SUMMARY Adult neurogenesis, a process of generating mature neurons from adult neural stem cells, proceeds concurrently with ongoing neuronal circuit activity and is modulated by various physiological and pathological stimuli. The niche mechanism underlying activity-dependent regulation of sequential steps of adult neurogenesis remains largely unknown. Here we report that neuronal activity decreases the expression of secreted frizzled-related protein 3 (sFRP3), a naturally secreted Wnt inhibitor highly expressed by adult dentate gyrus granule neurons. Sfrp3 deletion activates quiescent radial neural stem cells and promotes newborn neuron maturation, dendritic growth and spine formation in the adult mouse hippocampus. Furthermore, sfrp3 reduction is essential for activity-induced adult neural progenitor proliferation and acceleration of new neuron development. Our study identifies sFRP3 as an inhibitory niche factor from local mature dentate granule neurons that regulates multiple phases of adult hippocampal neurogenesis and suggests a novel activity-dependent mechanism governing adult neurogenesis via acute release of tonic inhibition.

Patients with Alzheimer's disease (AD) frequently suffer from spatial memory impairment and wandering behavior, but brain circuits causing such symptoms remain largely unclear.In healthy brains, spatially-tuned hippocampal place cells and entorhinal grid cells represent distinct spike patterns in different environments, a circuit function called "remapping" that underlies pattern separation of spatial memory. We investigated whether knock-in expression of mutated amyloid precursor protein deteriorates the remapping of place cells and grid cells. We found that the remapping of CA1 place cells was disrupted although their spatial tuning was only mildly diminished. Grid cells in the medial entorhinal cortex (MEC) were impaired, sending severely disrupted remapping signals to the hippocampus. Furthermore, fast gamma oscillations were disrupted in both CA1 and MEC, resulting in impaired fast gamma coupling in the MEC→CA1 circuit. These results point to the link between grid cell impairment and remapping disruption as a circuit mechanism causing spatial memory impairment in AD.

Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initiate stem cell dysfunction represent early targets to enhance tissue resiliency throughout life. Here, we pinpoint multiple factors that compromise neural stem cell (NSC) behavior in the adult hippocampus. We find that NSCs exhibit asynchronous depletion by identifying short-term (ST-NSC) and intermediate-term NSCs (IT-NSCs). ST-NSC divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent IT-NSCs are maintained for months, but are pushed out of homeostasis by lengthening quiescence. Single cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of cellular aging in the mature brain, including changes in tyrosine-protein kinases Abl1 and Abl2. Treatment with the Abl-inhibitor Imatinib was sufficient to overcome deep quiescence and restore NSC proliferation in the middle-aged brain.Further examination of mature NSC with old epidermal, hematopoietic and muscle stem cell transcriptomes identified consensus changes in stem cell aging. Our study elucidates multiple origins of adult neurogenesis decline and reveals that hippocampal NSCs are particularly vulnerable to a shared stem cell aging signature.