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.

Radiation is used in the study of neurogenesis in the adult mouse both as a model for patients undergoing radiation therapy for CNS malignancies and as a tool to interrupt neurogenesis. We describe the use of a dedicated CT-guided precision device to irradiate specific sub-regions of the adult mouse brain. Improved CT visualization was accomplished with intrathecal injection of iodinated contrast agent, which enhances the lateral ventricles. T2-weighted MRI images were also used for target localization. Visualization of delivered beams (10 Gy) in tissue was accomplished with immunohistochemical staining for the protein γ-H2AX, a marker of DNA double-strand breaks. γ-H2AX stains showed that the lateral ventricle wall could be targeted with an accuracy of 0.19 mm (n = 10). In the hippocampus, γ-H2AX staining showed that the dentate gyrus can be irradiated unilaterally with a localized arc treatment. This resulted in a significant decrease of proliferative neural progenitor cells as measured by Ki-67 staining (P < 0.001) while leaving the contralateral side intact. Two months after localized irradiation, neurogenesis was significantly inhibited in the irradiated region as seen with EdU/NeuN double labeling (P < 0.001). Localized radiation in the rodent brain is a promising new tool for the study of neurogenesis.

Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment.

No abstract

In an effort to better understand and treat mental disorders, the Wnt pathway and adult hippocampal neurogenesis have received increased attention in recent years. One is a signaling pathway regulating key aspects of embryonic patterning, cell specification, and adult tissue homeostasis. The other is the generation of newborn neurons in adulthood that integrate into the neural circuit and function in learning and memory, and mood behavior. In this review, we discuss the growing relationship between Wnt signaling-mediated regulation of adult hippocampal neurogenesis as it applies to neuropsychiatric disorders. Evidence suggests dysfunctional Wnt signaling may aberrantly regulate new neuron development and cognitive function. Indeed, altered expression of key Wnt pathway components are observed in the hippocampus of patients suffering from neuropsychiatric disorders. Clinically-utilized mood stabilizers also proceed through modulation of Wnt signaling in the hippocampus, while Wnt pathway antagonists can regulate the antidepressant response. Here, we review the role of Wnt signaling in disease etiology and pathogenesis, regulation of adult neurogenesis and behavior, and the therapeutic targeting of disease symptoms.

SummaryAging causes significant declines in adult hippocampal neurogenesis and leads to cognitive disability. Emerging evidence demonstrates that decline in the mitotic checkpoint kinase BubR1 level occurs with natural aging and induces progeroid features in both mice and children with mosaic variegated aneuploidy syndrome. Whether BubR1 contributes to age‐related deficits in hippocampal neurogenesis is yet to be determined. Here we report that BubR1 expression is significantly reduced with natural aging in the mouse brain. Using established progeroid mice expressing low amounts of BubR1, we demonstrate these mice exhibit deficits in neural progenitor proliferation and maturation, leading to reduction in new neuron production. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging‐related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age‐related cognitive deficits.