Project Summary Patients with Alzheimer’s disease (AD) exhibit progressive memory loss, depression, and anxiety, accompanied by impaired adult hippocampal neurogenesis (AHN). Although young adult-born neurons (ABNs) have been shown to play an important role in memory and emotion processing under physiological conditions, their function and therapeutic potential in degenerated AD brains remain largely undefined. A long-standing question has been centering on whether AHN could be enhanced in otherwise impaired AD brains to restore cognitive and affective functions. Our recent study showed that stimulating hypothalamic supramammillary nucleus (SuM) exerts robust neurogenic effects in healthy wild-type (WT) mice. Specifically, chronic patterned optogenetic stimulation of SuM leads to increased production of behaviorally-relevant ABNs with enhanced developmental properties. Importantly, acute chemogenetic activation of these SuM-enhanced ABNs improves memory performance and reduces anxiety-like behavior. We further tested this strategy in 5xFAD mice. Strikingly, patterned SuM stimulation restores the number and developmental properties of ABNs and acute chemogenetic activation of a small population of these SuM-enhanced ABNs (~500 ABNs/DG, <0.05% total granule cells/DG) is sufficient to restore memory and reduce anxiety/depression-like behaviors in AD mice. These findings highlight the therapeutic potential of enhanced ABNs (number, quality, and activity) in functional restoration in AD. Building upon these findings, we propose the following aims to decipher the mechanisms underlying these beneficial effects mediated by activation of SuM-enhanced ABNs using two complementary AD mouse models. Aim 1 will determine the functional properties of SuM-enhanced ABNs and the molecular regulators underlying SuM- mediated enhancement of neurogenesis in AD mice. Aim 2 will determine activity-dependent contribution of SuM-enhanced ABNs to local hippocampal circuit and brain-wide network dynamics in AD mice. Aim 3 will determine the effects of SuM-enhanced ABN activation on microglia properties, AD pathology, and hippocampal function in AD mice.