News and Publications

Chairman's Overview

Floyd E. Bloom, M.D.

As in all previous years of my departmental overviews, the amazing and continued productivity of our faculty defies any efforts to extract and simplify from their broad areas of interest and their multiple internal and external collaborations. Our essential departmental research strategy remains unchanged: we continue to focus our main efforts on the mechanisms by which infectious, environmental, and inheritable causes lead to psychiatric, neurologic, and endocrine disorders of the brain. We start here in order to acquire the information needed to devise treatments or preventions for these diseases.

Because of the finite amounts of space, human resources, and financial opportunities for serious engagement of the issues, we have elected to focus on a selected subset of human brain and behavioral problems: (1) the vulnerability to alcohol and other drugs of abuse, including opiates, psychostimulants such as cocaine and methylenedioxymethamphetamine (MDMA or Ecstasy), and cannabinoids; (2) the basis for the actions of ethanol on the developing brain (so-called fetal alcohol syndrome); (3) the basis for the neuropsychologic impairments associated with HIV disease (and CNS manifestations of other lentivirus infections) and the growing implications for the health benefits of sleep; (4) CNS inflammations, especially those that occur after destructive injuries; and (5) the entire interface between the neural and immune systems, as initially revealed through viral infections.

Although the disease-related implications are more clear from our studies in some instances than in others, we also do fundamental biomedical research on the mechanisms by which infectious microbes gain access to the brain or initiate inflammatory and immune responses in the brain (see the reports by Drs. Oldstone, Buchmeier, de la Torre, and Whitton). We are also studying the basic mechanisms by which the nervous system in developing or adult organisms selects the basic genetic information that is uniquely expressed by neurons (see the studies by Drs. Lai and Prieto) or by glia (see the reports by Drs. Gruol, Lane, Phillips, and Yu).

In keeping with the themes discussed in previous annual overviews, it is again a pleasure to note the continued progress in the refinement of our whole-animal models of the CNS dysfunctions (so called neuro-AIDS) in subjects with HIV disease (see the reports of Drs. Fox, Gold, Gruol, Henriksen, Phillips, and Siggins). This past year, we emphasized the implementation of the transgenic mice systems so nicely developed by Dr. Campbell and analyzed for cellular, circuitry, and behavioral manifestations by Drs. Gold, Henriksen, and Siggins. We have also begun to test the effect of antiretroviral compounds on the earliest electrophysiologic abnormalities seen in both the simian and feline immunodeficiency virus model systems. These compounds cannot enter the brain through the blood-brain barrier; thus, they can affect the peripheral viral load but should not directly influence the state of infection and consequent reactive situations in the CNS. The degree to which such peripherally restricted drugs can influence CNS pathophysiologic states should be quite revealing and of great potential importance to the current AIDS epidemic.

This year, I also wish to call attention to another series of studies, also undertaken in our traditional mode of multi-investigator collaborations, that focus on our efforts to understand the effects of acute and chronic stress on vulnerability to drug-taking behaviors, to chronic adaptive mechanisms, and to the effectiveness of possible antidrug medications. These studies rely heavily on animal models (see the reports from Drs. Koob, Weiss, Gold, and Markou) in which drug self-administration can be readily acquired. Drs. Koob, Weiss, Markou, Gold, and Parsons have uncovered multiple interactive consequences of prolonged drug exposure confounded by ongoing environmental stressors. The results suggest that treating the drug responses alone may be inadequate to reverse the brain's adaptive dependencies. Our senior faculty have also continued to investigate the basis for individual variation in susceptibility or resistance to the actions of alcohol. To help define the biological basis for dependence in male alcoholics, we have participated in the studies of the national Consortium on the Genetics of Alcoholism (see the report from Dr. Polich), and have examined these phenomena in Native Americans (see the report by Dr. Ehlers).

In addition, we have started several collaborations with scientists at Novartis to examine animal models of Alzheimer's disease. We will either examine lesions of specific chemical systems in the brain or use transgenic mouse models in which overexpression of different genetic constructs of the ß-amyloid protein have been engineered. In my own group, Warren Young and I have almost completed a collaboration with Drs. Koob and Ahmed on the quantitative neurocytologic and neurochemical sequelae of combination chemical lesions of noradrenergic and cholinergic projections in the forebrain as a possible model for treatment of patients with Alzheimer's disease. Cellular electrophysiologic studies by Dr. Giacchino with mouse models of Alzheimer's disease are also under way.

Our studies on these important interfaces between fundamental neuropharmacologic research and the need for medications to alleviate human brain diseases exemplify the hope that research brings to those who now have these illnesses.