Hippocampal and temporal lobe regulation of learning and memory in primates.

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The main research interest of our laboratory is to understand the mechanism and function of mRNA transport and local protein synthesis in neurons of the central and peripheral nervous system. We are using in vitro and in vivo models of synaptic activity and nerve injury, as well as mouse models of neurological diseases, to assess the function of mRNA regulation in axon guidance, nerve regeneration and synaptic plasticity. In particular, we are interested in how impairments in mRNA regulation may underlie Spinal Muscular Atrophy and Fragile X Syndrome, two inherited neurological diseases affecting children. Efforts are also underway to evaluate different therapeutic modalities in these mouse models. Our research utilizes a multi-disciplinary approach that involves primary neuronal culture, brain/nerve micro-dissection, viral vectors, fluorescently tagged mRNA and proteins, fluorescence live-cell imaging, and molecular and biochemical methods to isolate and characterize RNA-protein interactions. These studies will provide new insight into molecular and cellular mechanisms important for neuronal development and plasticity, as well as into defects in these pathways that underlie neurological diseases.

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My research is aimed at understanding the neurobiological basis for individual preferences and how the biology places constraints on the decisions people make -- a field now known as neuroeconomics. To achieve this goal, we use functional MRI to measure the activity in key parts of the brain involved in decision making. We then link these activity traces to various phenotypes of decision making. For example, we have linked the pattern of activity in the striatum with the receipt of unexpected, salient information with the tendency to alter one's behavior. More recently, we have used the timecourse of activity as a proxy for experiential utility, in the process, bridging the gap between experience and choice. Ongoing research projects are developing these methods to probe decision-making in adolescents as well as group decision-making and the influence of peer pressure at the neurobiological level.

My research interests are in the pathogenesis and pathology of neurodegenerative diseases including Parkinson's and Alzheimer's disease. More specifically, the interactions between PD/AD-related genetic factors and external stressors, including mitochondrial impairment, oxidative stress, proteasomal inhibition, and their involvement in protein trafficking pathways in neurodegeneration. I am also interested in the organizational changes in the basal ganglia circuitry that occur in Parkinson's disease including the dopaminergic and glutamatergic pathways.

The Boulis laboratory focuses on the translation of concepts in neural gene transfer and stem cell transplant to the treatment of functional and degenerative disorders of the nervous system. Functional disorders of interest include epilepsy and spasticity as well as the control of aberrant basal ganglion function in movement disorders. Degenerative disorders of interest include Parkinson's Disease and Amyotrophic Lateral Sclerosis. To treat degenerative disorders, we have explored a variety of anti-apoptotic and growth factor genes. These are screened through in vitro assays prior to testing in transgenic models. A recent manuscript describes neuroprotection through the delivery of the gene for X-Linked Inhibitor of Apoptosis (XIAP)1, Bcl-xL2, and Insulin-like Growth Factor I (IGF-I). Ongoing projects are exploring the application of cervical spinal cord surgery for the injection of adeno-associated viral vectors encoding IGF-I in SOD1 mutant rats.

In the Center for Biomedical Imaging Statistics (CBIS), a major focus of our research is on the development and applications of statistical methods for analyzing brain imaging data. These methods make use of data reflecting brain function, for example, from functional magnetic resonance imaging (fMRI) as well as structural information obtained from diffusion tensor imaging (DTI). Generally, our statistical methods attempt to improve our understanding of human brain function by (1) determining functional linkages between brain regions either at resting state or when performing specific experimental tasks, (2) identifying specific brain regions that drive the performance of a task and evaluating differences in these distributed patterns of task-related activity between subgroups (e.g. between a patient group and healthy control subjects), and (3) addressing various prediction objectives such as predicting neural responses to treatment and predicting clinical psychiatric symptoms (e.g. associated with major depression) based on functional imaging data. Please see http://www.sph.emory.edu/bios/CBIS/ for additional details.

My research focuses on the use of neuroimaging and neurobiology measures to study the neural correlates and neurobiology of posttramatic stress disorder (PTSD) related to combat and childhood abuse, as well as the related area of depression. Published studies include work on neurobiology and assessment of PTSD; hippocampus and memory in PTSD and depression; neural correlates of declarative memory and traumatic rememberance in PTSD; and PET measurement of neuroreceptor binding in mood and anxiety disorders.

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Our research is aimed at understanding the neural mechanisms that support learning and memory.  Using neurophysiological techniques, we record simultaneously from multiple electrodes in the hippocampus and surrounding cortex in awake, behaving monkeys.  We investigate how changes in neuronal activity correlate with the monkey's ability to learn and remember. We are particularly interested in the activity of neuronal networks that underlie learning and memory processes.  We use spectral analysis techniques to investigate the role of oscillatory activity and neuronal synchronization in cognition.

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Our lab studies the neural circuit that controls the hearts of medicinal leeches. We record the electrical activity of neurons in this circuit with microelectrodes. Using voltage clamp techniques, we isolate and characterize the individual ionic currents which contribute to this activity. We also study the biophysics of synaptic transmission and the role of background calcium in synaptic plasticity using Ca imaging. To understand how membrane currents and synaptic transmission interact to produce the activity of the circuit, we simulate the ionic currents and cell connectivity with realistic biophysical models. We also use such models in real time simulation to construct hybrid systems between computer and neuron to analyze circuit and neuronal function. We address the general questions of how rhythmic motor patterns are generated and coordinated by networks of interneurons and how these patterns are used to produce the final pattern of activity in motor neurons that produce functionally coordinated movement.

We are interested in identifying novel genes that control cell fate decisions in the developing nervous system. We do this in an unbiased manner by performing mutagenesis screens that identify recessive mutations that disrupt normal development of the nervous system. Once we map and clone the genes we use them as a entry point and combine molecular, cellular and biochemical methods to understand the molecular mechanisms that permit cells to make specific cell fate decisions. we have recently focused on one mutant, hennin (hnn), which affects the structure of cilia and leads to an overproduction of motor neurons in an expanded domain of the developing spinal cord.

The research interests of our laboratory include: 1. The development of a transgenic non-human primate model for human genetic disorders such as Huntington's, Alzheimer's and Parkinson's etc., 2. The biology of the differentiation control of rodent, non-human primate and human embryonic stem (ES) cells, and 3. The therapeutic applications of ES cells in diseases such as Huntington's and Parkinson's.

Our lab studies the molecular and cellular mechanisms underlying the morphogenesis of the mammalian auditory organ, the organ of Corti. In particular, we are interested at how cells at particular location of the developing inner ear are singled out to become the precursors of the sensory epithelium, withdraw from cell cycle, and subsequently differentiate into a given cell type of the organ of Corti, and how the differentiation process is coupled to the establishment of the polarity of the sensory epithelium

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My research focuses on the molecular pathogenic mechanisms of Parkinson's disease (PD). We are using molecular, cellular, proteomic, and biochemical approaches to delineate the molecular pathways by which the mutations in familial PD proteins DJ-1, Parkin, and PINK1 lead to neurodegeneration and to identify additional proteins and new pathways involved in PD pathogenesis (J. Biol. Chem. 279: 8506-8515; J. Comp. Neurol. 500: 585-599; PLoS Biology: 5: e172.). By using a redox proteomic approach, we are characterizing protein targets of oxidative damage in idiopathic PD brains and investigating the gene-environment interactions in PD pathogenesis (J. Biol. Chem. 281: 10816-10824). We are also studying the role of ubiquitination and aggresome formation in PD pathogenesis (J. Cell Biol. 178: 1025-1038). Our goal is to use the mechanistic insights gained from these studies for developing new intervention strategies to treat PD.

Our lab is interested in molecular mechanisms of acid-base regulation in the brain and kidney. In particular, we focus on the sodium/bicarbonate transporters that move Na+ and HCO3 ions across the cell membrane. These transporters not only regulate the acid-base balance in the cell or tissue, but they can also modulate distinct cell physiology such as neuronal activity, fluid secretion or reproduction. We are interested in how the transporters affect acid-base homeostasis of the cell, how they work at the molecular level, and how they are regulated.

While family and twin studies provide strong support for genetic contributions to many common psychiatric disorders, the roles of individual genes in these disorders have been difficult to determine, probably because multiple genes interact with environmental and developmental influences to produce these disorders. Our lab has pursued analysis of endophenotypes as a strategy for reducing the complexity of genotype-phenotype relationships in behavioral disorders. Endophenotypes are traits that correlate or otherwise are relevant to a complex disorder, but which themselves more directly reflect the action of one or a few genes. A major focus of our research to date has been on plasma levels of dopamine beta-hydroxylase, the enzyme catalyzing conversion of dopamine to norepinephrine. Building on early linkage findings from other groups, we have shown that sequence variation at the DBH locus accounts for up to 50% of the variance in plasma DbH activity, and we have used this finding as a basis for investigation of psychosis in major depression and cocaine dependence.

My lab studies the neurobiology of learning and memory using the fear-potentiated startle reflex in rats, mice, monkeys and humans. Another focus is the effects of stress on behavior with special emphasis on neuropeptides, neurotransmitters and second messenger systems in the extended amygdala.

The work in our lab involves the development of real-time, dynamical models of neuronal systems and on the interfacing of those models to living neuronal tissue. This research is focused in three primary areas: neuromorphic engineering, neural interfacing technology, and hybrid neural microsystems.

Glutamate receptors mediate the vast majority of excitatory synaptic transmission in the brain. A major research effort in my lab is focused on regulation of glutamate receptor-mediated synaptic transmission in the brain by the co-activation of selected G-protein coupled receptors. A second research emphasis involves the use of microarray and associated technologies to identify novel targets and pathways involved in the basic cellular and molecular mechanisms of epilepsy. These research interests converge and have highlighted a role for cyclooxygenase-2 (COX2) signaling pathways in the cognitive deficits, impaired synaptic inhibition, and neurodegeneration caused by seizures. We are currently seeking the prostaglandin receptors responsible for each of these effects; we will then employ a chemical biology approach to develop novel small molecule modulators of these receptors in an effort to interrupt the development of epilepsy. As a whole our work integrates information from a variety of experimental strategies to contribute to a better understanding of epilepsy, with broad implications for other brain disorders including stroke and schizophrenia.

The main interest in my laboratory is enhancing functional recovery following injury to the peripheral nervous system. Peripheral nerve injuries are common clinically but functional recovery from them is rare. Following nerve injury, denervated muscles are deprived of neural control and sensory feedback regulating muscle function is lost. In addition, synaptic inputs onto spinal motoneurons are withdrawn. The slow growth of regenerating axons and the slow reformation of synapses, both in the periphery and in the CNS, are the reasons given for poor functional outcomes. We have found that exercise or electrical stimulation enhances the growth of regenerating axons. Using a combination of transgenic and knockout mice we are investigating the roles played by the neurotrophins BDNF and NT-4/5 in that enhancement, as well as in the reformation of synapses at both neuromuscular junctions and spinal motoneurons. Using chronic electrophysiologic recordings in rats, we are evaluating the effects of exercise or electrical stimulation on functional recovery following peripheral nerve injury.

Our lab uses a combination of human and mouse genetics, mouse disease models and genome analysis/bioinformatics in order to determine the molecular basis of inherited neurological disorders. We have a broad interest in neurological disease and the disorders that we are currently working on include epilepsy, ataxia and other movement disorders, and migraine. The long-term goal of our research is to develop better diagnostic tools and more effective therapeutic agents.

The long-term goal of our laboratory is to understand the mechanisms that control the identity of the membranous organelles that define eukaryotic cells. The current hypothesis is that selective vesicle formation and fusion mechanisms account for the maintenance of organelles. This process is particularly critical when we consider that ~ 100 different human disease entities arise from defects in membrane organelle exchange or traffic. Our laboratory explores how organelles exchange components by means of vesicles in the context of the endolysosomal pathway of neurons. Our focus in this pathway and in neural tissue stems from the fundamental role of the endo-lysosomal route in the generation of synaptic vesicle and the role of endosome-lysosomes in the pathogenesis of a diverse set of genetic and non-genetic neurodegenerative diseases, epilepsy, and possibly schizophrenia.

My research focuses on the pathogenesis and treatment of axonal degeneration in neurodegenerative diseases. Axonal degeneration is the final common pathway of many neurological diseases of both the central and peripheral nervous systems. The loss of axons, even in the face of healthy and functioning neuronal cell bodies, disconnects neurons from their targets and causes neurological dysfunction. Understanding the pathogenesis of axonal degeneration will necessarily lead to novel therapies for treating a variety of neurological disorders. Our laboratory has several ongoing projects using animal and cell culture models of disease as well as investigations focusing on people with neurodegenerative diseases. ALS is a primary focus, including experimental studies of axonal degeneration in animal models, toxicity studies of mutant SOD1, and proteomic discovery of ALS biomarkers. We are also investigating the role of cysteine proteases in axonal degeneration and have developed novel protease inhibitors that prevent neuropathy in animals. These compounds and are being developed for use in humans.

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Research interests emcompass PET and SPECT radiotracer development of heart, brain and oncology agents with an emphasis on the design and evaluation of radiolabeled fatty acids for in vivo study of regional fatty acid metabolism in heart disorders, cocaine analogs for in vivo study of the dopamine, serotonin, and norepinephrine reuptake sites in neurodegenerative disease, psychiatric and addictive disorders, heterocyclic spiperone analogs for in vivo mapping of D2 dopamine recpetors in psychiatric disorders, peripheral benzodiazepine receptor ligands for imaging peripheral vascular disease and mappping of intracranial tumors, carbohydrates for in vivo study of regional glucose metabolism in heart disorders, brain disorders, and cancer, and alicyclic and branched chain amino acids for in vivo mapping of intracranial ans systemic tumors.

Our laboratory focuses on determining mechanisms of selective neuronal vulnerability in neurodegenerative diseases. Using behavioral analyses, global assessment of gene expression, live-cell imaging, and assays of cellular metabolism and toxicity, we are attempting to determine pathogenic mechanisms of neuron death and dysfunction in Parkinson's disease. This includes analysis of the enteric nervous system as one of the earliest sites of neuronal dysfunction in PD.

The goal of my laboratory is to develop novel surgical therapies utilizing cell and/or gene therapy, or electrical stimulation, for ameliorating neurological diseases: 1) Axon guidance molecules in the development and reconstruction of the nigrostriatal pathway. We have been examining the role of semaphorins and their receptors in the developing and adult nigrostriatal pathway. 2) The role of RhoGTPase in mediating the inhibitory effects of the adult CNS on neural reconstruction. RhoGTPases mediate inhibitory effects of a range of molecules, including semaphorins, on regenerating neurons. To counteract these effects, we have produced a lentiviral vector encoding C3 transferase which catalytically inhibits RhoA, and shown that it markedly increases outgrowth of axons from a variety of cells including neural stem cells derived neurons. 3) The role of microglia in neurotoxin-induced degeneration of the nigrostriatal pathway. Towards developing novel therapy for neuroprotection in Parkinson's disease and other degenerative conditions, we have been examining the role of microglial activation after treatment of young and old rats. We are currently embarking on examining the role of RhoGTPases in mediating the microglial-inhibitory effects of neuroprotective peptides. 4) Closed-loop multi-microelectrode recording and microstimulation in focal epilepsy in the rat. In collaboration with Steve Potter, we are examining whether a novel microrecording and stimulation algorithm is capable of blocking the onset of propagation of epileptic seizures in rat models of epilepsy 5) Deep brain stimulation (DBS) in Parkinson's disease, Dystonia, Tourette's Syndrome, Epilepsy and Depression. In collaboration with Emory neurologists, experimental protocols are underway to examine STN vs. GPi DBS in PD.

My research focuses on development of statistical methods for addressing research questions arising from brain imaging studies involving functional magnetic resonance imaging (fMRI), positron emission tomography (PET), or diffusion tensor imaging (DTI) data. My current research interests include: developing new methods for making group inferences and group comparisons in multi-subject imaging data; building prediction models for forecasting future neural activity or clinical/behavior outcomes, s.t. treatment responses, based on functional brain images

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We study the mechanisms of signal transduction by neurotransmitter and hormone receptors. Our typical approach is to first uncover receptor interactions with either intracellular proteins or other receptors, and then elucidate the physiological consequences of these interactions in a variety of functional studies. Understanding the mechanisms of signal transduction by neurotransmitter and hormone receptors is of paramount clinical importance, since such receptors are common targets for therapeutic pharmaceuticals in the treatment of many neuropsychiatric conditions.

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We have been studying C1 channels, which play an important role in neuro-degenerative diseases. Knockout of C1C-2, C1C-3 and C1C-7 in mice all produce post-natal degeneration of specific parts of the nervous system. I am particularly interested in bestrophin, a C1 channel that produces retinal (macular) degeneration.

Our laboratory uses molecular, genetic, anatomical and behavioral approaches to determine the contribution of the basal ganglia and cerebellum to normal movements and movement disorders. Our specific interest is the pathophysiological basis of dystonia, a movement disorder characterized by abnormal patterns and strengths of muscle contractions caused by dysfunction of the basal ganglia, the cerebellum or both.

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We have broad interests in synaptic plasticity and neuromodulation associated with spinal cord injury, pain, locomotion, and Restless Legs Syndrome (RLS).

Dr. Leonard L. Howell has an established research program in behavioral neuropharmacology with a focus on central nervous system stimulants and the development of medications to treat stimulant addiction. The program is multidisciplinary and integrates operant-conditioning techniques to study behavior and drug use, in vivo microdialysis to characterize brain neurochemistry, and functional brain imaging. Ongoing studies investigate in nonhuman primate models the neurochemical mechanisms that mediate drug effects on behavior. Recent efforts have focused on drug-induced changes in brain neurochemistry with in vivo microdialysis in behaving monkeys trained to self-administer cocaine. In addition, Dr. Howell serves as Director of the Yerkes Imaging Center. His neuroimaging program includes drug receptor occupancy, pharmacokinetics, brain metabolism and functional magnet resonance imaging (fMRI) in awake, behaving monkeys. The long-range objective is to develop a unique, multidisciplinary research program in substance abuse that effectively integrates behavior, neurochemistry and functional brain imaging in nonhuman primates.

The research in our lab lies in the development of biomedical imaging techniques, particularly those based on magnetic resonance imaging (MRI), and their application to the understanding of anatomy, function and physiology of brain in its normal state and diseased state. Specifically, we are focusing on functional MRI and diffusion tensor imaging and interested in furthering and using these techniques for understanding how brain works at a system level. Current projects include improvement of image acquisition and processing methods, investigation of underlying biophysics and physiology of imaging measurements, and elucidation of neurobiological underpinning of neuropsychiatric and neurodegenerative disorders.

Research in my laboratory focuses on circadian clocks and neuromodulators that regulate neuronal plasticity. Most studies utilize the retina as an experimental model, as it contains circadian oscillators that regulates the release of two neuromodulators, melatonin and dopamine, that fine-tune synaptic mechanisms controlling dark adaptation and light adaptation and many aspects of circadian retinal physiology. Expression of circadian clock genes and their effectors are studied using cellular, molecular and genetic approaches.

We combine electrophysiological recordings and detailed compartmental modelling to examine how neurons in the basal ganglia and in the cerebellum process their inputs. In particular we are interested in the functional role of inhibitory inputs and the role of active neural properties in network processing. We also apply these concepts to investigate the mechanisms underlying the clinical effects of deep brain stimulation using multisite recordings in anesthetized rodents.

The GABAA receptor is the most abundant fast inhibitory neurotransmitter receptor in the CNS. Our goal is to understand how neurosteroids, general anesthetics, sedative and anxiolytic drugs, alter the function of the receptor to mediate their clinically useful effects. We typically do this by using combinations of site directed mutagenesis, patch clamp electrophysiology and computational modeling. It is our hope that through a better understanding of receptor function, we will also gain a better understanding of the role receptor dysfunction plays in diseases such as epilepsy, schizophrenia and autism.

Peng Jin

[peng.jin@emory.edu]
The importance of noncoding RNAs has been increasingly recognized within the last several years, particularly with the identification of new classes of small RNAs, such as microRNAs (miRNAs). These noncoding RNAs play important roles in neural development and can be involved in neuronal translation control (miRNAs) or transcription regulation (small modulatory RNAs in the fate specification of adult neural stem cells), and can be pathogenic (noncoding repeats in neurodegeneration). The ultimate goal of my lab is to understand the roles of noncoding RNAs in neural development and the pathogenesis of brain disorders. Currently we are focusing on several areas: 1) the role of microRNA pathways in learning and memory; 2) the molecular basis of RNA-mediated neurodegeneration; 3) small noncoding RNAs and epigenetic regulation; 4) chemical genomic approach to dissect small RNA pathway.

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Our research interests are in the biological basis for neurological and behavioral disorders. We have a special interest in the biological basis of dystonia, a neurological disorder characterized by involuntary twisting movements and unnatural postures with many different etiologies. Our research strategy involves two complementary approaches. One approach entails studies of biological mechanisms responsible for dystonia in Lesch-Nyhan disease, a rare neurogenetic disorder for which the genetic mutations and biochemical defects are known. The other approach involves the investigation of biological mechanisms shared by different forms of dystonia, with the goal of identifying final common molecular and neural pathways.

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I am interested in investigating the rules by which cellular architecture is choreographed during two aspects of development: the mitotic cell division and post-mitotic neuronal differentiation. We have focused on microtubules, which play a crucial role in both of these processes. To understand diverse microtubule behavior during these biological processes, we first analyzed the genes that encode subunit proteins tubulins which assemble to form microtubules. We are now analyzing how different tubulin protein subunits contribute to different behavior of microtubules during neuronal morphogenesis. The approach we are taking combines genetics, molecular cell biology, biochemistry, and structural biology.

Research in my laboratory is focused on two areas of cell signaling. One is the regulation of the traffic and processing of transmembrane proteins involved in Alzheimer's disease pathogenesis; including the amyloid precursor protein (APP), beta-secretase (BACE), LR11/SorLA, and the low-density lipoprotein receptor-like protein (LRP). Particular attention is currently focused on the regulation of their sorting at the Golgi. We seek to better understand the molecules involved and regulatory steps in the generation of the neurotoxic A-beta to allow the design of better ways to prevent Alzheimer's Disease. The other area of research is broader in scope as we study the regulatory links between mitochondrial functions (including ATP generation and reactive oxygen), the cytoskeleton, and cell division. We hope to define the regulatory links between energy metabolism and other cell functions, particularly those defective in chronic disease states. Such an understanding will yield tremendous insights into cell regulation but will also provide researchers with the tools to design the next generation of targeted pharmaceutical for neurodegenerative diseases, cancer, and other diseases.

A major focus of my research program is the behavioral pharmacology of cocaine and related psychomotor stimulants in nonhuman primates. One of our major goals is to determine how monoamines and other neurotransmitters interact to produce the observed behavioral and neurochemical effects of these psychomotor stimulants. We are also involved in developing medications for reducing drug use in humans, working with several medicinal chemists in investigating the effectiveness of novel compounds. To achieve these goals, we use operant conditioning behavioral techniques, in vivo microdialysis with HPLC, and neuroimaging to determine the neuropharmacology of cocaine and related compounds in nonhuman primates.

Our general interests include the structure and function of the brain, and particulary the deficits that occur in neuropsychiatric disease. There is an emphasis on neurotransmitter systems and their involvement in brain function. A recent focus has been on molecular and cellular mechanisms of drug addiction, and particularly on novel genes associated with the addiction process. Current topics of research include CART peptides, development of medications for drug addicts, and a study of novel genes involved in the addiction process.

My research is driven by the goal of understanding basic pathogenic mechanisms in Alzheimer's disease (AD). Specific topics of interest include: regulation of amyloid precursor protein (APP) processing through control of intracellular trafficking, analysis of the role of the apolipoprotein (ApoE) receptor LR11 in amyloidogenesis, modulation of APP processing by muscarinic receptor activity, and characterization of new genes involved in AD and neurodegeneration. These questions are being addressed in a variety of cellular and animal models, using plasmid transfections, viral gene transfer, and siRNA techniques combined with biochemical and cell biological analytic methods.

Determining the principals underlying neuron computation within the context of the control of movement. Cellular neurophysiology, to determine how the whole cell behavior arises from their constituent sub-cellular structures in neurons and motoneurons.Computer modeling of neurons, developing advanced methods for automatically tuning neuronal models and for examining and validating the model's behavior.

Dr. Levey investigates Alzheimer's and related neurodegenerative diseases. The laboratory research focuses on pathogenesis of disease, studying novel genetic and proteomic factors and investigating their potential role in the disease as biomarkers and potential sites of action for new therapies. The laboratory is a multi-disciplinary and highly collaborative environment in the Center for Neurodegenerative Disease and Alzheimer’s Disease Research Center.

My laboratory studies the molecular basis of neurotransmitter release and pathogenic mechanisms of neurodegenerative disorders, such as Parkinson's, Alzheimer's, and Huntington's diseases. A current major focus of our work is to delineate the molecular pathways by which mutations in familial Parkinson's disease proteins ( -synuclein, parkin, DJ-1, and UCH-L1) lead to neurodegeneration and identify additional molecular players in the pathogenic pathways. We are also studying regulation mechanisms of vesicular trafficking and investigating the role of abnormal vesicular trafficking and protein ubiquitination in the pathogenesis of Parkinson's, Alzheimer's, and Huntington's diseases. Our research uses a combination of molecular biological, biochemical, cell biological, proteomic, and molecular genetic approaches, including targeted gene disruption.

The major interest of our laboratory is to elucidate the molecular mechanisms by which misfolded proteins mediate selective neurodegeneration. We focus on inherited neurodegenerative diseases, such as Huntington's disease, which are caused by the expansion of a polyglutamine domain in proteins associated with various diseases. We are using a combination of molecular neurobiology, biochemistry, cell biology, and transgenic mouse approaches to address how polyglutamine expansion in ubiquitous proteins selectively induces late-onset neurodegeneration. Understanding this issue will also help elucidate the pathogenesis of other age-dependent neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.

The general interest of my lab is to understand how ion channels and receptors contribute to the transduction and homeostasis in the cochlea. The transduction process in the cochlea turns the mechanical vibration into impulses in the auditory nerve. Maintenance of cochlear homeostasis ensures the balance of metabolic activities, normal fluid and ionic composition in the inner ear. Membrane channels in the cochlea are the key components in both processes that are essential for normal hearing. Currently our research focuses on the role of a type of intercellular channels called gap junctions in the cochlear functions. Mutations in the connexins (protein subunits of gap junctions) genes are one of the most common forms of human genetic defects. Genetic studies reveal that connexin mutations account for about 50% of prelingual severe-to-profound nonsyndromic hearing loss. How these genetic mutations affect normal cochlear functions remains unclear. We use both mouse models and in vitro reconstituted human mutant connexin26 and connexin30 to address two key questions: (1) What are the cellular and molecular mechanisms of deafness caused by various types of connexin mutations? (2) How to restore hearing in connexin mutant mice?

In addition to genetic mutations, many ototoxic and tinnitus-inducing drugs directly affect functions of ion channels/receptor in the inner ear. Our research, therefore, should help understanding how malfunctions of the membrane channels contribute to genetic sensorineural hearing loss, ototoxicity and certain forms of drug-induced tinnitus.

Our Computational Neuroethology laboratory is interested in understanding how behaviorally-relevant sensory signals are encoded by cortical neurons, and what factors (e.g. experience, hormones) might lead to plastic changes in that code. We investigate this in the mouse, where ultrasonic communication between animals provides a natural behavioral context for these studies, and transgenic methods offer future possibilities for mechanistic dissection of coding mechanisms. We perform electrophysiology in non-anesthetized mice, and employ computational methods to analyze the information processing capabilities of neurons.

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