Far less is known about Schwann cell myelination, but normal development & many disorders are the result of disruption of PNS myelin, including diabetic neuropathy, Gillian Barre disease, & recovery from all nerve injury which results in damage to myelin. We are applying our findings on activity-dependent myelination by oligodendrocytes to determine if similar mechanisms regulate PNS myelination.
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 are developing a novel nanocellulose material that binds and inactivates coronavirus to prevent infection. The research involves cell culture, atomic force and confocal microscopy, and biochemical studies.
Terms: <12-20 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><2nd trimester><Action Potentials><Adolescence><Adult><Adult Human><Antiproteases><Anxiety Disorders><Area><Astrocytes><Astrocytus><Astroglia><Atomic Force Microscopy><Autoimmune Diseases><Axon><Binding><Biochemical><Birth><Brain><Brain Hypoxia-Ischemia><Brain Nervous System><Brain region><CNS plasticity><COVID-19><COVID-19 virus><COVID19><COVID19 virus><CV-19><CV19><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cells><Cerebral Palsy><Child Development><Childhood><Chromatin Structure><Co-culture><CoV-2><CoV2><Cocultivation><Coculture><Coculture Techniques><Code><Coding System><Cognition><Communication><Confocal Microscopy><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coupling><Decision Making><Demyelinating Diseases><Demyelinating Disorders><Development><Developmental Delay><Developmental Delay Disorders><Diabetic Neuropathies><Disease><Disorder><Disseminated Sclerosis><Dyslexia><Electric Stimulation><Electrical Stimulation><Encephalon><Endopeptidase Inhibitors><Environmental Toxin><Exposure to><Force Microscopy><Foundations><Gene Action Regulation><Gene Expression Regulation><Gene Proteins><Gene Regulation><Gene Regulation Process><Genes><Glia><Glial Cells><Glutamates><Goals><Health><Human Development><Impairment><Impulsivity><Infant and Child Development><Infection prevention><Injury><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Kolliker's reticulum><L-Glutamate><Laboratories><Language Development><Leanness><Learning><Life><Life Experience><Mediating><Medical><Memory><Mental disorders><Mental health disorders><Midtrimester><Molecular><Molecular Interaction><Monitor><Multiple Sclerosis><Myelin><Myelin Sheath><NICHD><National Institute of Child Health and Human Development><National Institute of Children's Health and Human Development><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Nervous System><Nervous System Physiology><Nervous system structure><Neural Cell><Neural Development><Neural Transmission><Neurilemma Cell><Neurilemmal Cell><Neurocyte><Neuroglia><Neuroglial Cells><Neurologic Body System><Neurologic Organ System><Neurologic function><Neurological function><Neuronal Plasticity><Neurons><Neurophysiology - biologic function><Neurotransmitters><Non-neuronal cell><Nonneuronal cell><OL myelination><Oligodendrocytes><Oligodendrocytus><Oligodendroglia><Oligodendroglia Cell><Parturition><Pattern><Peptidase Inhibitors><Peptide Hydrolase Inhibitors><Peptide Peptidohydrolase Inhibitors><Peripheral Nervous System><Pesticides><Prefrontal Cortex><Prevent infection><Process><Protease Antagonists><Protease Inhibitor><Protein Gene Products><Proteinase Inhibitors><Psychiatric Disease><Psychiatric Disorder><RNA Seq><RNA sequencing><RNAseq><Ranvier's Nodes><Recovery><Research><SARS corona virus 2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scanning Force Microscopy><Schwann Cells><Second Pregnancy Trimester><Second Trimester><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Social Interaction><Specific Child Development Disorders><Speed><Structure><Synaptic Transmission><Synaptic plasticity><Thick><Thickness><Thinness><Thrombase><Thrombin><Time><Toxic Environmental Agents><Toxic Environmental Substances><Word Blindness><Wuhan coronavirus><acquiring language skills><adolescence (12-20)><adulthood><astrocytic glia><autoimmune condition><autoimmune disorder><biological signal transduction><brain cell><cell culture><cell type><central nervous system plasticity><corona virus><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 virus><developmental><diabetes-associated neuropathy><electrostimulation><environmental toxicant><executive control><executive function><experience><fetal><fibrinogenase><glutamatergic><hCoV19><healthy pregnancy><hypoxia ischemia><improved><in vivo><injuries><insular sclerosis><interest><interventional strategy><language acquisition><language learning><mental illness><myelination><nCoV2><nerve cement><nerve injury><nervous system development><nervous system function><neural><neural circuit><neural circuitry><neural function><neural injury><neural network><neural patterning><neural plasticity><neurocircuitry><neurodevelopment><neurofascin><neuronal><neuroplastic><neuroplasticity><neuropsychiatric><neuropsychiatry><neurotransmitter release><new approaches><novel><novel approaches><novel strategies><novel strategy><oligodendrocyte myelination><optogenetics><pediatric><post-natal development><postnatal><postnatal development><psychiatric illness><psychological disorder><relating to nervous system><spasticity><synaptic circuit><synaptic circuitry><transcriptome sequencing><treadmill><vesicle release><vesicular release><white matter damage>