Catecholaminergic Signaling in Normal Cognition, Aging and Models of Alzheimer's Disease

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SUMMARY Alzheimer’s disease (AD) and other dementias are a substantial and rapidly growing societal burden due to the aging of our population. This aging has occurred in part because modern medicine has identified risk factors and treatments for many other diseases, but not for AD. Thus there is a great and unmet need to do so. A hallmark symptom of AD and aging without dementia is impaired memory, including retrieval. Further, some of the earliest neuropathology found in AD is within the systems that provide the neuromodulators dopamine (DA) and norepinephrine (NE) to the brain (including the hippocampus, a center for declarative/episodic memory). The largest brainstem adrenergic nucleus is the locus coeruleus (LC), which supplies all of the NE and a substantial portion of the DA found in the dorsal hippocampus. The LC can also be affected in normal aging. As such, the goal of this proposal is to better understand the roles and mechanisms by which LC-derived DA and NE modulate the encoding and retrieval of declarative/episodic memory. Toward this goal, pharmacologic and genetic manipulations will be performed in rodents, for which there are excellent behavioral paradigms that rely on hippocampus-dependent memory. Our preliminary studies indicate that all three -adrenergic receptors that are activated by NE play a critical role in the hippocampus to promote memory retrieval. They also suggest that adrenergic DA is required for hippocampus-dependent memory. Thus the first aim will examine the molecular and cellular mechanisms by which -adrenergic receptors promote hippocampus-dependent memory using combined pharmacologic and genetic approaches. Subcellular localization of  receptors in the hippocampus will also be determined. The second aim will examine the modulation of hippocampus-dependent memory by “adrenergic” DA using combined pharmacologic and genetic approaches. The third aim will examine the ability of drugs that enhance DA and NE signaling to promote memory in models of AD and aging. The completion of these aims will provide a better understanding of how memory encoding and retrieval is facilitated within the hippocampus, and ultimately may suggest potential targets for enhancing memory in AD and aging.