Dissecting the role of the dentate gyrus microcircuit to improve cognitive discrimination in aging and Alzheimer's Disease

The dentate gyrus subregion of the hippocampus (DG) has been proposed to play a critical role in ‘pattern separation’, a computational process by which similar experiences are transformed into discrete non- overlapping neural representations. Deficits in pattern separation are found in normal aging as well as in Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD). The dentate gyrus is one of only two brain regions where new neurons are produced throughout life in mammals, a phenomenon termed adult hippocampal neurogenesis (AHN). AHN has been shown to decrease markedly both in normal aging and in AD. We have shown that AHN in mice is required for ‘cognitive discrimination’, a form of learning that may involve pattern separation. In addition, our preliminary results show that a genetic and a pharmacological manipulation that significantly increase AHN (iBax mice and Bax antagonist) rescues cognitive discrimination in aged mice. However, due to technical limitations, our knowledge about the specific role of AHN in the regulation of memory functions and how these processes are altered during age-related cognitive decline remain extremely limited. We will leverage unprecedented genetic access to AHN in combination with recent technical breakthroughs for neural recordings and manipulations to uncover the impact of AHN in aged mice. We will test the hypotheses that abGCs support sparse memory encoding enabling effective pattern separation and that increasing AHN can rescue age-related deficits in cognitive discrimination through improved pattern separation. In addition to unraveling the function of AHN we will also explore whether this process can be harnessed pharmacologically to rescue cognitive deficits associated with aging. We will test this in mouse models of aging by leveraging the complementary expertise of the Hen lab in targeted molecular and pharmacological manipulations of AHN in behaving mice, the expertise of the Losonczy lab with in vivo large- scale optical recordings, and the expertise of the Fusi lab in computational modeling approaches. At the end of the grant period, our experiments will have provided transformative new insights into the function of abGCs and into the therapeutic potential of targeting AHN to alleviate age-related cognitive deficits in normal aging and possibly in age-related disorders such as MCI and AD.