Hormone and Neurotransmitter Interactions in Cognitive Aging

描述(由申请人提供)：这份申请是为了获得NIH K01指导研究科学家发展奖，在那里我将获得必要的专业知识，以确立自己作为一名独立研究员的地位，探索认知老化背后的神经生物学。我将接受一种特定方法的培训，以调查认知老化的神经生物学基础，并结合使用认知的精神药理操作和功能磁共振成像(FMRI)，来自这一领域的两位知名专家，医学博士保罗·纽豪斯和心理学博士安德鲁·塞金。在纽豪斯和塞金博士的指导下，我将参加现场实习、教程、课程和实践研究项目。这一培训将为我提供独特的专业知识，因为我将之前接受的认知心理学培训与利用心理药理操作和功能磁共振成像的尖端组合来研究认知老化的神经生物学的能力相结合。作为我培训的一部分，我将进行两项药理学功能磁共振研究，这两项研究将扩展我的发现，展示胆碱能完整性在观察雌激素对认知的影响方面的重要性。研究1将验证这样一种假设，即当老年女性比枕叶皮质激活更多额叶时，观察到的神经补偿受到胆碱能完整性和雌激素治疗的调节。研究2将检验这一假设，即胆碱能系统的老化是注意力、工作记忆和情景记忆任务中与年龄相关的神经补偿的主要原因。研究2还将使用雌激素来调节胆碱能相关的认知过程。这些研究将首次结合胆碱能药理学挑战、性激素治疗和功能磁共振成像的强大操作来检测神经递质-激素相互作用对认知的影响。这些研究的结果将为胆碱能完整性和雌激素治疗对老年女性大脑和认知功能的重要性提供证据。了解雌激素对认知的影响背后的神经生物学对于未来制定年龄相关性认知功能障碍的治疗策略非常重要。相关性(见说明书)：这些研究将强调认知老化背后的神经生物学知识对临床干预措施设计的重要性。这一结果对于理解为什么之前的雌激素对认知的影响试验失败也很重要，因为老年女性的胆碱能系统受损，看不到雌激素的积极影响。

DESCRIPTION (provided by applicant): This application is for an NIH K01 Mentored Research Scientist Development Award where I will gain the xpertise necessary to establish myself as an independent investigator exploring the neurobiology underlying cognitive aging. I will receive training in a specific approach to investigating the neurobiological underpinnings of cognitive aging with the combined use of psychopharmacological manipulations of cognition and functional magnetic resonance imaging (fMRI) from two established experts in these fields, Paul Newhouse, M.D. and Andrew Saykin, Psy.D. Under the mentorship of Drs. Newhouse and Saykin, I will participate in on-site residencies, tutorials, courses, and hands-on research projects. This training will provide me with unique expertise as I combine my prior training in cognitive psychology with the ability to utilize the cutting edge combination of psychopharmacological manipulations and fMRI to study the neurobiology of cognitive aging. As an integral part of my training I will conduct two pharmacological fMRI studies that will extend my findings showing the importance of cholinergic integrity in observing effects of estrogen on cognition. Study 1 will test the hypothesis that neural compensation that is observed when older women activate more frontal relative to occipital cortex is modulated by cholinergic integrity and estrogen treatment. Study 2 will test the hypothesis that aging of the cholinergic system is principally responsible for age-associated neural compensation seen in attention, working memory, and episodic memory tasks. Study 2 will also use estrogen to modulate cholinergic-related cognitive processes. These studies will be the first to combine the powerful manipulations of cholinergic pharmacological challenge, sex hormone treatment, and fMRI to examine the neurotransmitter-hormone interaction effect on cognition. The results of these studies will provide evidence for the importance of cholinergic integrity and estrogen treatment on brain and cognitive functioning in older women. Understanding the neurobiology underlying the estrogen effect on cognition is important for the future development of treatment strategies for age-related cognitive dysfunction. RELEVANCE (See instructions): These studies will emphasize the importance of knowledge of the neurobiology underlying cognitive aging for the furure design of clinical interventions. The results will also be important for an understanding why prior trials of estrogen effects on cognition have failed because cholinergic systems in older women were impaired such that no positive effects of estrogen were seen.