Etan J. Markus - US grants

The objective of this project is understanding the neuronal mechanisms that underlie age-related deficits in learning and memory. Aging is characterized by deficits in spatial abilities, exploration, reversals, and sensitivity to interference. In humans (esp. Alzheimer's disease) and other mammals these deficits have been related to the hippocampus, with correlations between an aged rat's spatial ability and a number of hippocampal cellular variables. These cellular changes presumably underlie functional changes in hippocampal information processing affecting the aged animal's behavioral ability. The goal is to discern this relationship between hippocampal function and behavior, by examining the hippocampal representation of the environment. Spatial ability will be related to single unity network activity in the hippocampus, recorded in freely behaving young and old rats. Age related changes examined: 1) Learning and Retention: Experiments will examine age related changes in learning and retention using two paradigms: fear conditioning and radial maze spatial memory. While both types of paradigms have been shown to be related to hippocampal function they differ greatly due to the fact that one is an aversive, and the second an appetitive task. Animals exhibiting deficits in both types of tasks will be presumed to have impaired hippocampal function. 2) Hippocampal Representation: The behavioral battery will allow the animals to be divided into those with impaired and unimpaired hippocampal function. These rats will be surgically implanted with electrodes into the hippocampus and the parallel single unity recording technique employed to record simultaneously the activity of many neurons. The cells will be monitored as the rats search for randomly scattered food. The hippocampal representation of the environment (inferred by the activity of these cells) will be related to the animal's ability on the behavioral battery. 3) Hippocampal Dynamics: Hippocampal cells will be monitored as the rats learn a simple new task in the familiar environment. It has been shown that young animals can show many different hippocampal representations of the same environment, and can switch between them depending on the behavioral situation. The effects of changing the behavioral context (new task) will be examined in the hippocamplly impaired and unimpaired old rats. Both individual cell and network properties will be examined. The distinctive aspect of the research lies in combining the behavioral analysis with parallel single unit recording. While there is already a considerable amount of information about the correlates of hippocampal neuronal activity, far less is known on how this activity relates to the animals cognitive ability This research will be the first to incorporate parallel single unit recording to investigate hippocampal functional changes during aging, and how these changes related to information processing ability. The results will facilitate understanding the hippocampal mechanisms underlying both normal and abnormal memory processes, and may form the basis for developing therapeutic interventions in cases of age-related learning and memory dysfunction.

IBN-9809958 PI= Markus, E. Sex differences and estrous cycle changes in hippocampal information processing: Relating learning to hippocampal single unit network representation The long-term objective of the research is understanding the neuronal mechanisms that underlie learning and memory processes; examining the relationship between behavioral ability and the activity of brain cells. The focus of the work is the hippocampus, a brain structure important for establishing new memories and for navigation. There is evidence of sex differences in the hippocampus, and it has also been shown that there are changes in this brain region over the course of the female rat's natural estrous cycle. Male and female rats will be tested on a series of memory and navigation tasks. Solving some of the tasks depends of having an intact hippocampus while the rest are hippocampus independent (this has been shown by others in experiments where the hippocampus is removed). Sex differences in hippocampal related abilities will be examined; in addition, the female rat's estrous cycle will be monitored to investigate whether sex differences found are related to this natural cycle. Some of the animals will have electrodes implanted into their hippocampus. This will enable us to monitor the activity of individual cells in the hippocampus as the animal performs the different tasks. The distinctive aspect of the research lies in combining the behavioral analysis with the monitoring of the neuronal activity. This research will enhance our understanding of how memories are formed and provide a basis for the development of therapeutic intervention in cases of memory dysfunction.