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Program in Developmental Neuroscience
The Program in Developmental Neuroscience (PDN) takes a comprehensive approach to the study of developmental neuroscience by using techniques of neurophysiology, molecular and cellular biology, crystallography, imaging, and biobehavioral analysis in a variety of animal models as well as in humans and non-human primates. Overall, the research focuses on the development, physiology, and pathophysiology of the mammalian central nervous system. Researchers study receptors, ion channels, and signaling mechanisms in preparations that range from isolated proteins and cells to highly ordered neural networks in both physiological and pathophysiological conditions observed in both wild-type and numerous transgenic animals. Basic biobehavioral research aims to understand cognitive, social-emotional, and biological development in humans and non-human primates. The PDN studies both genetic and environmental factors and their interactions from a comparative perspective in order to characterize the developmental trajectories of individuals across a broad range of species, populations, and settings.
Tamás Balla’s Section on Molecular Signal Transduction investigates the role of phosphoinositide-derived messengers in mediating the actions of hormones, growth factors, and neurotransmitters in mammalian cells. The Section’s studies focus on the cellular functions of phosphatidylinositol 4-kinase (PI4K) enzymes that regulate the first committed step in phosphoinositide synthesis. Over the last year, the Section characterized the developmental defects caused by the elimination of one of these enzymes, PI4KIIIalpha, from zebrafish embryos. The Section found that downregulation of the enzyme resulted in the loss of pectoral fins as a result of a defect in the Fgf signaling cascade. The defect is attributable to the inability of PI 3-kinases to activate their downstream targets because of an insufficient supply of phosphoinositides. The studies are the first to identify the role of a PI4K enzyme in the developmental process of a vertebrate organism.
Marc Bornstein’s Child and Family Research Section investigates dispositional, experiential, and environmental factors that contribute to physical, mental, emotional, and social development in human beings across the first two decades of life. The Section’s overall goals are to describe, analyze, and assess the capabilities and proclivities of developing human beings, including their physiological functioning; perceptual and cognitive abilities; and emotional, social, and interactional styles. At the same time, the Section describes and analyzes the nature and consequences for children and parents of family development and children’s exposure to and interactions with their designed and natural surroundings. Project designs are experimental, longitudinal, and cross-sectional as well as intra- and cross-cultural.
Using a combination of molecular, cellular, electrophysiological, and behavioral approaches, Andres Buonanno and colleagues in the Section on Molecular Neurobiology study how experience (activity) modulates neuronal plasticity during development. The Section has focused on the neurotrophic factor Neuregulin-1 and signaling via its receptor ErbB4, recognizing that this signaling pathway uniquely reverses long-term potentiation (LTP) at glutamatergic synapses in an activity-dependent fashion and modulates gamma oscillatory network activity in the hippocampus. The Section recently uncovered a novel, potentially important functional link among NRG-1/ErbB4, dopamine, and glutamate signaling pathways—important because the three pathways are genetically and pharmacologically implicated in cognitive functions and psychiatric disorders.
Dax Hoffman’s Unit on Molecular Neurophysiology and Biophysics continues to investigate the role of the voltage-gated K+ channel subunit Kv4.2 in the regulation of dendritic excitability and synaptic integration of CA1 pyramidal neurons of the hippocampus. Over the past year, the Unit demonstrated bidirectional remodeling of CA1 synapses by Kv4.2. Neurons exhibiting enhanced A-type K+ current showed a reduced synaptic fraction of the NMDA receptor subunit NR2B while genetic reduction of A-currents led to an increased fraction of synaptic NR2B. Bidirectional synaptic remodeling was dependent on spontaneous activation of NMDA receptors and active CaMKII. The data suggest that A-type K+ channels are an integral part of a synaptic complex that regulates Ca2+ signaling through spontaneous NMDAR activation to control synaptic NMDAR expression and plasticity.
Kuo-Ping Huang’s Section on Metabolic Regulation investigates the signaling mechanisms involved in synaptic plasticity. Using neurogranin (Ng) knockout mice, the Section demonstrated the protein’s critical role in the expression of LTP and normal cognitive function. Environmental enrichment and treatment with Ritalin® ameliorated the behavioral impairments of young adult Ng-knockout mice. Immunohistochemical studies demonstrated that Ng localized in neuronal cell bodies and dendrites in the hippocampus, whereas calmodulin (CaM) was concentrated in the nucleus. High-frequency stimulation resulted in the co-localization of Ng and CaM in the dendritic spines, which may function as tags for directing the stimulated neuronal network to increase synaptic efficacy.
Y. Peng Loh’s Section on Cellular Neurobiology explores the mechanisms of intracellular trafficking and secretion of peptide hormones, neuropeptides, and neurotrophins in endocrine cells and neurons as well as the role of the prohormoneprocessing enzyme carboxypeptidase E in tumorogenesis. Major accomplishments over the past year include: elucidation of the carboxypeptidase E–dependent mechanisms for microtubule-based transport and tethering of BDNF and ACTH vesicles at specific sites on the plasma membrane for exocytosis in hippocampal neurons and pituitary cells; and identification of a novel splice isoform of carboxypeptidase E that promotes and predicts metastasis in various human cancers.
Mark Mayer’s Section on Neurophysiology and Biophysics investigates ionotropic glutamate receptors (iGluRs)—the molecular pores that mediate signal transmission at the majority of excitatory synapses in the mammalian central nervous system. Given the receptors’ essential role in normal brain function and development and increasing evidence that dysfunction of GluR activity mediates several central nervous system diseases and damage during stroke, the Section studies receptor mechanisms by combining atomic-resolution structural data obtained by X-ray diffraction and functional data collected from rapid perfusion techniques and patch clamp recording. The Section recently identified the binding site for allosteric ions and solved structures for NR3 subtype NMDA receptors.
Chris McBain’s Section on Cellular and Synaptic Physiology investigates the development and regulation of cortical excitability, in particular glutamatergic and GABAergic synaptic transmission and plasticity in hippocampal formation. Work over the past year focused on the differential regulation of transmitter release at functionally divergent presynaptic terminals along a common axon, the roles of ionotropic and metabotropic glutamatergic and cholinergic receptors in controlling cell excitability, and bidirectional synaptic plasticity at both inhibitory and excitatory axon terminals. The Section also investigated the embryonic neurogenesis, migration, and development of specific cohorts of local circuit inhibitory interneurons of the hippocampus.
John Newman’s Unit on Developmental Neuroethology studies the mechanisms of primate vocal communication during development. This year, the Unit found that, in the brains of marmosets exposed to infant cries, Fos labeling increased in cells in all components of the limbic system as well as in the superior temporal gyrus (auditory cortex), insular cortex, and ventro-medial frontal cortex. In crying infant marmosets, more cortical cells were positive for Fos labeling at one month than at two months of age.
James Russell’s Section on Cell Biology and Signal Transduction studies signaling between neurons and glia in the nervous system. To enable direct measurement of glial cell Ca2+ signals, the Section developed transgenic mouse lines expressing a fluorescent Ca2+ indicator photoprotein in astrocytes and Schwann cells, using the S-100β promoter. The Section uses two-photon microscopy to image labeled cells deep (500 to 700 μm) within brains in the transgenic mice as well as glial cell signals in isolated brain slice and isolated nerve preparations. In a collaborative study with an NINDS intramural laboratory, the Section is investigating the role of astrocytes in regulating cerebral blood flow and is developing new transgenic lines by using an improved indicator protein together with other cell-specific promoters that target astrocytes, oligodendrocyte progenitor cells, and Schwann cells.
Stanko Stojilkovic and colleagues in the Section on Cellular Signaling investigate receptors and channels expressed in pituitary cells. The Section has identified a novel pathway by which dopamine 2 receptors control prolactin release downstream of voltage-gated calcium influx. The Section also showed that hypotonicity induces hormone discharge from readily releasable prolactin-containing vesicles in a “kiss-and-run” mode. In related studies, the Section characterized molecular, pharmacological, and functional properties of GABA-A receptors in normal and immortalized pituitary cells and demonstrated that activation of the receptors results in depolarization of cell membranes and modulation of spontaneous electrical activity. The Section’s work on purinergic P2X4 channels cloned from pituitary lactotrophs revealed the helical topology of the two transmembrane regions of the receptor in the activated state.
Mark Stopfer’s group, the Unit on Sensory Coding and Neural Ensembles, is interested in understanding how brain mechanisms gather and organize sensory information to build transient and sometimes enduring internal representations of an animal’s surroundings; the animal actively collects information, which is then processed and dramatically transformed in myriad ways. The Unit’s goal is to understand the fundamental mechanisms by which sensory information is collected, transformed, stabilized, and compared as it makes its way through the nervous system. Using relatively simple animals and focusing primarily on olfaction, the Unit combines electrophysiological, anatomical, genetic, behavioral, computational, and other strategies to examine how fully intact neural circuits, driven by real sensory stimuli, process information.
Stephen Suomi and colleagues in the Comparative Behavior Genetics Section conduct broad-based investigations of primate biological and behavioral development through comparative longitudinal studies of rhesus monkeys and other primates. Their primary goals are to characterize various distinctive biobehavioral phenotypes in their rhesus monkey colony, to determine how genetic and environmental factors interact to shape the developmental trajectories of each phenotype, and to assess the long-term behavioral and biological consequences, for monkeys from various genetic backgrounds, of rearing in different physical and social environments. A second major program of research investigates how rhesus monkeys and other non-human primate species born and raised under different laboratory conditions adapt to placement into environments that model specific features of their natural habitat.