Cellular Neurobiology Research Branch
Cellular Neurophysiology Section
Mission Statement
Our laboratory focuses on several facets of CNS function at the cellular level – neural plasticity and effects of neurotrophic factors on the CNS; physiological properties of dopaminergic systems; neuroanatomical methods; electrophysiology; animal models of neurodegeneration.
Program Areas
• Neurotrophic Factors
• Neurodegeneration
• Stroke
• Parkinson’s Disease
• Drug Abuse
Name: Barry J. Hoffer, M.D., Ph.D.
Title: Chief, Cellular Neurophysiology Section
Telephone Number: (410) 550-1538
Synopsis of Research
The Cellular Neurophysiology Section contains a Molecular Biology Module and an In Vivo Electrophysiology Module. The Molecular Biology Module focuses on several areas involving the study of growth factors and transcription factors that are directly related to the function and development of the dopaminergic system of the ventral mesencephalon. This work includes studies of the role of the transcription factor Nurr1, which plays an essential role for the generation of DA neurons during development. Our findings have shown that Nurr1, which is highly expressed in dopamine neurons during adulthood, may also play an essential role during exposure to drugs of abuse (Bäckman et al., 2003). Currently, we are using molecular approaches to further investigate the function of Nurr1 in the adult dopaminergic system. We have also been involved in collaborative efforts to create and test short interfering RNAs (siRNA) to suppress the expression of Nurr1, and other genes related to the ventral mesencephalic dopaminergic system. The characterization of these highly effective siRNAs for DA phenotypic markers may open new avenues for loss-of-function analysis and may help us to further elucidate the function of these genes in vivo. In another line of research, using quantitative PCR approaches, we have analyzed the expression levels of several growth factors and transcription factors present in the substantia nigra/VTA and target areas from control and Parkinson’s disease (PD) patients. Laser capture microdissection (LCM) and microarray techniques are being used to study gene expression patterns occurring in neuromelanin positive neurons from the substantia nigra of Parkinson’s disease patients (PD) to investigate what gene pathways may lead to the development of this neurodegenerative disorder. These studies will be extended to the analysis of subjects exposed to drugs of abuse. Finally, several projects are underway that would lead to the generation of novel transgenic mice and stem cell line strains specifically designed to enlighten the understanding of the cellular components that lead to addiction and other conditions that affect the mesolimbic dopaminergic system.
The In Vivo Electrophysiology Module studies are generally focused on brain mechanisms underlying goal-directed behavior and the actions of psychoactive drugs. Since behavior is organized and regulated via the well-coordinated activities of multiple neural cells. A number of behavioral and physiological techniques are used in our experimental work in NIDA-IRP, and this work is aimed at understanding the action of various addictive drugs, drug-taking behavior, and the adverse health effects of drugs of abuse. While our work is focused on various addictive drugs (heroin, cocaine, meth-amphetamine, MDMA), considerable efforts are made to study how addictive behavior develops and is regulated and what differences and commonalities exist between drug-taking and natural motivated behaviors. As a primary technique in this work, we use brain thermorecording in freely moving rats—an approach instrumental to the study of neural function, addictive drugs, and drug-taking behavior. This physiological technique was developed in our group, and is supplemented by other physiological and behavioral techniques. The second major focus of our unit is the study of neurochemical interactions occurring at the single-neuron level in brain areas critical for behavioral organization and the action of addictive drugs. As a primary technique, we use single-unit recording coupled with microiontophoresis in awake, unrestrained rats.
A Proteomics Core is also part of the Section administratively but this core collaborates with investigators in many Branches and Sections within the Intramural Program, as well as the extramural community. In the past five years we have set about creating alternative Mass Spectrometric (MS) approaches to better determine the basic mechanisms that govern protein-protein, protein-peptide, peptide-peptide, protein-drug and lipid-drugs interactions in general and receptor-receptor interactions in particular. Several substantial and promising accomplishments both in instrumentation development and their MS applications to drug related research issues have resulted. Innovative drugs and drug design procedures using the new MS approaches have been validated in two sets of animal studies 1) proving that specific peptide sequences limit dynorphin mediated neurotoxicity, and 2) defining the site of action of chlorisondamine (defining the interaction sites of chlorisonamine with the alpha-2 subunit of the neuronal nicotinic receptor). Bioinformatics and quantum chemical structural modeling augment and reinforce the experimental molecular structural identifications obtained with MS, and the new technique of MALDI-Ion Mobility- time of flight mass spectrometry (MALDI-IM-oTOFMS) to spatially map lipids, peptides, cocaine, and chlorisondamine in rat brain tissue.
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Cellular Neurobiology Research Branch
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