Rhodes/UT Neuroscience Research Fellowship 2007 Faculty
Matt Ennis, Ph.D.
My primary interests are centered on the functional organization and physiological properties of neural networks involved in nociception/analgesia processing and the chemical senses (i.e., olfaction and gustation). My research utilizes an integrative, multidisciplinary approach combining tract tracing, immunocytochemistry, immediate early gene expression and electrophysiology to delineate cellular and circuit properties of functionally defined networks. Additional details can be found on my websites:
The major current projects in my laboratory are:
•Regulation of Brainstem Opioid Analgesic Circuits. A well defined brainstem-spinal cord circuit is known to play a key role in opioid-mediated analgesia. We are investigating how higher levels of the CNS (cortical and subcortical sites) involved in emotions, motivational state and cognitive processing can regulate this brainstem analgesic circuit to allow for state-dependent modulation of pain thresholds. We are also investigating how sweet and fatty components of mothers milk produces profound opiate receptor-dependent analgesic and calming effects in newborn rats and humans.
•Synaptic Integration and Information Processing in the Olfactory Bulb. We are investigating how neuronal membrane properties and extrinsic/intrinsic neurotransmitter systems modulate information processing and output from the olfactory bulb circuit using functional imaging and neurophysiology approaches in vivo and in vitro.
•Integration in the Olfactory Bulb (OB)-Piriform Cortex (PC) Circuit. Olfactory receptor neurons that express a single common odorant receptor project to one glomerulus in the OB. The glomeruli thus form a map that mirrors receptor activity. Different odors stimulate different patterns of glomerular activity. The OB and PC comprise the major components of the neural network that decipher such patterns to arrive at the recognition of an odor. The goal of this research is to understand how glomerular activity is relayed to, and processed within PC using neuroanatomical and neurophysiological approaches.
Kristen Hamre, Ph.D.
There are 2 major foci of my research, both centered on the interaction between genetics and the nervous system. The first major focus is centered on examining the relationship between genetics and several ethanol-related phenotypes in both the developing embryo and the adult animal. This research uses both strategies that attempt to identify the critical genes in mediating a phenotype as well as the opposite strategy of determining the role of a specific gene in a phenotype using mutant mice. Both behavioral and anatomic phenotypes (e.g. cell death markers) are examined. The second major focus is examining how specific genes impact the development of various neuronal populations. In this approach the effect of a mutated gene, either in naturally-occurring or induced mutations, on the morphology of a specific structure or cell type is examined
Tony Reiner, Ph.D.
The work in this laboratory focuses on the organization, function, and diseases of the basal ganglia and visual system, and on the evolution and fundamental organization of the vertebrate forebrain.
With respect to basal ganglia organization and function, we are exploring the neural substrate by which different types of cortical and basal ganglia neurons differ in their role in movement control. We are particularly interested in whether different types of cortical neurons communicate with different types of basal ganglia neurons to mediate different aspects of movement control. To address such issues, we use LM and EM labeling methods (pathway tracing, immunohistochemistry and in situ hybridization) in various combinations to determine the neurotransmitters used by specific cells types, the inputs and outputs of those cells types, and the receptor mechanisms involved in those inputs and outputs.
In our work on basal ganglia disease, we study the means by which the gene mutation in Huntington′s disease leads to selective destruction of neurons in the striatal part of the basal ganglia. We use experimental animal models and genetically engineered mice, and we have been particularly interested in the possibility that the mutation perturbs the function of cortical neurons projecting to striatum so as to render them injurious to their target striatal neurons. This injury process could involve excess glutamate release from corticostriatal terminals or diminished production by corticostriatal neurons of neurotrophic factors needed for survival by striatal neurons.
In our work on the visual system, we are interested in the neural mechanisms by which blood flow in the choroid of the eye is adaptively controlled according to retinal need and in the role disturbances in such neural control may play in age-related decline in retinal function.
Finally, we have a longstanding interest in the evolution of the cerebral cortex, basal ganglia, and thalamus, and in how these structures differ among birds, reptiles and mammals. In our studies, we use neurochemistry, hodology and the localization of developmentally regulated genes to characterize the organization of these regions and ascertain the course evolution has taken.
Department of Neurology
Lawrence T. Reiter, Ph.D.
My laboratory utilizes the powerful genetic model organism Drosophila melanogaster (fruit flies) to investigate the functions of genes involved in human neurological disease. Our main focus is the study of genes related to autism and autism spectrum disorders. Autism spectrum disorders include the severely debilitating Rett syndrome (RTT) and Angelman syndrome (AS). These disorders are interrelated at the molecular level and mutations in the gene that causes RTT can also cause AS. In addition, approximately 3% of all inherited autism cases may result from maternally inherited duplications of the region containing the gene that causes AS, UBE3A. Mutations in the protein targets of the ubiquitin ligase UBE3A or the transcriptional regulator MECP2 may, therefore, account for a significant percentage of inherited autism cases as well.
In our laboratory we utilize Drosophila specific genetic techniques that allow us to generate artificially high levels of normal and mutant fly ube3a proteins in fly heads. Wild type, dominant negative and epitope tagged forms of ube3a are over-expressed in the brains of flies using the GAL4/UAS system in order to increase or decrease the levels of ube3a protein targets. We then identify these targets by 2D gel electrophoresis and mass spectrometry (proteomics). Potential targets will be validated though genetic suppressor/enhancer screens, immunoprecipitation binding assays in 293T cells and immunohistochemistry in the brains of the appropriate mouse models.
We have also been working in the Drosophila embryonic nervous system and larval neuromuscular junction to determine the normal expression patterns of UBE3A targets as well as how these proteins are regulated by UBE3A expression or loss of function in neurons. Our long term hypothesis is that synaptic plasticity in post-mitotic neurons, which requires ubiquitination, is regulated and or executed by the genes transcriptionally repressed by MECP2 and the post translationally modified proteins ubiquitinated by UBE3A. The identification of these target genes may also prove useful in the future since they may be appropriate therapeutic targets for the treatment of
Department of Pharmacology
Alex Dopico, M.D., Ph.D.
My laboratory is interested in determining the mechanism of action of small amphiphilic compounds on ion channels from excitable cells. One of these amphiphiles is alcohol, the most widely used and abused drug. Some others are physiological modulators, such as bile acids and neurosteroids. Our current research is focused on two projects dealing with large conductance, Ca++-activated K+ (BK) channels. These channel proteins have been demonstrated to be involved in both controlling central neuron excitability and regulating arterial smooth muscle tone. Project 1: To determine the molecular basis for differential actions of alcohol on BK channels from mammalian brain vs. arterial smooth muscle, including modulation of drug action by membrane lipids. Project 2: To determine the structural requirements (both in the amphiphile molecule and the ion channel protein) for the modulation of arterial muscle BK channels by bile acids.
For these studies we combine electrophysiological and molecular biology techniques. Ion channel responses to drug exposure are evaluated in: 1) freshly isolated cells, where we study drug modification of channel behavior in the native environment of the channel protein; 2) isolated patches of cell membrane, where we can address the differential role of different membrane-bound vs. cytosolic second messengers in drug action; 3) artificial bilayers of controlled lipid composition, where we can determine the modulatory role of membrane lipids in drug action.
Ion channel isoforms from relevant tissue are identified. Following mRNA isolation and cloning, channel subunits of known sequence are expressed in heterologous systems such as Xenopus oocytes or HEK-293 cells. Then, we can determine the role of channel subunit composition in drug action by studying drug effects on ion channel complexes that differ in pore-forming and/or modulatory subunit composition. In addition, differential responses to a drug by channels that differ in a given region of a subunit, when studied in the same proteolipid environment, allow us to postulate sites in that subunit for drug recognition. This is probed by studying drug action on expressed channel proteins that include mutations in the postulated region(s).
My laboratory is interested in determining the molecular mechanism of action of alcohol and other small amphiphiles on ion channel proteins from the brain and arterial vessels. To determine the recognition sites for alcohol in these proteins and how alcohol modifies protein function upon interaction with these sites, will provide critical information for understanding how the drug interacts with its targets and, eventually, lead to the design of clinically useful agents to treat conditions associated with alcohol intake.
Shannon G. Matta, Ph.D.
Our lab is studying the effects of nicotine on the brain, focussing on the correlation(s) between gene expression, neurotransmitter release, neuroanatomical markers, and behavioral responses. We recently have refined a self-administration animal (rat) model for nicotine exposure that more closely approximates human nicotine consumption - i.e., exposure is truly chronic, intermittent and motivated. This behavioral model is the underpinning to ongoing studies designed to 1) determine individual sensitivity to drug-taking behavior, 2) elucidate the mechanism(s) by which nicotine (like cocaine, amphetamine and other drugs of abuse) activates and maintains the reward neurocircuitry, leading to addiction, and 3) investigate the (anecdotal) property of nicotine in alleviating anxiety and stress. Drug-induced neuronal plasticity after such chronic nicotine exposure (indicated by alterations in gene expression and/or neuronal firing pattern) also is under investigation. Our most recent emphasis has been to investigate neuronal plasticity resulting from the combined gestational exposure to nicotine and alcohol - an all-too-common circumstance in the human population.
Fu-Ming Zhou, PhD.
Dr. Fu-Ming Zhou’s research focuses on the dopamine and serotonin systems in the brain and their involvement in neuropsychiatric disorders.
Fu-Ming started his research career at University of Alabama at Birmingham (UAB). A close and productive collaboration with Professor John Hablitz resulted in a series of studies on a special set of cortical interneurons, the layer I cells of the cerebral cortex, and their modulation by dopamine and serotonin receptors. After earning his PhD from UAB, Dr. Zhou studied the dopamine system in the main olfactory bulb, in collaboration with Drs. Matt Ennis and Michael Shipley at University of Maryland at Baltimore. Then Dr. Zhou went to Baylor College of Medicine in Houston, Texas. At Baylor, he had a pleasant and productive collaboration with Professor John Dani, studying the mesostriatal dopamine system and its interactions with the cholinergic and serotonin systems.
Dr. Zhou currently conducts a multidisciplinary research program designed to determine the cellular and neuropharmacological mechanisms of the brain monoamine systems. Particular attention is being paid to the contributions of these monoamine systems to neuropsychiatric disorders such as Parkinson’s disease, depression, schizophrenia, drug abuse, and attention deficit hyperactivity disorder (ADHD).
Several techniques are being used in combination to study how dopamine and serotonin affect neuronal activity. These techniques include electrophysiology (patch clamp), electrochemistry (fast cyclic voltammetry at the carbon fiber microelectrode; high pressure liquid chromatography), and immunohistochemistry.
Department of Physiology
Charles W. Leffler, Ph.D.
Research in the laboratory concentrates on control of cerebral circulation. The primary focus of this research involves autocrine/paracrine control of the newborn cerebral microvasculature during physiologically stressful and pathological situations, and the cellular mechanisms involved in such control. We investigate autocrine and paracrine communication within the vessel wall, with specific current focus on the novel gasotransmitter, carbon monoxide.