The role of the septo-hippocampal cholinergic circuit in regulating hippocampal function

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Project Summary As our population ages, the number of people inflicted with Alzheimer’s disease (AD) will continue to grow. One of the major problems associated with AD, a neurodegenerative disorder, is progressive memory decline that arises as a result of defective hippocampal functions including hippocampal neurogenesis and hippocampal network activity. A major regulatory circuit of broad hippocampal function is known as the Septo- Hippocampal Circuit (SHC), which is susceptible to degeneration in AD. Ample evidence has shown degeneration of the cholinergic component of the SHC correlates positively with the severity of dementia and memory dysfunction. Hippocampal neurogenesis and hippocampal network dynamics play a crucial role in regulating proper memory function. Our findings suggest that modulating the SHC can increase hippocampal neurogenesis and that DG network dynamics are impaired at the 3 month stage in AD mice, highlighting the importance of this critical time period. I will test the hypothesis that SHC cholinergic regulation of adult neurogenesis and DG dynamics is impaired in AD and that stimulation of the cholinergic circuit can restore neurogenesis levels and DG dynamics. I will use a mouse model that harbors 5 AD related transgenes (5xFAD) and test the early stage of the disease (3 months) for 1) SHC cholinergic control of adult neurogenesis in AD mice and 2) SHC cholinergic control of dentate gyrus dynamics in AD mice. Completion of proposed work will establish a circuit specific mechanism that regulates hippocampal neurogenesis and hippocampal network dynamics in AD. Ultimately, mimicking basic features of identified circuitry mechanisms may constitute a novel strategy to repair the degenerated brain.