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The hippocampus is one of the most affected areas in Alzheimer’s disease (AD)1. Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely, the addition of new neurons throughout life2. This process, called adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry3,4. Nonetheless, direct evidence of AHN in humans has remained elusive. Thus, determining whether new neurons are continuously incorporated into the human dentate gyrus (DG) during physiological and pathological aging is a crucial question with outstanding therapeutic potential. By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing methods, we identified thousands of immature neurons in the DG of neurologically healthy human subjects up to the ninth decade of life. These neurons exhibited variable degrees of maturation along differentiation stages of AHN. In sharp contrast, the number and maturation of these neurons progressively declined as AD advanced. These results demonstrate the persistence of AHN during both physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits in AD that might be amenable to novel therapeutic strategies.Newborn neurons are continuously incorporated into the healthy adult human hippocampus up to the ninth decade of life. However, robust adult hippocampal neurogenesis sharply declines during the progression of Alzheimer’s disease.

Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration 1 . The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus 2 – 4 , yet little is known about the factors and mechanisms that mediate these effects. Here we show that ‘runner plasma’, collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer’s disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise. Plasma from voluntarily running mice reduces baseline expression of neuroinflammatory genes and experimentally induced brain inflammation when infused into sedentary mice.

There has been considerable speculation regarding the function of the dentate gyrus (DG) — a subregion of the mammalian hippocampus — in learning and memory. In this Perspective article, we compare leading theories of DG function. We note that these theories all critically rely on the generation of distinct patterns of activity in the region to signal differences between experiences and to reduce interference between memories. However, these theories are divided by the roles they attribute to the DG during learning and recall and by the contributions they ascribe to specific inputs or cell types within the DG. These differences influence the information that the DG is thought to impart to downstream structures. We work towards a holistic view of the role of DG in learning and memory by first developing three critical questions to foster a dialogue between the leading theories. We then evaluate the extent to which previous studies address our questions, highlight remaining areas of conflict, and suggest future experiments to bridge these theories.Various theories exist for the function of the dentate gyrus in learning and memory. In this Perspective article, Rangel and colleagues compare a number of these theories and discuss how they may be further tested to develop a better understanding of dentate gyrus function.

Key Points The ventral hippocampus is a crucial brain region in the neural circuitry that regulates mood and anxiety. Adult-born neurons in the dentate gyrus of the hippocampus have been proposed both to encode information as independent encoding units and to modulate the overall activity of the dentate gyrus by inhibiting mature granule cells. Neurogenesis-mediated inhibition of mature cells may reduce memory interference and may enable reversal learning both in neutral and in fearful situations. This improved capacity for reversal learning and cognitive flexibility may facilitate the switch from perceiving a safe environment as fearful in the absence of a persistent threat to no longer associating the safe environment with fear. Treating dentate gyrus function and cognitive flexibility deficits may be promising new treatment strategies for mood and anxiety disorders. In this Review, Anacker and Hen explore how regulation of dentate gyrus function by adult hippocampal neurogenesis may link the memory and mood functions of the hippocampus. They also examine the potential of targeting such regulation for mood disorders. Adult hippocampal neurogenesis has been implicated in cognitive processes, such as pattern separation, and in the behavioural effects of stress and antidepressants. Young adult-born neurons have been shown to inhibit the overall activity of the dentate gyrus by recruiting local interneurons, which may result in sparse contextual representations and improved pattern separation. We propose that neurogenesis-mediated inhibition also reduces memory interference and enables reversal learning both in neutral situations and in emotionally charged ones. Such improved cognitive flexibility may in turn help to decrease anxiety-like and depressive-like behaviour.

Recruitment of young neurons to the hippocampus decreases rapidly during the first years of life, and neurogenesis does not continue, or is extremely rare, in the adult human brain. No new neurons in adult humans Previous lines of evidence have suggested that neural precursors are present in adult humans and continue to generate new neurons in the hippocampus even after full maturation. Here, Arturo Alvarez-Buylla and colleagues re-visit that concept and come to a different conclusion. Using a more comprehensive and larger set of samples of human hippocampus than those analysed in previous studies, the authors find evidence for the production of new neurons early in life, but note that hippocampal neurogenesis rates decline rapidly within the first few years of childhood. The authors were unable to detect the production of any new neurons in adults. The same patterns of neurogenesis were observed in rhesus macaques. New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus 1 , 2 , 3 , 4 , 5 . This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease 6 , 7 , 8 , 9 , 10 . In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day 11 , whereas other studies find many fewer putative new neurons 12 , 13 , 14 . Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18–77 years; n  = 17 post-mortem samples from controls; n  = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey ( Macaca mulatta ) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.

Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by environmental influences, and functionally implicated in behavioural responses to stress and antidepressants 1 – 4 . However, how adult-born neurons regulate dentate gyrus information processing to protect from stress-induced anxiety-like behaviour is unknown. Here we show in mice that neurogenesis confers resilience to chronic stress by inhibiting the activity of mature granule cells in the ventral dentate gyrus (vDG), a subregion that is implicated in mood regulation. We found that chemogenetic inhibition of adult-born neurons in the vDG promotes susceptibility to social defeat stress, whereas increasing neurogenesis confers resilience to chronic stress. By using in vivo calcium imaging to record neuronal activity from large cell populations in the vDG, we show that increased neurogenesis results in a decrease in the activity of stress-responsive cells that are active preferentially during attacks or while mice explore anxiogenic environments. These effects on dentate gyrus activity are necessary and sufficient for stress resilience, as direct silencing of the vDG confers resilience whereas excitation promotes susceptibility. Our results suggest that the activity of the vDG may be a key factor in determining individual levels of vulnerability to stress and related psychiatric disorders. Adult neurogenesis in the hippocampus confers resilience to chronic stress in mice by inhibiting the activity of mature granule cells in the ventral dentate gyrus.

Neural stem cells (NSCs) generate new neurons throughout life in the mammalian brain. Adult-born neurons shape brain function, and endogenous NSCs could potentially be harnessed for brain repair. In this Review, focused on hippocampal neurogenesis in rodents, we highlight recent advances in the field based on novel technologies (including single-cell RNA sequencing, intravital imaging and functional observation of newborn cells in behaving mice) and characterize the distinct developmental steps from stem cell activation to the integration of newborn neurons into pre-existing circuits. Further, we review current knowledge of how levels of neurogenesis are regulated, discuss findings regarding survival and maturation of adult-born cells and describe how newborn neurons affect brain function. The evidence arguing for (and against) lifelong neurogenesis in the human hippocampus is briefly summarized. Finally, we provide an outlook of what is needed to improve our understanding of the mechanisms and functional consequences of adult neurogenesis and how the field may move towards more translational relevance in the context of acute and chronic neural injury and stem cell-based brain repair.In this Review, Denoth-Lippuner and Jessberger present recent insights into adult hippocampal neurogenesis in rodents — from stem cell activation to the integration of newborn neurons into pre-existing circuits — and describe how newborn neurons affect brain function.

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents 1 , 2 and are dysregulated in multiple human neurological disorders 3 – 5 . Little is known about the molecular characteristics of adult human hippocampal imGCs, and even their existence is under debate 1 , 6 – 8 . Here we performed single-nucleus RNA sequencing aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus at different stages across the lifespan. We identified common molecular hallmarks of human imGCs across the lifespan and observed age-dependent transcriptional dynamics in human imGCs that suggest changes in cellular functionality, niche interactions and disease relevance, that differ from those in mice 9 . We also found a decreased number of imGCs with altered gene expression in Alzheimer's disease. Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a substantial number of imGCs in the adult human hippocampus via low-frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in Alzheimer's disease. Single-nucleus RNA-sequencing analysis supports the presence of immature dentate granule cells throughout the human lifespan and shows that these cells are reduced in number and dysregulated in Alzheimer's disease.

Adult hippocampal neurogenesis plays a critical role in memory and emotion processing, and this process is dynamically regulated by neural circuit activity. However, it remains unknown whether manipulation of neural circuit activity can achieve sufficient neurogenic effects to modulate behavior. Here we report that chronic patterned optogenetic stimulation of supramammillary nucleus (SuM) neurons in the mouse hypothalamus robustly promotes neurogenesis at multiple stages, leading to increased production of neural stem cells and behaviorally relevant adult-born neurons (ABNs) with enhanced maturity. Functionally, selective manipulation of the activity of these SuM-promoted ABNs modulates memory retrieval and anxiety-like behaviors. Furthermore, we show that SuM neurons are highly responsive to environmental novelty (EN) and are required for EN-induced enhancement of neurogenesis. Moreover, SuM is required for ABN activity-dependent behavioral modulation under a novel environment. Our study identifies a key hypothalamic circuit that couples novelty signals to the production and maturation of ABNs, and highlights the activity-dependent contribution of circuit-modified ABNs in behavioral regulation.Li et al. report a key brain region in the hypothalamus that effectively modulates the production and properties of new neurons generated in adulthood. These hypothalamic modified new neurons are critical for memory and anxiety-like behavior.

The mammalian brain contains neurogenic niches that comprise neural stem cells and other cell types. Neurogenic niches become less functional with age, but how they change during ageing remains unclear. Here we perform single-cell RNA sequencing of young and old neurogenic niches in mice. The analysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells and microglia, and an infiltration of T cells in old neurogenic niches. T cells in old brains are clonally expanded and are generally distinct from those in old blood, which suggests that they may experience specific antigens. T cells in old brains also express interferon-γ, and the subset of neural stem cells that has a high interferon response shows decreased proliferation in vivo. We find that T cells can inhibit the proliferation of neural stem cells in co-cultures and in vivo, in part by secreting interferon-γ. Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function. Single-cell transcriptomic analysis of neurogenic niches in young and old mice reveals that T cells infiltrate the neurogenic niches of old mice and inhibit the proliferation of neural stem cells, in part through expression of interferon-γ.