PROGRAM IN DEVELOPMENTAL NEUROSCIENCE
The Program in Development Neuroscience (PDN) takes a comprehensive approach to the study of developmental neuroscience by using the techniques of neurophysiology, molecular and cellular biology, crystallography, imaging, and biobehavioral analysis in a variety of animal models as well as in humans and nonhuman primates. Together, 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 from both wild-type and numerous transgenic animals. Basic biobehavioral research is targeted to understanding cognitive, social-emotional, and biological development in humans and nonhuman primates. The PDN studies both genetic and environmental factors and their multiple 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 signal transduction pathways mediating the actions of hormones, growth factors, and neurotransmitters in mammalian cells, with an emphasis on the role of phosphoinositide-derived messengers. Over the last year, the section established a new method based on the rapamycin-induced heterodimerization of the FKBP12 and FRB fragment of mTOR proteins to determine how the level of specific phosphoinositides can be altered acutely in living cells. Using this method, the section addressed the roles that PtdIns(4,5)P2 play in ion channels and GAP junctions as well as in recruiting components of the clathrin-mediated endocytic machinery to the membrane.
Marc Bornstein’s group, the Child and Family Research Section, investigates dispositional, experiential, and environmental factors that contribute to physical, mental, emotional, and social development in human beings during 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 genetic characteristics; physiological functioning; perceptual and cognitive abilities; emotional, social, and interactional styles; and the nature of and consequences of family development for children and parents and of children’s exposure to and interactions with their physical surroundings. Project designs are experimental, longitudinal, and cross-sectional as well as intra- and cross-cultural.
Andres Buonanno's Section on Molecular Neurobiology observed that neuregulin-1 signaling, via its ErbB4 receptor, regulates plasticity at glutamatergic synapses and that trafficking of ErbB4 changes during development through its interaction with PSD-95. The section isolated and characterized a novel form of Neuregulin-1 that is associated with a higher risk for developing psychosis in psychiatric disorders. The section also investigated how NFAT and NFkB, two calcium-dependent transcription factors, sense distinct types of motor neuron activity in adult muscles to regulate differentially the genes responsible for the adaptive properties of skeletal muscles.
Dax Hoffman's group, the Molecular Neurophysiology and Biophysics Unit, has continued to elucidate 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. Work over the past year demonstrated that activity-dependent trafficking of Kv4.2 in dendrites affects dendritic excitability and synaptic plasticity. In the coming year, the unit plans to extend these findings to determine the mechanisms and requirements of Kv4.2 activity–dependent trafficking as well as the effect of Kv4.2 trafficking on the intrinsic excitability of CA1 neurons.
Kuo-Ping Huang’s Section on Metabolic Regulation investigates the signal transduction mechanisms involved in synaptic transmission and plasticity. Using neurogranin (Ng) knockout (KO) mice, the section demonstrated that the cognitive impairments of aging in such mice could be improved by physical exercise and environmental enrichment without the enhancement of hippocampal long-term potentiation (LTP). Direct stimulation of PKC, PKA, or chromatin remodeling rectified the deficits of LTP in the mice, suggesting potential drug treatments for alleviating the cognition deficits of these animals. Ischemia caused a suppression of LTP accompanied by oxidative modification of Ca2+/calmodulin-dependent protein kinase II, likely via glutathione disulfide S-oxides.
Y. Peng Loh's Section on Cellular Neurobiology investigates the mechanisms of intracellular trafficking of peptide hormones, neuropeptides, and neurotrophins and their processing enzymes and the regulation of secretory granule biogenesis in endocrine cells and neurons. Major accomplishments over the past year included the discoveries of (1) a carboxypeptidase E–dependent mechanism for microtubule-based transport of BDNF and ACTH vesicles to their respective release sites in hippocampal neurons and pituitary cells and (2) carboxypeptidase E’s promotion of growth and metastasis of tumor cells and its role in neuroprotection of CA3 neurons in the adult hippocampus.
Bai Lu and his colleagues in the Section on Neuronal Development study the developmental neurobiology of psychiatric diseases. Using a retrovirus-mediated RNA interference approach, they revealed several unexpected roles of the Disrupted-In-Schizophrenia 1 (DISC1) gene in the development of new neurons in the adult hippocampus. They also began addressing the role of BDNF in depression and anxiety, proposing that BDNF is a target of antidepressants and that pro– and mature BDNF play different and even opposing roles in the brain's stress and reward systems.
Mark Mayer's Section on Neurophysiology and Biophysics is working to define the molecular mechanisms by which the neurotransmitter L-glutamate activates ion channels at synaptic membranes. The section's research requires high-resolution structures of the receptor proteins, which are encoded by 18 genes that co-assemble in different combinations to form tetrameric ligand-gated ion channels. Crystal structures and functional studies revealed the molecular mechanism of anion modulation of kainate receptors, the basis of GluR5 subtype antagonist selectivity, and ligand binding by NR3A- and NR3B-subtype NMDA receptor subunits.
Chris McBain's group, the Section on Cellular and Synaptic Physiology, is interested in the development and regulation of cortical excitability, particularly 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 common axons, specifically the role of ionotropic and metabotropic glutamatergic and cholinergic receptors in controlling cell excitability and bidirectional synaptic plasticity at both inhibitory and excitatory axon terminals.
John Newman’s Unit on Developmental Neuroethology continues to study the mechanisms of primate vocal communication during development. Most recently, the unit initiated a study of the brain areas activated in the common marmoset monkey upon hearing marmoset infant cries. The study uses c-fos immunocytochemistry to parallel the section’s earlier collaborative studies that used functional MRI to investigate brain activation in human mothers upon hearing human infant cries. The unit discovered that the previously developed adult marmoset brain atlas is useful for the brains of 1-, 2-, and 3-month-old marmoset infants.
James Russell’s Section on Cell Biology and Signal Transduction studies signaling between neurons and glial cells. Current research has characterized mutual signals between axons and Schwann cells during action potential propagation. To enable direct measurement of glial cell Ca2+ signals, the section developed a transgenic mouse that expresses a Ca2+ indicator photoprotein selectively in astrocytes and Schwann cells. Two-photon confocal microscopy enabled imaging of isolated brain slices and nerve preparations to record glial cell Ca2+ signals evoked by direct stimulation. Understanding the signaling between axons and Schwann cells in healthy nerves permits the investigation of alterations in signaling that occur in peripheral neuropathies and in nerve injury.
Stanko Stojilkovic and his colleagues in the Section on Cellular Signaling investigate receptors and channels expressed in pituitary cells. They identified novel endothelin receptor isoforms and their roles in signaling and control of electrical activity. They also generated a mathematical model of spontaneous and receptor-controlled electrical activity in pituitary cells. Work on purinergic channels revealed that lysines-67 and -313 and arginine-295 are critical in forming the proper three-dimensional structure of receptors for agonist binding and that the glycine-316–isoleucine-333 sequence serves as a signal transduction module between the ligand-binding domain and the channel gate.
Mark Stopfer's group, the Unit on Sensory Coding and Neural Ensembles, examines how a well-characterized neural circuit extracts information about the natural environment. Combining recordings from primary sensory neurons and their follower cells, together with realistic computational modeling, the group established that neural codes for stimuli are generated surprisingly early in the sensory pathway—by the receptors themselves. The unit also established that several neural mechanisms interact to extract important features from the sensory environment and found that the olfactory system employs a feed-forward inhibition mechanism to maintain precise action-potential timing necessary for encoding information about odors.
Stephen Suomi and his colleagues in the Section on Comparative Behavioral Genetics carry out broad-based investigations of primate biological and behavioral development through comparative longitudinal studies of rhesus monkeys and other nonhuman primate species. Highlights from the past year include continued characterization of the short- and long-term consequences of rearing monkeys of different genetic backgrounds in different social environments (gene-environment interactions), expanded investigation of early infant imitation, and assessment of the utility of using cortisol extracted from hair samples as a measure of chronic psychosocial stress in monkeys of different ages and from different rearing backgrounds.
