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

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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.