Richard F. Thompson - US grants

How do we learn to protect ourselves from approaching danger? One of the oldest paradigms for studying this kind of learning is classical Pavlovian conditioning. In classical conditioning, the repeated presentation of two stimuli together, one that the organism normally would avoid (the unconditioned stimulus), and one that it does not (the neutral stimulus), leads eventually to the organism trying to avoid the neutral stimulus. The previously neutral stimulus has acquired a value -- it has become conditioned. Pavlov thought that the new associations necessary for conditioning occur in the cerebral cortex, that part of the brain devoted to thinking and perception. Dr. Thompson and his students have shown, surprisingly, that circuits in the cerebellum, not the cerebral cortex, are necessary for conditioning to take place. In this renewal of his NSF grant, he will use newly developed reversible inactivation methods to demonstrate that the new associations are actually formed in the cerebellum. He will then use a variety of sophisticated neurobiological techniques to determine the mechanisms by which these new memories are stored. The investigators have a good chance of being the first to delineate a complete information storing circuit in the mammalian brain. Their work will further our understanding of human learning and memory and will be also useful to designers of artificial neural nets and teaching machines.***//

The long-term goal of Dr. Thompson's research is to understand how the mammalian brain codes, stores, and retrieves memories. This has proved to be one of the most complex problems in the fields of neuroscience and psychology. It is also one of the most important. Over the course of evolution, biological organisms have developed two ways of storing information. One is the familiar genetic code embedded in the DNA; the other, no less important, is the ability to store acquired information and experience in the brain. In order to understand the mechanisms of memory storage, it is necessary to identify the specific circuitry in the brain required to store a given type of memory. Dr. Thompson has selected a basic form of associative learning shared equally by humans and other mammals, classical conditioning of discrete behavioral responses learned to deal with aversive events. An example of such conditioning is learning to close the eyelid in response to a tone (conditional stimulus, or CS) that signals the occurrence of a puff of air on the eye (unconditional stimulus, or US). Dr. Thompson and his colleagues have discovered that very discrete regions of the cerebellum are essential for this basic form of learning. They have also succeeded in identifying most of the essential brain circuitry involved in this basic form of associative learning. Dr. Thompson and his colleagues will use several neurophysiological methods and behavioral training procedures to (1) complete the identification of the essential auditory CS pathway, (2) determine whether or not memory traces are formed in this pathway before it reaches the cerebellum, (3) characterize the patterns of neuronal response in the essential US pathway and in the essential conditional- response pathway, (4) determine the exact locations where memory traces are formed, (5) begin analysis of the mechanism of memory-trace formation, (6) determine if the essential cerebellar circuit can mediate the "cognitive" behavioral phenomenon of "blocking," and (7) explore how higher brain structures (cerebral cortex, hippocampus) modulate the essential cerebellar memory-trace circuit. In addition to understanding basic mechanisms of memory storage, Dr. Thompson's work offers the promise of understanding how motor skills are coded and learned. The potential practical applications range from treatment of learning disabilities to enhancement of skilled human performance to the development of an entirely new approach to the problem of control of movement in robotics.

A major problem in society concerns impairments in memory. These occur naturally with aging, as a result of stress and, in the extreme, in Alzheimer's disease. One brain structure, the hippocampus, is critical for key aspects of memory formation, and the most widely accepted possible mechanisms of memory storage in this structure are long-term potentiation (LTP) and long-term depression (LTD). There are age-related alterations in hippocampal LTP and LTD that correlate with age-impairments in hippocampal- dependent memory tasks. Recent evidence in humans suggests that estrogenic hormones appear to ameliorate early effects of Alzheimer's disease (and aging) on memory in women. Studies with rat brain slices in vitro indicate that estrogen (and testosterone) an modulate synaptic transmission in the hippocampus and our pilot data show that estrogen can markedly enhance LTP (CA1, clice). There appear to be sex differences in the inducibility of hippocampal LTP in animal models. Stress impairs hippocampal- dependent memory and we have shown that prior behavioral stress markedly impairs subsequent hippocampal LTP and enhances LTD in vitro, and that these effects are dependent upon the N-methyl-D- aspartate (NMDA) receptors. Our specific aims are thus to determine the effects of sex differences and estrogenic hormones on hippocampal plasticity (LTP and LTD), the roles of aging and stress on these effects, and possible mechanisms of action of these variables on hippocampal plasticity.

Project 2: Progesterone Regulation of Synaptic Plasticity &Memory. In this Program Project, we jointly hypothesize that the sex steroid hormone progesterone promotes the brain's molecular, synaptic, cellular, and behavioral plasticity and reduces its vulnerability to the development of Alzheimer's disease (AD). We further hypothesize that the reproductive endocrine status, duration of ovariprivation and presence of AD related pathology regulates the plasticity response to ovarian steroids. Realizing the potential neural benefits of hormone therapy is constrained, at least in part, by our currently limited knowledge of the (1) basic neurobiology of progesterone, (2) the neural response to clinically relevant progestogens, (3) the complex modulatory interactions between progesterone and estrogen and (4) the impact of extended ovarian hormone privation and AD neuropathology on the brain's responsiveness to progesterone and estrogen. Our component of the Program Project is directed at investigating the effects of progesterone, as well as the interactions between estrogen, progesterone, and progesterone metabolites on biochemical, cellular and behavioral models of memory function in adult and aging rodent models. At the biochemical level, we will evaluate the acute and chronic effects of progesterone on the activation of the MAP kinase pathway and the phosphorylation of AMPA and NMDA receptors in hippocampus and cortex, which represent critical steps in synaptic plasticity. Parallel experiments at the cellular level will evaluate the acute and chronic effects of progesterone on synaptic transmission and synaptic plasticity (long-term potentiation and long-term depression) in the CA1 hippocampal in vitro slice preparation. Finally, the acute and chronic effects of progesterone will be determined on delayed conditioned taste aversion learning and context/tone fear conditioning in order to correlate effects at the molecular/cellular levels with those at the behavioral level. These same parameters will be evaluated in new animal models shared by the other investigators of the Program Project: a model of the peri-menopausal and menopausal period in rats as well as in a mouse model of Alzheimer's disease. The results obtained from these studies should provide critical information to understand the complex interactions between female sex hormones and processes underlying learning and memory and their modifications during postmenopausal period and aging and age-related disorders.