DESCRIPTION (provided by applicant): 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.

PUBLIC HEALTH RELEVANCE: 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. __SpecificAimsTextDelimiter__ Hippocampal neurogenesis, pattern separation & age-related cognitive impairments. 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 (Marr, 1971; 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 cognitive discrimination that may involve pattern separation (Sahay et al., 2011a; Burghardt et al., 2012). We are proposing to test the hypothesis that pharmacological or environmental 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. Aim 1: Impact of genetic, pharmacological, and environmental manipulations aimed at stimulating neurogenesis on cognitive discrimination in aged mice. Rationale: In order to selectively increase neurogenesis in the adult hippocampus we have generated iBax mice where the proapoptotic gene Bax can be conditionally deleted specifically in adult hippocampal progenitors (Sahay et al., 2011a). In iBax mice treated with tamoxifen most young adult-born granule cells (GC) survive and functionally integrate into the hippocampal network resulting in a four-fold increase in neurogenesis. These mice show normal object recognition and spatial learning but are more efficient in differentiating between similar contexts in contextual fear discrimination paradigms, suggestive of enhanced pattern separation. 1A. We will test the hypothesis that a genetic manipulation aimed at stimulating neurogenesis in aged mice is sufficient to restore normal cognitive discrimination. We will breed a cohort of iBax mice and let them age until 16 months, an age at which these mice display a number of cognitive impairments including cognitive discrimination deficits (Creer et al., 2010). We will then treat half of them with tamoxifen to increase neurogenesis and test them in a contextual fear discrimination task. We will also assess ACSF-LTP, which is a form of plasticity sensitive to neurogenesis levels and involved in cognitive discrimination (Kheirbek et al., 2012). We expect that a stimulation of neurogenesis in aged mice (as a result of the genetic ablation of Bax) will result in increased ACSF-LTP, and improved cognitive discrimination. 1B. We will test the hypothesis that a pharmacological or an environmental manipulation aimed at stimulating neurogenesis in adult mice, and aged mice will result in an increase in ACSF-LTP, and an improvement in cognitive discrimination. Specifically we will test the effects of a chronic regimen of Bax antagonists, fluoxetine or exercise. Aim 2: Hippocampal neurogenesis and pattern separation in the dentate gyrus/CA3 circuit. Rationale: These experiments investigate the neural mechanisms by which adult-born granule cells (GC) influence pattern separation. We will exploit a combined electrophysiological/behavioral paradigm (Kelemen and Fenton, 2010) to concurrently measure pattern separation and cognitive discrimination by recording the action potential discharge of spatially-tuned cells while mice do a cognitive discrimination task that requires intact adult dentate neurogenesis (Burghardt et al., 2012, and Fig. 6). 2A. We will test the hypothesis that stimulation of neurogenesis improves hippocampal pattern separation. We will use the iBax mice or a pharmacological manipulation identified in aim 1, to stimulate neurogenesis and assess pattern separation of spatial representations in the hippocampal circuit of adult and aged mice. 2B. If stimulating neurogenesis is sufficient to improve pattern separation, then selective inhibition of adult-born GCs should eliminate this effect. We will test whether the effects of stimulating neurogenesis on pattern separation are mediated by adult-born GCs by utilizing mice that express halorhodopsin (HR) selectively in adult-born GCs. We will assess whether photo-inhibition of HR-expressing adult-born GCs influences pattern separation both in baseline conditions and after pharmacological stimulation of neurogenesis. This strategy will also permit determining the critical period during which adult-born GCs contribute to pattern separation.