Manipulating cellular excitability and CREB expression in CA1 to restore spatial processing in aged mice to young-like levels

项目摘要 衰老是不可避免的，但与年龄相关的认知能力下降可能并非如此。轻度认知障碍 和痴呆症在老年人群中普遍存在，即使是正常的衰老也会导致发作性痴呆的微妙下降。 记忆，使正常的认知老化可以说是最普遍的心理健康问题，在发达国家 世界空间记忆是情景记忆的一个组成部分，特别是受年龄的影响，但 造成这一赤字的原因尚不清楚。如果不了解与年龄相关的空间变化背后的机制， 记忆力下降，社会将缺乏克服这一障碍的手段，以健康老龄化或减轻潜力 更严重的疾病如阿尔茨海默病的风险因素。该提案将寻求两个可能的 在衰老小鼠模型中与空间记忆功能障碍相关的因素，其结论可能有助于 转化为潜在的人类干预途径。Cai实验室的初步数据和已发表的数据 已经表明，在海马CA1区，细胞兴奋性和转录因子cAMP反应 元件结合蛋白（CREB）在老年啮齿动物中减少，影响记忆功能。在这些 实验中，增加CA1兴奋性和CREB表达改善了这些记忆缺陷。 动物然而，这些研究无法验证潜在的神经记忆表征是否 通过这些操作得到了改善。该提案的总体目标是确定是否增加 CA1细胞的兴奋性和CREB可以恢复空间记忆和神经表征到类ESTA水平。 在第一个目标中，我将使用专门由设计药物激活的设计受体（DREADDs）来增加 老年小鼠海马CA1区锥体细胞兴奋。同时，我将进行体内钙成像 在不同的线性轨道上运行期间，每个轨道具有特定的奖励位置，以量化 神经空间表征和空间记忆。在第二个目标中，我将使用病毒式方法， 过表达CREB在老年小鼠的CA1锥体细胞，同时进行钙显像相同的任务。 这些目标的发现将使我能够得出结论，增加CA1兴奋性或CREB是否可以 改善空间记忆表征和老化引起的缺陷。通过结合化学遗传学，病毒 操纵蛋白质表达，并在体内成像，这一建议将阐明神经机制 与年龄相关的空间记忆力衰退。

Project Abstract Aging is inevitable, but maybe age-related cognitive decline does not have to be. Mild cognitive impairment and dementia are prevalent in the elderly population, and even normal aging causes subtle decline in episodic memory, making normal cognitive aging arguably the most widespread mental health issue in the developed world. Spatial memory is an integral component of episodic memory and is particularly impacted by aging, but the causes behind this deficit are unknown. Without understanding the mechanisms behind age-related spatial memory decline, society will lack the means to overcome this obstacle to healthy aging or mitigate potential risk factors for more serious disorders such as Alzheimer's disease. This proposal will pursue two possible factors related to spatial memory dysfunction in a mouse model of aging and its conclusions could help translate to potential avenues of intervention in humans. Preliminary data from the Cai lab and published data has shown that, in CA1 of the hippocampus, cellular excitability and the transcription factor cAMP response element binding protein (CREB) are reduced in aged rodents, impacting memory function. In these experiments, increasing CA1 excitability and CREB expression ameliorated the memory deficits of these animals. However, these studies were unable to verify whether the underlying neural memory representations were improved by those manipulations. The overarching goal of this proposal is determine whether increasing CA1 cellular excitability and CREB can restore spatial memory and neural representations to young-like levels. In the first aim, I will use designer receptors exclusively activated by designer drugs (DREADDs) to increase excitation coming into CA1 pyramidal cells in aged mice. Simultaneously, I will perform in vivo calcium imaging during running on different linear tracks with specific reward locations for each track to quantify the accuracy of neural spatial representations and spatial memory. In the second aim, I will use a viral approach to overexpress CREB in CA1 pyramidal cells of aged mice while performing calcium imaging on the same task. The findings from these aims will allow me to conclude whether increasing CA1 excitability or CREB can improve spatial memory representations and deficits that arise from aging. By combining chemogenetics, viral manipulations of protein expression, and in vivo imaging, this proposal will illuminate the neural mechanisms behind age-related spatial memory decline.