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Name, Field, Position, Department, and Keyword |
 
Faculty Keywords: Cell and Molecular Neuroscience (23), Hippocampus (11), Neurotransmitter receptors and transporters (9), Neurotransmitter release (3) The main focus of my laboratory is on the mechanisms of exocytosis, neurotransmitter release and synaptic transmission. The multidisciplinary lab employs a broad battery of tools to investigate these topics including moloecular biology, patch clamp electrophysiology, capacitance, amperometry, electrochemical imaging using nanofabricated electrode arrays, microcip devices, total internal reflection fluorescence microscopy, and optical tweezers. |
Faculty Keywords: caged neurotransmitters (1), Cell and Molecular Neuroscience (23), Ion channel (6), Ligand-activated ion channels (2), Neurotransmitter receptors and transporters (9), Patch clamp (2) We are investigating the structure and function of membrane-bound proteins (neurotransmitter receptors) that control and integrate communication between the cells of the nervous system. Malfunction of the receptors is implicated in many diseases of the nervous system, and the receptor proteins are the targets of a large class of clinically important compounds and abused drugs. Until recently investigation of the mechanism of action of these receptor proteins has been hampered by the lack of techniques with adequate time resolution (microseconds-to-milliseconds). My group has developed new biophysical techniques, most recently a laser-pulse photolysis method using caged neruotranmsitters, for investigating the receptors in cells isolated from specific areas of the nervous system to fill this gap. When a neurotransmitter binds to the active receptor forms, ion-conducting receptor-channels open, initiating electrical signals that transmit information in the nervous system. Whether or not a signal is transmitted depends on the concentration of open receptor-channels. This in turn depends on the neurotransmitter concentration and the length of time receptors are exposed to it. The immediate goal is to determine quantitative models, on a physiologically relevant time scale, for the chemical kinetic reactions of excitatory and inhibitory neurotransmitter [acetylcholine, gamma-aminobutyric acid, (GABA), glycine, glutamate, N-methyl-D-aspartate (NMDA) and serotonin receptors]. This goal has already been achieved with the nicotinic acetylcholine receptor from the electric organ (modified muscle) of certain fish. The eventual aim is to integrate all the available information into a consistent mechanism of signal transmission in the mammalian central nervous system. The chemical mechanism of neurotransmitter receptor-mediated reactions is expected to set limits to the various hypotheses concerning the operation of neuronal circuits and brain function, and to lead to an understanding of the effects of pharmacological agents and abused drugs on receptor function. An interdisciplinary approach, involving physical and organic chemistry, instrument development, molecular biology, electrophysiology, cellular neurobiology, and computer simulation, is being used to achieve these aims. |
Faculty Keywords: Cell and Molecular Neuroscience (23), Ligand-activated ion channels (2), Mathematical Modeling (14), Neurotransmitter receptors and transporters (9), Patch clamp (2) Members of my laboratory are studying excitatory amino acid (EAA) or "glutamate" activated receptor-channels in the vertebrate central nervous system. The principal approach to these investigations involves recordings of EAA activated receptor-channels in mammalian brain neurons in primary culture and recombinant receptor-channels expressed in mammalian cell lines and in Xenopus oocytes. Single channel recordings are employed to determine basic biophysical parameters of receptor channel function. Hidden Markov models are develpoed to model channel opening and closing rates. Chimeric cross-family subunit proteins are designed to study channel ion selectivity, gating, and receptor trafficking. Whole cell voltage-clamp recordings are also combined with single cell molecular biology methods in an effort to ascertain the likely subunit compositions of pharmacologically and biophysically distinct receptor-channel subtypes observed in cerebellar granule neurons and cerebral cortical neurons. |
Faculty Keywords: Cell and Molecular Neuroscience (23), Hippocampus (11), Mouse (11), Neurotransmitter receptors and transporters (9) The solution of seeming impossible experimental problems drives our creation of new experimental technologies for neuroscience, which during the past thirty years have focused primarily on observing the dynamics of the biomolecular processes of life. This challenge requires benign, effectively non-invasive methods that frequently push the physical limits of resolution in space, time and sensitivity. Several of these innovations: Multiphoton Microscopy (MPM), Fluorescence Correlation Spectroscopy (FCS), nanoscopic molecular tracking and most recently, nanostructured molecular dynamic probes are being applied to some of these seeming impossible biological problems. Over the years, about 35 of our publications have focused on the challenges of neuroscience, including: molecular mechanisms and physics of auditory transduction, the first successful single channel recording of reconstituted natural ion channels and on their structural fluctuations and mechano-sensitivity, signal delays along neural processes in neural networks, detection and imaging of serotonin and its secretion, imaging the development of the lesions of AlzheimerÌs Disease in transgenic mice, and most recently (now in press) successful optical imaging of action potentials with time resolutions corresponding to patch clamp recordings which promises to supplement the usual application of MPM to calcium signals as a method of choice for neural response measurements in live neural networks. |
Faculty Keywords: Cell and Molecular Neuroscience (23), Ion channel (6), Neuromodulation (12), Neurotransmitter receptors and transporters (9), Proteins (3) My general research interest is in the modulation of receptor properties by neurotransmitters and drugs. Currently we are studying the mechanisms of modulation of the nicotinic cholinergic receptor by its neurotransmitter acetylcholine and by the neuropeptide substance P. Nicotinic receptor responsiveness is regulated by acetylcholine and other cholinergic agonists via desensitization. In fact there are several desensitization processes each of which occurs on a different time scale, ranging from milliseconds to several minutes. Nicotinic receptor responsiveness also appears to be regulated physiologically by substance P, an eleven amino acid peptide that inhibits nicotinic receptor activation. One reason we have focused on both of these modulatory mechanisms is that they appear to be interrelated since at least part of the inhibition by substance P seems to be mediated by an increase in the rate and extent of desensitization. For more information, follow the web link above. |
Please report corrections, questions, comments, and problems to: Lori Miller (lmm8 AT cornell.edu)