1988 — 1994 |
Rose, Gregory |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Hippocampal Plasticity Induced by Patterned Stimulation @ University of Colorado At Denver
A major goal of behavioral neuroscience research is the identification of the neurobiological processes which underlie learning and memory. One important model system for examining experience-based changes in neuronal activity is long-term potentiation, or LTP. This is a relatively long-lasting change in the efficiency of synapses, which results from stimulation with a brief, high frequency train of weak electrical pulses. This form of "neuronal plasticity" was first discovered in the hippocampal formation, a brain region known to be involved in memory formation. Dr. Rose' recent work has shown that by using a pattern of electrical stimulation which mimics either of two prominent electrophysiological activity patterns of the hippocampus (complex spike discharge and theta rhythm), he could markedly reduce the threshold for inducing LTP. This effect, termed "primed burst" (PB) potentiation, is invoked quite reliably by as few as five appropriately patterned stimuli. Because of its low threshold, and of its similarity to well-known electrical activity patterns, it is proposed that a PB-like process may occur within the hippocampus during the formation of new memories. Dr. Rose is recording electrophysiological activity from the hippocampi of normal, awake rats to evaluate this hypothesis. This work is clarifying both the physiological and behavioral conditions which promote PB potentiation, thus suggesting their role in the learning process. He is also examining the correlation between PB potentiation and memory by examining the effects of stress and aging (two conditions known to impair mnemonic function) upon the capacity of hippocampal synapses to show this PB effect.
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0.908 |
1991 — 1995 |
Rose, Gregory M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cholinergic Circuits and Hippocampal Function in Aging @ University of Colorado Denver
Severe deterioration in the ability to learn and remember is a hallmark of patients with Alzheimer's disease. Foremost among the neuropathological changes that occur in the brains of the victims of Alzheimer's disease is a loss of basal forebrain cholinergic neurons. The loss of cholinergic innervation to the hippocampal formation, a brain region known to be necessary for the formation of new long-term memories, is thought to be major contributor to memory loss. The objective of the experiments described in this proposal is to understand the contributions of muscarinic and nicotinic cholinergic function in the hippocampus to hippocampus-dependent learning and memory. A rodent model will be used to determine the relationship between age-related alterations in cholinergic neurotransmission in the hippocampus and the mnemonic deficits with aging. Experimental measures of cholinergic function will be assessed in rats of different ages after their learning ability has been evaluated using the Morris water maze, a place learning task known to depend upon intact cholinergic input to the hippocampus, and for which age-related decrements have been well documented. Subsequently, several measures of cholinergic function will be evaluated: 1) the responsiveness of hippocampal neurons to local application of muscarine and nicotine; 2) the capacity of intrinsic hippocampal connections to demonstrate long-lasting synaptic plasticity, and the ability of muscarinic and nicotinic drugs to modulate this phenomenon; and 3) biochemical measures of the status of the cholinergic projection to the hippocampus, including measures of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity, the status of pre- and post-synaptic nicotinic receptors. A key element of the experimental design is that ages of the rats to be tested will be selected so that the influences of aging and cholinergic system function upon learning ability can be independently evaluated. Thus, in addition to using young (3 months old; learning unimpaired) and aged (24 months old; learning impaired) rats in the experiments, a third group (20 months old) be used. In this latter population, some animals will have intact learning ability, while others will be learning impaired. Within-subject comparisons of learning ability and measures of hippocampal cholinergic function can be made in this group independent of age, and will provide the strongest test of correlations between physiological/biochemical parameters and learning ability. Finally, the effect of chronic infusion of nerve growth factor (NGF), a trophic substance which is necessary for the survival of central cholinergic neurons, upon the above described behavioral and electrophysiological/biochemical measures will be evaluated.
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1994 — 1998 |
Rose, Gregory M. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Animal Models of Sensory Gating Defects @ University of Colorado Denver
Deficits in sensory processing are a hallmark of schizophrenia. These deficits can be evaluated by surface recording of auditory evoked potential (AEPs) elicited in response to closely paired click stimuli. Normal individuals have a reduced, or gated, middle latency (P50) response to the second click as compared to the first, while schizophrenics are not able to gate their responses to the same stimuli. Fill delineation of the synaptic pathways and neurobiological mechanisms of sensory gating cannot be investigated in humans due to the invasive nature of the anatomical and physiological techniques involved. Although there is no animal model of schizophrenia available,, a model of sensory gating has been developed. Rats (both anesthetized and awake) show gating of a middle latency AEP (N40), in response to paired clicks; administration of psychogenic agents (amphetamine, PCP) produces a schizophrenia-like response pattern. This model permits inquiry into the neuronal circuitry and neurochemical basis of sensory gating which may be of heuristic value in indicating future directions for human investigations in other projects in the Center. In this project, the animal model will be used to further several areas of investigation. Intrinsic interanimal variability in gating will be used to evaluate the relative roles of catecholaminergic and cholinergic neurotransmission in the regulation of gating. Since recent data have indicated a role for the cholinergic system in the regulation of sensory gating in both humans and rats, the specific contribution of forebrain cholinergic pathways to sensory gating will be evaluated. In addition, the neuronal circuitry responsible for the regulation of septal modulation of gating will be identified through PHA-L tracing and immunohistochemical techniques. Finally, the specific role of the alpha-bungarotoxin binding site in gating will be assessed through acute hippocampal recordings of mice selectively bred for differing numbers of these binding sites.
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