In the mammalian adult brain, there are two regions where stem cells continuously give rise to new neurons, a process termed neurogenesis: the subventricular zone and the subgranular zone of the dentate gyrus. The dentate gyrus has been proposed to play a role in pattern separation, a process by which similar experiences or events are transformed into discrete non-overlapping representations (Leutgeb et al., 2007;Treves et al., 2008). Recent studies have found pattern separation deficits in humans during normal aging and in patients with Mild Cognitive Impairment (Toner et al., 2009;Yassa et al., 2011). We have shown that hippocampal neurogenesis is required for specific forms of learning such as context discrimination learning that may involve pattern separation (Sahay et al., 2011a). We are proposing to test the hypothesis that pharmacological strategies aimed at stimulating adult hippocampal neurogenesis, may have therapeutic potential for reversing impairments in pattern separation such as those seen during normal aging and in patients with Mild Cognitive Impairment. Specifically, we will use mice where the Bax pro-apoptotic gene has been deleted specifically from adult-born granule cells, as well as pharmacological strategies to increase neurogenesis in the dentate gyrus of aged mice and test whether such manipulations improve both cognitive discrimination and pattern separation.
The overarching theme of this proposal is that adult hippocampal neurogenesis may be harnessed to treat age-related memory impairments. Specifically, we will test the hypothesis that stimulating neurogenesis in the dentate gyrus, leads to an improvement in pattern separation in aged mice.
|Lovett-Barron, Matthew; Kaifosh, Patrick; Kheirbek, Mazen A et al. (2014) Dendritic inhibition in the hippocampus supports fear learning. Science 343:857-63|