Robert E. Clark - US grants

Robert E. Clark, Ph.D.
NSF Proposal Number: 0237053
NSF Proposal Title: Memory and Hippocampus: Analysis of Retrograde Amnesia

A considerable body of work has been directed toward understanding how a brain structure known as the hippocampus contributes to memory function. A phenomenon that has been especially important to this tradition of work is temporally-graded retrograde amnesia (TGRA). TGRA refers to the finding that information (memories) learned long before the onset of memory impairment are often spared relative to information learned more recently. For example, humans who have sustained damage to the hippocampus, have little or no memory for facts and events that was learned just prior to their brain damage, but retain memories that were learned well before the damage. Accordingly, memory that is initially hippocampus-dependent, gradually becomes hippocampus-independent. A critical question is how hippocampal activity participates in this process.
These experiments provide a systematic investigation of when and for how long the hippocampus must be active to support memory. Using rats, reversible lesions will be used to selectively inactivate the hippocampus (by infusing a drug that disrupts hippocampal function without damaging the neurons). Accordingly, the hippocampus can be turned on or off during different phases of the learning and memory process. That is, reversible lesions will be applied during different portions of the learning, retention, or retrieval phase of memory to determine if and when hippocampal activity is important for memory. These reversible lesions are created and sustained for long periods of time with implanted osmotic minipumps (devices that can slowly deliver the drugs to the hippocampus continuously for many days).
These results will provide important insights into how hippocampal activity following learning contributes to the establishment of long-term memory. Clarifying this pattern of memory loss (TGRA) is critical for understanding how memory is organized and stored in the brain. The proposed activities will provide research training for graduate students and post-doctoral students in psychology, cognitive science, and neuroscience.

Neuroscience has made enormous progress during the past half century as new tools and technological advances have made it possible to ask increasingly specific questions about the structure and function of neurons, synapses, proteins, and genes. Progress has been slower in understanding the organization and function of circuits, networks, and brain systems. And in that context, it is sometimes overlooked how important it is to have an account of cognition itself ? perception, attention, memory, language, and the organization of action. One wants to understand its components and to understand how the components of cognition can be related to brain substrates. The work proposed herein addresses a fundamental issue about how the brain has organized its memory functions. The issue is whether short-term and long-term memory are indeed distinct entities, such that short-term memory is independent of the hippocampus (and related structures); or whether an exception to that principle exists in the case of spatial cognition. It is a deep and fundamental matter. Do the hippocampus and related structures have online, computational functions? Or are these structures in fact needed only when short-term memory capacity has been exceeded. To evaluate these two perspectives, five studies are proposed in individuals with hippocampal lesions (or larger lesions that include related structures) using navigation in open space, virtual reality, as well as a test of spatial imagining. Parallel work on path integration is proposed for rats with selective lesions of the hippocampal, entorhinal, or parietal cortex. Understanding the relationship between memory and spatial cognition is fundamental to understanding how the brain has organized its memory functions.

DESCRIPTION (provided by applicant): Neuron loss and the reorganization of neural circuits in the medial temporal lobe are hallmarks of traumatic brain injury, temporal lobe epilepsy, brain ischemia, and Alzheimer's disease. Various degrees of memory impairments are among the troubling symptoms of each of these diseases, but the exact pattern of histopathology varies between diseases. The memory loss that is common to the diseases is thought to emerge from entorhino-hippocampal dysfunction. The entorhinal cortex and hippocampus function as a feedback loop and a loss of function could thus emerge by disrupting neuronal processing when damaging any part of the circuit. Alternatively, each subregion within the circuit may be able to independently perform its characteristic function, but different pattern of neuronal injury within the medial temporal lobe might nonetheless manifest in a common way because the entorhinal cortex and hippocampus can only incompletely compensate for each other's function. Although questions about the mechanisms of neural dysfunction can be studied in animal models that are specific for a neurological disease, an understanding of the sources for memory problems can also be obtained from investigating different patterns of injury within the medial temporal lobe. Because many cell types for spatial processing have been described in the medial entorhinal cortex (MEC) and hippocampus, we propose to initially focus on these brain regions. We have begun to investigate the extent of spatial memory impairments after lesions to the rat hippocampus and/or MEC. Our preliminary data show substantial dysfunction of spatial and temporal processing in the hippocampus after MEC lesions and in the MEC after hippocampal lesions. We also find that memory impairments are less severe after lesions to individual brain regions compared to combined lesions. Based on our preliminary results, we hypothesize that spatial functions can, in part, be independently performed by the MEC and the hippocampus, but that temporal aspects of MEC and hippocampal neuronal processing require that the entire loop be intact. This hypothesis will be tested in three aims: (1) further characterize memory dysfunction after complete MEC lesions and after combined lesions of the MEC and the hippocampus with behavioral testing, (2) determine the extent of neuronal network dysfunction in hippocampus after MEC lesions with single-unit recordings during behavior, and (3) determine which neuronal firing patterns in MEC are disrupted after complete hippocampal lesions and, additionally, identify whether neuronal computations in the MEC can be restored by brain stimulation. Identifying spared functions after different patterns of damage and revealing how manipulations of the remaining circuits can compensate for lost functions will provide insight into the network mechanisms that can be strengthened or restored in neurological and neurodegenerative diseases.