David Olton - US grants

Remembering information is critical in our daily lives, and impairments of memory are profoundly disturbing. These observations motivate research to understand the brain mechanisms involved in normal memory and the types of pathology that produce amnesia. Animal models are especially useful in this endeavor, and experiments with rats are proposed because of the scarcity of monkeys. The experiments are designed to describe the characteristics of the amnesic syndrome seen in rats following damage to different temporal lobe structures, compare these to those seen in primates and humans, and use single unit recordings as a converging operation to examine the role of the hippocampus in normal memory processing. The neuroanatomical focus is on the hippocampus, its external projections through the fimbira-fornix, and the amygdala. The behavioral analyses look at memory for the following types information: the duration of an ongoing event; the duration of an already completed event; spatital locations as compared to cues; procedures; trial unique stimuli as compared to often repeated stimuli. The electrophysiological recordings are made from complex spike units in theta units in the pyramidal cell layer of the hippocampus while rats perform a delayed conditional discrimination, the type of task in which performance is impaired following lesions of the hippocampus. The activity of these units is correlated with the mnemonic aspects of the task (such as the relevant, nonspatial discriminative stimuli; registration, storage, and retrieval of information; correct and incorrect responding, etc.). Together, these experiments help determine the ways in which temporal lobe structures process memory, and the types of memory dysfunctions seen after pathology in them.

Funds requested in this application will be used as partial support for the expansion and development of a competitive biomedical research program at Atlanta University. The research capability will be focused in the areas of molecular biology and biochemistry and cellular and developmental biology. The programmatic thrust will center around four major goals. These are: 1) The planned and orderly addition of both junior and senior level faculty with specific research expertise that will strengthen and broaden existing research capabilities at the University. Funds are requested to support 10 of the expected 16 appointments over the next 5 years. 2) The immediate renovation and modification of facilities to accommodate the addition of faculty beginning year 1 of this award and prior to the currently planned completion of the Graudate Research Center for Science and Technology building in 1988. 3) The acquisition of major equipment items that will offer a substantial increase in the research capability of existing and newly acquired faculty. 4) A targeted move to improve the University research infrastructure to promote research productivity of the faculty.

Experiments will develop a battery of test for four different classes of biomarkers of aging: Sensory and motor function, learning and memory, reproductive function, neuroendocrine function. For each biomarker, two strains of mice and two strains of rats will be tested in a series of preliminary experiments designed to establish the most effective task parameters to detect age-related changes in the biomarker at different chronological ages. The performance of diet-restricted and ad libitum fed animals will assess the effects of this manipulation, which increases longevity, on behavioral and physiological functions. The data analysis will provide measures of reliability and validity, and assess different theoretical descriptions of aging of processes. The most reliable and valid procedures will be combined into a test battery that can be administered to an animal to assess the four classes of biomarkers. A cross-sectional between-subjects design will assess the interrelationship of the different biomarkers, and a longitudinal, within-subjects design will assess the predictability of the biomarker profile at one age for the profile at a subsequent age, and the interrelationship between the rates of change in the different biomarkers.

WENK Drs. Olton and Wenk are continuing their highly productive investigations of the neurochemical bases of learning and memory. This project focuses particularly on the interactions between two different neurotransmitter systems, and how they interact to influence memory. Of particular interest are acetylcholine and serotonin, both of which have been shown to be profoundly important in different types, and phases, of learning. These investigators are using a combination of behavioral and physiological techniques to study the neurochemical interactions that underlie learned behavior. In addition to contributing to our understanding of the "molecular mechanisms" of learning and memory, these experiments will also address a question of paramount importance: Can these neurochemical interactions be enhanced or impaired to alter recovery of function after one system is damaged? The answer is of extreme significance, for it could help to form the foundation of new treatment strategies for people who have suffered memory and cognition losses as the result of brain damage caused by head injury.

The long-term objective of this project is to understand the relation among recent memory, septohippocampal function, and aging. Normal aging and age-related neurodegenerative diseases can both produce impairments of memory. Understanding the neural mechanisms related to these memory impairments, and attempting to alleviate them through neural manipulations, can have a significant impact on the quality of life of the aged population. This project has three specific goals. (1) Determine the extent to which direct microinfusion of substances into the medial septal area (MSA) of rats can improve mnemonic function in aged rats with impaired memory, and examine the correlations among mnemonic improvements, hippocampal electrophysiology as measured by theta, and cholinergic stimulation as measured by hemicholinium-3 (HC-3) binding. (2) Determine the extent to which aging changes the sensitivity of the septohippocampal system to disruption by compounds directly infused into the MSA, producing shifts of the dose-response curve relating the dose of these compounds to the magnitude of the memory impairment. (3) Examine the individual differences in aged populations with respect to the magnitude of the memory impairment, sensitivity to MSA infusions, and activity of the cholinergic system as examined by HC-3 binding. The experimental design tests rats of 4 different ages in two tasks to assess recent memory. Compounds infused into the MSA are designed to stimulate and inhibit, respectively the cholinergic system (scopolamine, oxotremorine) and the GABAergic system (picrotoxin, bicuculline, muscimol). Theta is recorded from the hippocampus to indicate the electrophysiological effects of these compounds. HC-3 is measured to determine the extent to which cholinergic system is affected.

Experiments will develop a battery of test for four different classes of biomarkers of aging: Sensory and motor function, learning and memory, reproductive function, neuroendocrine function. For each biomarker, two strains of mice and two strains of rats will be tested in a series of preliminary experiments designed to establish the most effective task parameters to detect age-related changes in the biomarker at different chronological ages. The performance of diet-restricted and ad libitum fed animals will assess the effects of this manipulation, which increases longevity, on behavioral and physiological functions. The data analysis will provide measures of reliability and validity, and assess different theoretical descriptions of aging of processes. The most reliable and valid procedures will be combined into a test battery that can be administered to an animal to assess the four classes of biomarkers. A cross-sectional between-subjects design will assess the interrelationship of the different biomarkers, and a longitudinal, within-subjects design will assess the predictability of the biomarker profile at one age for the profile at a subsequent age, and the interrelationship between the rates of change in the different biomarkers.