Berg, Darwin - University of California, San Diego - Division of Biological Sciences

研究领域

We are interested in the role of nicotinic cholinergic signaling both in guiding the formation of complex neural networks and in regulating their function. We find that endogenous nicotinic activity promotes early glutamatergic (excitatory) innervation of neurons during development. Further, it helps drive the conversion of GABAergic transmission from excitation to inhibition at this time. Direct exposure to nicotine during early development produces long-lasting changes in synaptic wiring that persist into the adult and remain long after nicotine cessation. These kinds of changes suggest serious behavioral consequences and increased vulnerability to subsequent nicotine challenges. We are also pursuing other mechanisms guiding network formation, including the role of micro-RNAs in orchestrating major transitions in brain development. Our laboratory takes a multidisciplinary approach. We want to identify the molecular players mediating nicotinic signaling and understand how they work. We want to understand how these components interact in complex ways to regulate circuit construction and system output. To do this, we combine molecular, physiological, imaging, and biochemical techniques, applying them both in acute slices and in vivo. Recent collaborations have also incorporated computational and ultrastructural analyses. We use viral constructs and mutant mice to manipulate signaling pathways in vivo both during development and in the adult to gain insight into mechanism. It is an exciting time to be investigating nicotinic signaling in the central nervous system. At the behavioral level nicotinic cholinergic activity has been implicated in a broad array of phenomena including cognition, memory formation, and arousal. It is also associated with numerous pathologies including Alzheimer's disease, schizophrenia, and addiction. These physiological consequences of nicotinic activity offer intriguing windows into higher brain function while at the same time suggesting biomedical applications. How the cellular and molecular features of nicotinic signaling collaborate to achieve these effects in the brain remains a mystery and presents ongoing challenges. Molecular tools are now in place to make major advances in these areas.

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Halff AW, Gomez-Varela D, John D, Berg DK (2014) A novel mechanism for nicotinic potentiation of glutamatergic synapses. J Neurosci 34:2051-2064. (PMID: 24501347) Gomez-Varela D, Berg DK (2013) Lateral mobility of presynaptic α7-containing nicotinic receptors and its relevance for glutamate release. J Neurosci 33:17062-17071. (PMID: 20592206 Wang, X, Lippi G, Carlson D, Berg DK (2013) Activation of7-containing nicotinic receptors on astrocytes triggers AMPA receptor recruitment to glutamatergic synapses. J Neurochem 127:632-643. (PMID: 24032433) Lozada AF, Wang X, Gounko NV, Massey KA, Duan J, Liu Z, Berg DK (2012a) Glutamatergic synapse formation is promoted by α7-containing nicotinic acetylcholine receptors. J Neurosci 32:7651-7661. (PMID: 22649244 Lozada AF, Wang X, Gounko NV, Massey KA, Duan J, Liu Z, Berg DK (2012b) Induction of dendritic spines by β2-containing nicotinic receptors. J Neurosci 32:8391-8400. (PMID: 22699919) Gomez-Varela D, Schmidt M, Schoellerman J, Peters E, Berg DK (2012) PMCA2 via PSD-95 controls signaling by α7-containing nicotinic acetylcholine receptors on aspiny neurons. J Neurosci 32:6894-6905. (PMID: 22593058) Fernandes CC, Berg DK, Gomez-Varela D (2010)Lateral mobility of nicotinic acetylcholine receptors on neurons is determined by receptor composition, local domain, and cell type.J Neurosci 30:8841-8851 (and Journal cover). (PMID: 20592206) Campbell NR, Fernandes CC, Halff AW, Berg DK (2010)Endogenous signaling through7-containing nicotinic receptors promotes maturation and integration of adult-born neurons in the hippocampu. J Neurosci 30:8734-8744. (PMID: 20592195) Neff RA, Conroy WG, Schoellerman JD, Berg DK (2009) Synchronous and asynchronous transmitter release at nicotinic synapses are differentially regulated by postsynaptic PSD-95 proteins. J Neurosci 29:15770-15779. (PMID: 200116093 Liu Z, Neff RA, Berg DK (2006) Sequential interplay of nicotinic and GABAergic signaling guides neuronal development. Science 314:1610-1613. PMID: 1715833) Coggan JS, Bartol TM, Esquenazi E, Stiles JR, Lamont S, Martone ME, Berg DK, Ellisman MH, Sejnowski TJ (2005) Ectopic neurotransmitter release at a neuronal synapse. Science 309:446-451. PMID: 1602073) Conroy WG, Liu Z, Nai Q, Coggan JS, Berg DK (2003) PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons. Neuron 38:759-771. PMID: 1279796) Chang K, Berg DK (2001) Voltage-gated channels block nicotinic regulation of CREB phosphorylation and gene expression in neurons. Neuron 32:855-865. PMID: 1173803) Liu, Q.-s., Kawai, H., and Berg, D.K. (2001). β-Amyloid peptide blocks the response of a7-containing nicotinic receptors on hippocampal neurons. Proc. Natl. Acad. Sci. (USA) 98: 4734-4739. (PMID: 11274373 Zhang Z-W, Coggan JS, Berg DK (1996) Synaptic currents generated by neuronal acetylcholine receptors sensitive to-bungarotoxin. Neuron 17:1231-1240. PMID: 898216) Zhang Z-W, Vijayaraghavan S, Berg DK (1994) Neuronal acetylcholine receptors that bind-bungarotoxin with high affinity function as ligand-gated ion channels. Neuron 12:167-177. PMID: 750733) Margiotta, J.F. and Berg, D.K. (1982). Functional synapses are established between ciliary ganglion neurones in dissociated cell culture. Nature 296: 152-154. (PMID: 7063016) Nishi, R. and Berg, D.K. (1979). Survival and development of ciliary ganglion neurones grown alone in cell culture. Nature 277: 232-234. (PMID: 551252) Berg, D.K. and Hall, Z.W. (1974). Fate of -bungarotoxin bound to acetylcholine receptors in normal and denervated muscle. Science 184: 473-475. (PMID: 4819679