Molecular and Integrative
Neurosciences Department

Chairman's Overview

Tamas Bartfai, Ph.D.

The Department of Neuropharmacology, now called the Molecular and Integrative Neurosciences Department, was successfully led for more than 2 decades by Floyd Bloom, the outstanding researcher and organizer of neurosciences at Scripps Research, in the United States, and around the world. Under his leadership, the department became one of the key sites for research on drug and alcohol abuse and on neurovirology, nationally and internationally. Dr. Bloom became an emeritus professor March 1, 2005. We thank him for his contributions in building this department.

Neuroscience is an area that benefits most from the human genome project, because many hereditary diseases are neurologic and psychiatric disorders. The ability of modern molecular biologists to manipulate the protein composition of individual selected neurons is opening up possibilities to delineate neuronal networks that underlie specific behaviors. In order to tap into these new possibilities, the coming years will see an addition of a new research branch to the department to complement neurovirology and addiction research. Researchers in this new branch will study in molecular detail those ion channels, receptors, and other proteins that contribute to changes at the levels of cells, networks, and whole organisms that are manifested as different behaviors. The explicit goal of the department is to link its successful in vivo work in rodents, primates, and humans to the outstanding chemistry and structural biology of other departments at Scripps Research via a strengthened molecular neuroscience effort, based on the work of several new faculty members. The recruitment of these scientists is in progress.

The research reviewed in the following paragraphs describes findings in 2 main areas of activity this past year. It showcases the work of 2 young scientists who already have attracted ample attention with the originality of their approaches to important basic science problems that also carry serious weight in addressing diseases such as alcohol addiction and viral infections of the brain.

Marisa Roberto, who has received the prestigious Research Society on Alcoholism Young Investigator Award for 2005, has addressed the cellular and in vivo correlates of acute and chronic alcohol exposure. The focus of most research on the cellular modifications caused by ethanol intake has been g-aminobutyric acid, which is crucially involved in the anxiolytic effects of alcohol. George Siggins has played a key role in these studies. The stress hormone corticotropin-releasing factor and the antistress and antipain sensation hormone nociceptin compete for regulation of the effects of ethanol on the release of g-aminobutyric acid, and thus their competition decides if the intake of ethanol will be associated with lessened anxiety and reward or not. During chronic ethanol exposure, the relative strength of these interactions is changing, as Dr. Roberto has shown. The strength of the research done by Dr. Roberto and Loren Parsons is that the results with cells in vitro are similar to the results in free-moving control (no previous exposure to ethanol) and ethanol-addicted animals. Thus, the findings form a much closer link to the human disease than did those of many earlier in vitro studies. Drs. Roberto and Parsons have also placed the site of interaction between g-aminobutyric acid, ethanol, and corticotropin-releasing factor at the releasing presynaptic site of the communication place: synapses between neurons.

Dorian McGavern’s research joins questions pertaining to virology-immunology and brain research. He studies how the brain can rid itself of a persistent viral infection when the most common mechanism by which the body fights viral infections in the periphery (i.e., the mobilization of cytotoxic T lymphocytes) is not easily applicable. This situation occurs because the blood-brain barrier restricts entry of the lymphocytes into the brain and regulates interactions of the cytotoxic cells with infected target cells, such as neurons. Dr. McGavern studies viral clearance by using infection with a neurotropic virus, lymphocytic choriomeningitis virus (LCMV), that has been studied in the department for more than 3 decades by Michael Oldstone and colleagues.

When mice are infected at birth or in utero with LCMV, the virus establishes lifelong persistence in every tissue compartment (e.g., spleen, thymus, lymph nodes, liver, lung, heart, kidney, CNS; Fig. 1A). As a further complication, neurons are the sole population of LCMV-infected cells in the CNS parenchyma (Figs. 1B and 1C). Adoptive transfer of LCMV-specific memory T lymphocytes (both CD8+ and CD4+) obtained from syngeneic mice immune to LCMV can completely eliminate virus from all tissue compartments (including the CNS) of LCMV carrier mice. During this therapeutic process, peripheral tissues are purged of virus within 15 days; CNS viral clearance requires 100 days. The reason for this considerable delay in viral clearance from the brain and the mechanism by which it occurs are not entirely understood. Dr. McGavern is now conducting studies to determine how cytotoxic T lymphocytes accomplish this mission within the brain. Understanding these mechanisms will enable us to manufacture therapeutic T cells to resolve CNS viral infections.