Laboratories
(Partial Listing)

Timothy C. Cope, Ph.D.
Chair and Professor of Neuroscience, Cell Biology and Physiology
Director, Comprehensive Neuroscience Center

My research interests center on motor control and sensorimotor integration in the mammalian spinal cord. Using predominantly electrophysiological methods we study spinal motoneurons, muscle stretch afferents, and their center synapses. We are actively examining how these neurons and synapses respond soon and long after peripheral nerve injury and after manipulations in the functional relations between nerve and muscle. These studies are yielding insight into factors that influence the function and dysfunction of sensorimotor circuits in adult animals. In addition we are studying activity patterns among populations of motoneurons recruited during movement in order to infer strategies and mechanisms used by the central nervous system to control movement. Ongoing collaborative efforts involve studies in motoneuron disease, activity dependence of synaptic function, and neurotransmitter receptor expression.

Francisco J. Alvarez, Ph.D.
Associate Professor of Neuroscience, Cell Biology and Physiology
Director of Microscopy Core Facilities

Our lab is interested in the development of synaptic circuits in the spinal cord. Newborns express immature spinal circuits reflected in abnormal reflexes and limited capacity to make effective postural adjustments or fine movements. The neurobiological principles that drive the postnatal maturation of spinal cord motor circuits, in particular the development of inhibitory synapses and interneurons that modulate motoneuron activity, are largely unknown. Our laboratory uses electron microscopy, confocal microscopy and electrophysiological methods to study the postnatal maturation of structure, molecular composition and synaptic function of key inhibitory circuits in the spinal cord. Our latest work analyzes the postnatal specification of adult inhibitory interneurons from embryonic spinal neuronal groups. Using transgenic mice that carry linage markers for the subpopulation of embryonic neurons derived from the V1 group, we have shown that several different types of segmental ventral inhibitory adult interneurons derive from this group and therefore share a similar genetic background.

Francisco Javier Alvarez-Leefmans, M.D., Ph.D.
Professor of Pharmacology and Toxicology

Research in my laboratory is funded by NIH and involves two tightly linked areas: 1.) Mechanisms regulating intracellular chloride in neurons and their impact on GABA-mediated synaptic inhibition — Our long-term objective in the first area is to understand the molecular mechanisms that determine the concentration of intracellular chloride (Cl-) in primary afferent neurons (PANs), their regulation and the role they play in acute somatic pain and neurogenic inflammation. PANs convey sensory information from the body to the central nervous system. Electric signals arising from peripheral sensory receptors enter the spinal cord and the brain stem through the central processes of PANs and ultimately evoke sensations such as touch, warmth, cold and pain. Work originating in my lab established that the depolarizing action of GABA is possible because [Cl-]i in PANs is higher than predicted for electrochemical equilibrium due to Na+,K+,2 Cl- cotransporters, membrane proteins that actively accumulate Cl-. 2.) Cellular and molecular mechanisms underlying cell volume control under normal and pathophysiological conditions in neurons and glial cells — We are currently focusing on the mechanisms underlying short-term changes in cell water volume and intracellular H+, Ca2+ and Cl- produced by exposure to ammonia (NH3) and ammonium (NH4+). These studies are important for understanding the pathophysiology of cellular brain edema that follows increased blood levels of NH3 and NH4+ (hyperammonemia) in humans with acute liver failure. Hyperammonemic brain edemas are a leading cause of mortality in patients with acute liver failure. We have developed in vitro models and optical methods for studying the pathophysiology of these edemas at the cellular and molecular levels.

Steven J. Berberich, Ph.D.
Interim Chair and Professor of Biochemistry and Molecular Biology

Our laboratory has been studying cellular regulators of the p53 tumor suppressor protein since 1993. Our first NIH grant focused on examining the role of the Mdm2 protein on regulating p53 function. Those studies led several novel discoveries, including an Mdm-2 chromosomal translocation, Mdm-2 gene amplification and Mdm-2 phosphorylation. We then began to study MdmX, a Mdm2-related gene that, unlike Mdm2, was not p53-regulated. Our subsequent NIH grant focused on the role of MdmX protein on p53 function. Our current five-year NIH grant continues our studies on MdmX but combines RNAi approaches with our gene expression profiling capabilities of the Center for Genomics Research (CGR) in an effort to further understand the effects of MdmX deregulation on the p53 pathway. Our primary goal is to test whether loss of MdmX can improve cancer therapies in human tumors harboring wild-type p53 that is inactivated by the deregulation of either Mdm2 or MdmX. While the majority of our research has focused on p53 regulators, the CGR has enabled us to initiate several new research collaborations. One project examining the role of 2-deoxy-glucose treatment of glioblastomas prior to irradiation has led to a recent publication with a group in India and a pending clinical trial where CGR will provide gene expression profiling of glioblastoma biopsies. Collaborations involving rat skin toxicogenomics, schizophrenic patient genotyping and lung cancer gene expression profiling are currently ongoing.

David R. Cool, Ph.D.
Associate Professor of Pharmacology and Toxicology
Director, Proteome Analysis Laboratory

The focus of my laboratory is to investigate the proteome and genome of the hypothalamic, pituitary, adrenal, pancreatic-axis (HPAP-Axis) under normal, disease or chemically challenged conditions. My research involves studying the expression, sorting, processing and secretion of HPAP peptide hormones such as vasopressin, oxytocin, insulin and ACTH. I am currently funded to study these processes in diseases such as familial neurohypophyseal diabetes insipidus, type 1 diabetes, autism and in response to nerve agents such as sarin. My long term goals are to identify and investigate the effects that these disease have on the regulation and dysfunction of the neuroendocrine system.

Kathrin Engisch, Ph.D.
Associate Professor of Neuroscience, Cell Biology and Physiology

Our laboratory uses highly specialized electrophysiological measurements in combination with genetic manipulations of individual synaptic proteins, to study the basic mechanisms of neurotransmitter release and its modulation. Neurotransmitter release shows dramatic activity-dependent behaviors. Rapid repetitive stimulation can cause an increase in release, called facilitation, in some nerve terminals. In others, the same protocol can cause depression, or a decrease in release. These types of short-term plasticity are essential for information processing in the brain, but the underlying mechanisms are unknown. We are currently studying the characteristics of neurotransmitter release in a Rab3A mutant mouse. We are also interested in longer term regulation of neurotransmitter release by activity. In collaboration with Mark Rich's laboratory, we have found that block of activity causes increases in synaptic strength by increasing the number of vesicles that fuse, and the size of the individual release events. We are currently examining the role of particular synaptic proteins in this long term plasticity.

Robert E.W. Fyffe, Ph.D.
Professor of Neuroscience, Cell Biology and Physiology
Associate Dean for Research Affairs
University Professor

Our laboratory is interested in synaptic mechanisms and integrative properties of neurons in spinal cord and brainstem circuits, involved in motor control and auditory processing respectively. Current studies are focused on the patterns of expression, and the subcellular localization, of pre- and post-synaptic membrane ion channels and neurotransmitter receptors. We use a range of quantitative light and electron microscopic experimental and analytical methods, in conjunction with electrophysiological and computation approaches. Our primary collaborators, in addition to colleagues within the department, include Bruce Walmsley (Australian National University), Ken Rose (Queen's University, Kingston, Ontario) and Brian Robertson (University of Leeds, UK).

Dan R. Halm, Ph.D.
Associate Professorr of Neuroscience, Cell Biology and Physiology

Current research interests in my lab focus on the response of intestinal epithelial cells to stimulation from the sympathetic and enteric nervous systems. During digestion enteric nerves contribute to production of the fluid necessary for enzyme action and motility along the gut. A combined stimulation via cholinergic and peptidergic classes of enteric nerves produces the highest rates of epithelial fluid secretion, in a super-additive manner. Sympathetic input suppresses this enteric nerve activity such that fluid secretion is minimal, but direct sympathetic activation of epithelial cells produces a distinct secretory mode. And, it is this specific potassium secretory mode that is characteristic of inter-meal periods. We use several in vitro techniques to examine the cellular regulatory mechanisms controlling this secretory response, including patch-clamp electrophysiology, enzyme activity assays, protein expression and live cell microscopy. Activation and inhibition of both potassium channels and chloride channels are key regulatory steps for determining the rate of fluid secretion. Errors in regulating this intestinal secretion often occur as a loss of the inhibitory sympathetic input that normally limits fluid output. Any unchecked fluid secretion is life-threatening and contributes to several chronic disease states including inflammatory bowel disease and irritable bowel syndrome.

Lynn Hartzler, Ph.D.
Assistant Professor, Biological Sciences
College of Science and Mathematics

As a comparative physiologist, my research interests are in examining how animals adapt to environmental (temperature changes) and metabolic (exercise, feeding, etc.) perturbations to their acid-base status. Alterations in breathing are the primary, acute response to a metabolic acidosis or alkalosis. Poikilothermic ectotherms (most reptiles, amphibians, and fish) have varied ventilatory and acid-base responses to changes in ambient temperature, so comparisons of their chemosensors may provide insights into why there are multiple chemosensitive regions of neurons in the brainstem that influence ventilation. Current projects in my lab involve experiments designed to understand how central (brainstem) chemoreceptors sense changes in blood gases and pH. We use the combined techniques of fluorescence imaging microscopy and whole-cell electrophysiology to measure neuronal responses to changes in CO2, O2, and pH in brainstem neurons. I am interested in understanding how these chemoreceptors are altered by changes in the animal’s environment; this comparative approach offers an alternative to using disease models that may have confounding variables associated with co-morbidities of disease.

Michael Hennessey, Ph.D.
Professor of Psychology
College of Science and Mathematics

Our laboratory studies the relation between neuroendocrine activity and behavior, particularly during development. Hormones (endocrines) have important influences on adaptive behavior. But not all effects of hormones are adaptive. For instance, prolonged activation of the body’s primary stress-related neuroendocrine system, the hypothalamic-pituitary-adrenal (HPA) axis, may impair both our physical and mental health. Because psychological “stressors”, such as exposure to novel or uncertain situations, can activate the HPA axis, and because other psychological factors, such as the presence of an important social companion (an attachment figure) can inhibit HPA activation, psychological factors may have important influences on our well being. Young organisms appear to be particularly susceptible to such effects. Therefore, it is important to better understand how behavior, psychological factors, and endocrine activity are related in young organisms.

Susan Kraner, Ph.D.
Research Scientist, Department of Neuroscience, Cell Biology & Physiology and Center for Genomics Research

Dr. Kraner uses proteomic techniques to identify the modification of the muscle sodium channel that causes loss of electrical excitability in muscle in critical illness myopathy. This work is central to Dr. Rich’s R01 grant from NIH and will hopefully lead to renewal of the grant in two years. This work has direct clinical relevance and will hopefully lead to a treatment for this devastating muscle disease. Dr. Kraner also uses proteomic techniques to determine what changes in peripheral nerve ion channels underlie the neuropathy following treatment with chemotherapy. Neuropathy following chemotherapy is a serious problem that often limits treatment of cancer and understanding mechanisms underlying the neuropathy will hopefully lead to treatment and thus improve cancer therapy. This project will generate preliminary data that will be used in a new NIH grant application with co-investigators Drs. Cope and Rich. Dr. Kraner has a great deal of expertise in generating adenoviral vectors and was in charge of a vector core at University of Kentucky. As part of her job in the genomics core at Wright State, she will generate adenoviral vectors. One use of these vectors will be to assist Dr. Engisch in generating preliminary data on studies of synaptic function using chromaffin cells as a model system. These data will be used to submit a new NIH grant application.

Michal Kraszpulski, Ph.D.
Research Scientist, Department of Neuroscience, Cell Biology & Physiology

My projects include the following: 1.) Using electron microscopy to determine whether increased synaptic strength in a mouse with a mutation in Rab3A is due to increased synaptic vesicle size. This work is central to Dr. Engisch’s project, which is part of a PPG grant from NIH. The goal of the project is to understand the role of protein Rab3A in plasticity of the nervous system. 2.) Using electron microscopy to determine whether synaptic vesicle size is increased following loss of synaptic activity. This work is central to Dr. Rich’s project, which is part of a PPG grant from NIH. This part of the PPG is attempting to understand how changes in neural activity trigger changes in nervous system function. 3.) Using confocal microscopy to determine possible structural and/or molecular changes in the central arborization and synapses of Ia afferent fibers after peripheral nerve injury and peripheral regeneration. This project is related to the projects of Dr. Alvarez and Dr. Cope in the PPG NIH grant. The projects with Dr. Engisch, Dr. Rich, Dr. Alvarez, and Dr. Cope have implications for understanding how the nervous system responds to injury and thus have implications for many diseases of the nervous system.

David R. Ladle, Ph.D.
Assistant Professor of Neuroscience, Cell Biology and Physiology

My lab is interested in the development of neural circuits. The establishment of appropriate connections between specific neurons generates an organism's perception of the outside world and controls behavioral responses. We use the relatively simple circuits in the spinal cord that control reflex movements as a model system to understand the molecular and physiological mechanisms by which circuits develop. These studies employ a wide variety of techniques including mouse genetics, electrophysiology, immunohistochemistry, confocal microscopy and other advanced imaging techniques.

Douglas S. Lehrer, M.D.
Associate Professor of Psychiatry
Medical Director, Boonshoft Schizophrenia Center, Wallace-Kettering Neuroscience Institute

The Department of Psychiatry undertakes neurobiological research in partnership with the Wallace-Kettering Neuroscience Institute (WKNI) located at the nearby Kettering Memorial Hospital, home of fully equipped positron emission tomography (PET) and magnetic resonance imaging (MRI) labs, including research-dedicated facilities supported by a full staff of Ph.D.-level radiochemists, physicists, and computer scientists. My group is conducting a number of investigations into the neurobiology of psychoses, including a study of pathophysiology of never- and unmedicated schizophrenics using PET (FDG and fallypride), MRI (structural, functional, diffusion tensor), neurological and neuropsychological examinations; a study to identify biomarkers of differential antipsychotic treatment response (again, using PET, MRI, neuropsychological and neurological variables, as well as pharmacogenomic markers); a study of non-verbal language characteristics of schizophrenic subjects using advanced computer-assisted analysis of audio/video recordings; and a study of self-injury in women with borderline personality disorder using functional MRI.

Michael Markey, Ph.D.
Research Assistant Professor of Biochemistry and Molecular Biology
Director, Center for Genomics Research

My research is currently focused on the gene MDM4, also known as MDMX or HDMX. MDM4 is an important negative regulator of the p53 tumor suppressor. MDM4 binds to p53 and inhibits the ability of p53 to transactivate target genes. Although it is closely related and structurally similar to MDM2, MDM4 does not share the ability to act as an E3 ubiquitin ligase towards p53. MDM4 is widely known to be regulated at the protein level by association with MDM2, which ubiquitinates MDM4, targeting it for degradation. Recently I have shown that the mRNA levels of MDM4 are decreased in response to DNA damage in a p53-independent manner. This appears not to be a transcriptional effect, as an MDM4 reporter gene is not affected by DNA damage within the time frame of the observed decrease in MDM4 transcripts. Although transcription remains constant, alternative splicing seems to increase after damage, pushing MDM4 towards certain truncated versions and away from the full length transcript. Additionally, MDM4 mRNA becomes less stable after DNA damage, possibly due to the influence of micro RNAs. The role of the 3′ UTR of MDM4 and the functional consequences of MDM4 alternative transcription are currently under investigation.

Robert W. Putnam, Ph.D.
Professor of Neuroscience, Cell Biology and Physiology

My research focuses on the cellular neuroscience of respiratory control. We study the neurons from the brainstem of neonatal rats and their response to elevated levels of CO₂. It is believed that these neurons play a major role in controlling ventilation, and our work is thus of relevance to disorders that involve altered respiratory drive, such as sudden infant death syndrome (SIDS) and sleep apnea. There are two main thrusts of our work: 1.) Cellular Signals and Targets in CO₂-sensitive Neurons: We are looking at the cellular signaling pathways and the ion channel targets involved in the sensing of elevated CO₂ by central chemosensitive neurons. This work involves pH and calcium sensitive fluorescent dyes to study changes of intracellular pH and intracellular calcium and their role in CO₂-induced increased firing rate of these neurons. We have recently begun studies to alter central chemosensitivity in rats to determine the cellular alterations that correlate with the altered central chemosensitivity. 2.) Development of Central Chemosensitivity: We have done some of the first studies to fully characterize the development of the CO₂ responsiveness of ventilation in neonatal rats. Our studies suggested a triphasic pattern of development, with an early neonatal form of chemosensitivity that gives way after two weeks to an adult form of chemosensitivity, and a critical window of minimal chemosenstivity at week one. We are also studying the development of chemosensitivity in individual neurons within various chemosensitive regions. Finally, we are examining which brainstem regions are responsible for each type of chemosensitivity and the effects of chronic exposures to hypercapnia or hypoxia on these developmental patterns.

Mark Rich, M.D., Ph.D.
Associate Professor of Neuroscience, Cell Biology, and Physiology
Director, Neurological Medicine

My research focuses on two areas. We study the cause of paralysis in patients with Critical Illness Myopathy. We have found that paralysis in this syndrome is due to abnormal behavior of skeletal muscle sodium channels. Our goal is to determine the cause of altered sodium channel behavior. We study the mechanisms underlying activity-induced changes in synaptic strength. We use the neuromuscular junction as a model synapse in which it is possible to determine both the signals triggering changes in synaptic strength as well as the types of changes underlying alterations in synaptic strength.