Nicotinic receptor density and nicotinic function decline beyond normal aging in schizophrenia, dementia with Lewy bodies, Parkinson's disease, and Alzheimer's dementia. Evidence indicates that especially in degenerative diseases, impaired nicotinic function contributes to cognitive deficits, and nicotinic therapies have their main impact on cognitive dysfunction. Behavioral studies have identified nicotinic roles in memory, learning, and attention;and in particular, decreased nicotinic activity in the hippocampus has been linked to impaired memory. Recent advances indicate that addiction shares many commonalities with the synaptic plasticity normally attributed to learning and memory. Drugs subvert normal memory mechanisms, leading to long-lasting changes in behavior that accrue with the ongoing progression of addiction. Subsequently, environmental cues that elicit memories linked to addictive behaviors motivate cravings and relapse. The hippocampus is among the areas associated with internally generated craving. The perforant path is particularly important, relaying information that is rich in contextual and spatial content. Although behavioral and synaptic studies have examined nicotinic roles, there have been practically no in vivo physiological studies that directly link nicotinic mechanisms to the synaptic changes underlying memory. The main goal of this study is to reveal the in vivo link between nicotinic function and synaptic mechanisms of the memory process. A combination of in vivo recording approaches and in vitro physiology will examine the following working hypothesis: nicotinic cholinergic systems modulate circuit excitability, and nicotinic mechanisms influence local and long-range circuits causing synaptic changes that underlie memory. We have direct preliminary measures of in vivo perforant path synaptic plasticity arising from nicotinic action. Furthermore, our preliminary results indicate that long-range signaling from dopamine centers enables this synaptic plasticity, which arises from local nicotinic modulation of dentate gyrus circuits. The experiments monitor the strength of perforant path transmission in vivo. In addition, long-term tetrode implants are used to measure in vivo neuronal activity underlying local interactions between GABAergic interneurons and granule cells as well as long-range signaling from dopamine neurons. To gain more experimental control, cellular and synaptic mechanisms are being investigated using in vitro brain slices. These studies directly assess in vivo controls that are the basis for nicotinic involvement in cognition. The results immediately apply to associative memory of addiction, and more broadly indicate the synaptic mechanisms that likely underlie the nicotinic component of normal memory and memory dysfunction during degenerative diseases.
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