Thomas J. Walsh - US grants

toxicant interaction; neurotoxins; metal poisoning; brain; lead poisoning; chordate locomotion; adenylate cyclase; somesthesis; neurologic manifestations; limbic system; molecular site; neurochemistry; neuropharmacology; stereotaxic techniques; histology; radiotracer; high performance liquid chromatography;

Triethyllead (TEL) is a neurotoxic organometal that produces behavioral and neurological alterations in both laboratory animals and man. Despite the prevalence of this compound in the environment and the repeated episodes of human poisoning, the sites and mechanisms of action of TEL-induced neurotoxicity remain undetermined. The experiments outlined in this proposal are designed to address the hypothesis that TEL enhances dopamine-mediated processes in specific neural loci. More specifically, it is suggested that TEL augments D1-mediated receptor events in mesolimbic regions that participate in the control of locomotor behavior. This hypothesis is consitent with neurochemical, pharmacological and behavioral studies demonstrating an augmented behavioral response to both direct (apomorphine and indirect-acting (d-ampehtamine) dopamine agonists concomitant with an enhanced reactivity of dopamine-stimulated cyclase activity in mesolimbic sites, following acute exposure to TEL. Furthermore, the expression of TEL's behavioral effects can be modified by pharmacological manipulation of brain dopamine systems. Because basal levels of cyclase activity and motor activity are not affected by TEL, it is likely that the responsivity of dopamine systems is primarily affected by this neurotoxicant. That is, an appropriate stimulus will produce an exaggerated or supersensitive response in affected neural regions. A general principle organizing this proposal is that neurotoxic insult may produce alterations in dopaminergic function that are only detectable in specific neuroanatomical regions and in subpopulations of dopamine receptors. The primary goal of these studies is to further delineate the sites and mechanisms of TEL-induced alterations in brain dopamine systems. This information will be useful for understanding the biological substrates of organolead toxicity. Furthermore, at a more general level, these studies will help to define the ways in which subpopulations of dopamine receptors react and adapt to toxic insult.

Triethyllead (TEL) is a neurotoxic organometal that produces behavioral and neurological alterations in both laboratory animals and man. Despite the prevalence of this compound in the environment and the repeated episodes of human poisoning, the sites and mechanisms of action of TEL-induced neurotoxicity remain undetermined. The experiments outlined in this proposal are designed to address the hypothesis that TEL enhances dopamine-mediated processes in specific neural loci. More specifically, it is suggested that TEL augments D1-mediated receptor events in mesolimbic regions that participate in the control of locomotor behavior. This hypothesis is consitent with neurochemical, pharmacological and behavioral studies demonstrating an augmented behavioral response to both direct (apomorphine and indirect-acting (d-ampehtamine) dopamine agonists concomitant with an enhanced reactivity of dopamine-stimulated cyclase activity in mesolimbic sites, following acute exposure to TEL. Furthermore, the expression of TEL's behavioral effects can be modified by pharmacological manipulation of brain dopamine systems. Because basal levels of cyclase activity and motor activity are not affected by TEL, it is likely that the responsivity of dopamine systems is primarily affected by this neurotoxicant. That is, an appropriate stimulus will produce an exaggerated or supersensitive response in affected neural regions. A general principle organizing this proposal is that neurotoxic insult may produce alterations in dopaminergic function that are only detectable in specific neuroanatomical regions and in subpopulations of dopamine receptors. The primary goal of these studies is to further delineate the sites and mechanisms of TEL-induced alterations in brain dopamine systems. This information will be useful for understanding the biological substrates of organolead toxicity. Furthermore, at a more general level, these studies will help to define the ways in which subpopulations of dopamine receptors react and adapt to toxic insult.

How do we construct maps of the real world in our brain? Apparently there is a structure called the hippocampus that contains a spatial map that is laid down through experience. Dr. Walsh has devised a novel behavioral test to assess how various chemical inputs affect the behavioral function of this structure. With this NSF grant he will manipulate the chemical environment of the cells that provide major inputs to the hippocampus. By measuring the number and types of errors made in a spatial maze after each manipulation he will be able to determine whether his chemical manipulations have improved or interfered with hippocampal function. The results of these experiments will improve our understanding of the neurobiological foundations of learning and memory. The future applications will include drugs that can be used to improve memory or, alternatively, reduce the influence of unwanted, intrusive memories.***//

9514557 Walsh An exciting, unresolved question in neuroscience is how animals acquire and store memories. For mammals there is an identified site, the hippocampus, at which memory processing appears to occur. The structure and function of this site is known in some detail, however the nature of the inputs that control the functioning of hippocampal neurons is largely unknown. One of the input brain regions, the medial septum, contains neurons that project to and control the hippocampus. The medial septum appears to integrate subcortical information about the 'biological significance' of episodes or events and in turn modulate the responsiveness of the hippocampus to its primary, cortical input. Septal neurons release two types of neurotransmitter molecules, acetylcholine and GABA, which modulate the physiology of hippocampal neurons and hence the memory- related functions of the hippocampus. Studies conducted through funding by this award examine the neurotransmitters and brain circuits involved in a specific type of learning related to remembering a position in space. One set of experiments is designed to examine whether site-specific manipulations of different molecular receptors (benzodiazepine receptors), in the medial septum, will alter the activity of septal neurons and of memory processes. In other experiments, tests are conducted to determine the physiological mechanisms through which intraseptal injection of a receptor blocker drug (flumazenil) enhances the activity of neurons that project to the hippocampus and increases working memory. These studies should provide a better understanding of specific brain circuits and neurochemical mechanisms that control memory in mammals. The expectation is that such a detailed understanding of a specific type of learning at a specific site will contribute importantly to a general understanding of how animals learn, and remember what they learn.

DESCRIPTION (provided by applicant): Over the past decade, testosterone (T) treatment has increased markedly in older hypogonadal men, yet the long-term benefits and risks of T treatment are unknown because prior studies have been inadequately powered. A significant public health challenge is to assess the long-term risks of T treatment in older men with low T levels in the absence of a long-term randomized controlled trial. We propose to conduct a pharmaco-epidemiologic study to ascertain long-term risks of T treatment in a national VA database of ~480,000 older, hypogonadal men that includes ~160,000 men who initiated T treatment between January 1, 2001 and July 1, 2012, and have a maximal follow-up time of 10.5 years. Our primary outcomes will be combined cardiovascular (CV) events (recurrent and incident myocardial infarction, ischemic stroke, and venous thrombosis) and incident aggressive prostate cancer (Gleason grade >8 or PSA >20 ng/dl or T3 stage or greater or nodal or metastatic disease). Secondary outcomes will be specific CV events, overall (aggressive and non-aggressive) incident prostate cancer, and total mortality. We will examine outcomes by different T formulations (intramuscular, patch, and gel) and whether risks are modified by age, ethnicity, and prevalent diabetes. A unique strength of the VA database is its linkage to Medicare data and a VA Prostate Cancer registry that will enhance ascertainment of outcomes. Our research team has relevant experience in: 1) the use of a VA database to assess effects of T treatment in hypogonadal men; 2) outcome assessment of CV events, prostate cancer, and mortality; and 3) pharmaco-epidemiology of hormone treatment. We will employ several analytic techniques to strengthen the results of our study. Specifically, we will use a vetted propensity score analysis to adjust for the non-randomization to T-treatment and will adjust for potential bias related to increased prostate cancer screening in the T-treated group, by adjusting for screening intensity with PSA levels, frequency of PSA levels, and prostate biopsy. Strengths of this study include 1) a large cohort of older, ethnically diverse, hypogonadal men with high medical morbidity and event rates and a long follow-up period, 2) primary aims focused on clinically relevant outcomes and 3) innovative analytic approach and methods. Our team has successfully collaborated in the past and has the clinical, pharmaco-epidemiologic, and biostatistical expertise to complete a high-quality study on the long-term risks of T- treatment. Given the high prevalence of hypogonadism and increasing number of T-treated men, this study will provide crucial data to clarify risks of T treatment and provide impetus for a large, randomized, controlled, clinical trial. PUBLIC HEALTH RELEVANCE: Testosterone treatment is increasing markedly in older men, even though the long-term risks of testosterone treatment are unknown. We will use a clinical database of 500,000 men with low testosterone levels to examine if testosterone treatment is associated with serious health problems such as aggressive prostate cancer, heart attacks, strokes, blood clots, and death. These results will be highly relevant for public health, due to th large and growing numbers of older men treated with testosterone, who may be at risk for serious health problems from long-term testosterone treatment.