Cognitive dysfunction and decline associated with disease and aging are serious health problems. Nicotinic cholinergic and dopaminergic neurotransmitter systems contribute to the impairments that prevent many patients from entering the work force and fully socializing. For example, these neurotransmitter systems are major contributes to schizophrenia and Alzheimer's dementia, which are estimated to cost >$62 billion and >$100 billion a year respectively in the United States. Ultimately, therapeutic approaches to decrease cognitive impairments must influence pertinent neural circuits. Identifying critical neural pathways, neurotransmitters, and mechanisms will provide rational targets for therapeutic approaches to decrease cognitive impairments, produce memory enhancement, cause forgetting (e.g. in post traumatic stress disorder), or prevent forgetting (e.g. in dementia). Our preliminary results show that cholinergic activity dose-dependently induces in vivo hippocampal long-term synaptic potentiation correlated with mice learning spatial tasks or novel objects. The earlier work showed that induction of in vivo synaptic plasticity requires local disinhibition of excitatory circuits coupled with an afferent dopamine signal arriving from the midbrain. The results are consistent with the view that dopamine signals into the hippocampus lower the threshold for synaptic plasticity that underlies learning. In the proposed studies, we will examine the basis for the nicotinic/dopaminergic influences, and will investigate the following working hypothesis: The dopamine signal lowers the threshold and regulates the magnitude of synaptic plasticity underlying learning. Furthermore, the dopamine signal enhances learning associations among environmental events because dopamine causes a broader timing window for the induction of synaptic plasticity. Dopamine normally contributes to the efficient learning of appropriate behavioral responses motivated by environmental cues. The working hypothesis, however, also helps to explain the cognitive dysfunctions that arise during dopamine signaling imbalances found in diseases where inappropriate sensory gating, attention, and learning produce maladaptive behavior. A multidisciplinary approach applied to wild-type and strategically prepared mutant mice will cross neural levels of integration to understand the synaptic mechanisms underlying performance of behavioral tasks. While mice run behavioral tasks, endogenous cholinergic and dopaminergic signals will be controlled and in vivo synaptic plasticity will be measured in real time. Guided by the in vivo results, brain slices will be cut from these same pertinent neural areas to understand the mechanisms that control synaptic plasticity and learning. The delineated mechanisms within these critical neural circuits will provide targets for developing therapeutic strategies that diminish cognitive impairments. Future research will examine therapeutic interventions targeted to the characterized mechanisms using this mouse model platform.

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Cholinergic and dopaminergic neurotransmitter systems underlie a number of cognitive disorders, such as schizophrenia and Alzheimer's disease. During defined behavioral tasks, cholinergic and dopaminergic signaling will be controlled and the neural events in the learning center, the hippocampus, will be monitored. Then, in vitro brain slices will be used to understand the processes of the brain that underlie normal and dysfunctional behavior, offering mechanistic points of entry for future therapeutic approaches.

National Institute of Health (NIH)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Stewart, Randall R
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University of Pennsylvania
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