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，但也许与年龄相关的认知能力下降不一定是这样。轻度认知障碍 痴呆症在老年人中很普遍，即使是正常的衰老也会导致发作性疾病的轻微下降 记忆，使正常的认知老化可以说是发达国家最普遍的心理健康问题 世界。空间记忆是情节记忆的一个组成部分，特别受衰老的影响，但 这一赤字背后的原因尚不清楚。不了解与年龄相关的空间分布背后的机制 记忆力下降，社会将缺乏克服这一健康老龄化障碍或缓解潜力的手段 更严重疾病的风险因素，如阿尔茨海默病。这项提案将探讨两种可能性 衰老小鼠模型中与空间记忆功能障碍相关的因素及其结论可能有助于 转化为对人类进行干预的潜在途径。来自蔡氏实验室的初步数据和发布的数据 已经表明，在海马区的CA1区，细胞的兴奋性和转录因子cAMP反应 元素结合蛋白(CREB)在老年啮齿动物中减少，影响记忆功能。在这些 实验证明，增加CA1的兴奋性和CREB的表达可以改善这些大鼠的记忆障碍 动物。然而，这些研究无法验证潜在的神经记忆表征 通过这些操作得到了改善。这项提案的首要目标是决定是否增加 CA1细胞的兴奋性和CREB可以将空间记忆和神经表征恢复到年轻的水平。 在第一个目标中，我将使用由设计师药物(DREADD)独家激活的设计师受体来增加 老年小鼠CA1区锥体细胞的兴奋性。同时，我将在体内进行钙质成像 在不同的线性赛道上跑步，每个赛道有特定的奖励位置，以量化 神经空间表征和空间记忆。在第二个目标中，我将使用病毒方法来 在老年小鼠的CA1锥体细胞中过表达CREB，同时在相同的任务中进行钙成像。 来自这些目标的发现将使我得出结论，增加CA1兴奋性或CREB是否可以 改善因衰老而产生的空间记忆表征和缺陷。通过将化学遗传学、病毒 蛋白质表达的操纵和活体成像，这一提议将阐明神经机制 在与年龄相关的空间记忆衰退的背后。

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.