Neural Circuits Underlying Post-operative Delirium in Early Stage Alzheimer's Disease

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Postoperative delirium (POD) is a common and serious postoperative complication among the elderly, especially those with Alzheimer’s disease (AD), and has no available treatments. Interestingly, the risk for POD begins at preclinical AD stages when mild sustained attention deficits emerge. For this K99/R00, I will investigate the role of the locus coeruleus and ventral tegmental area – two regions affected by AD pathology and inhibited by general anesthetics – on the development of sustained attention deficits and POD using the rodent model of AD, TgF344-AD. I have developed a variant of the 5-choice serial reaction time task, a touchscreen sustained attention task, in which real-time cognitive recovery is assessed in rats following general anesthesia to capture the severity and duration of POD symptoms. In Aim 1 (K99), I will characterize the progression of sustained attention deficits in TgF344-AD and aging rats and its association with POD and AD histopathology. In Aim 2.1 (K99), I will use a novel dual-viral mediated chemogenetic targeting technique to establish the role of ventral tegmental area dopaminergic neurons in AD-related attentional impairments. With these skills, I will be well- equipped to independently pursue Aim 2.2 (R00), which applies the same techniques to investigate noradrenergic locus coeruleus neurons in AD-related attention impairments, and Aim 3 (R00), where chronic and acute activation of the ventral tegmental area and locus coeruleus will be used to mitigate AD-associated POD. My overall career goal is to lead an independent research group examining the underlying neural circuits impacting POD in AD with the long-term goal of creating interventional therapeutic strategies against dementia- associated POD. To accomplish this goal, I will need additional training in chemogenetic techniques, transgenic rodent models of AD, and AD neuropathology. For the K99 phase, I will have the guidance of my mentor, Dr. Ken Solt, who will train me in chemogenetics, and co-mentor, Dr. Zhongcong Xie, an expert in AD and POD research. My Advisory Committee, Drs. Christiane Wrann (AD transgenic model expertise) and Timothy Houle (statistics expertise), will provide research and professional guidance as I near independence. My career development plan integrates didactics in AD pathology and neuroengineering; training in communication, lab management, and grant writing; and professional networking opportunities. Massachusetts General Hospital and Harvard Medical School provide the ideal environment to conduct the proposed research, providing all the facilities necessary within a supportive, collaborative team of researchers and clinicians. The protected time and mentorship provided by this K99/R00 will allow me to acquire the technical and conceptual skills required to lead a focused research program on POD and AD research as an independent investigator. The outcome of this work will yield important insight into the role of neural circuits implicated in prodromal AD and aging and how they may be targeted to prevent and treat POD.