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The dentate gyrus–CA3 circuit of the hippocampus is continuously modified by the integration of adult-born dentate granule cells (abDGCs). All abDGCs undergo a prolonged period of maturation, during which they exhibit heightened synaptic plasticity and refinement of electrophysiological properties and connectivity. Consistent with theoretical models and the known functions of the dentate gyrus–CA3 circuit, acute or chronic manipulations of abDGCs support a role for abDGCs in the regulation of memory interference. In this Review, we integrate insights from studies that examine the maturation of abDGCs and their integration into the circuit with network mechanisms that support memory discrimination, consolidation and clearance. We propose that adult hippocampal neurogenesis enables the generation of a library of experiences, each registered in mature abDGC physiology and connectivity. Mature abDGCs recruit inhibitory microcircuits to support pattern separation and memory indexing.

Early life experience influences stress reactivity and mental health through effects on cognitive-emotional functions that are, in part, linked to gene expression in the dorsal and ventral hippocampus. The hippocampal dentate gyrus (DG) is a major site for experience-dependent plasticity associated with sustained transcriptional alterations, potentially mediated by epigenetic modifications. Here, we report comprehensive DNA methylome, hydroxymethylome and transcriptome data sets from mouse dorsal and ventral DG. We find genome-wide transcriptional and methylation differences between dorsal and ventral DG, including at key developmental transcriptional factors. Peripubertal environmental enrichment increases hippocampal volume and enhances dorsal DG-specific differences in gene expression. Enrichment also enhances dorsal-ventral differences in DNA methylation, including at binding sites of the transcription factor NeuroD1, a regulator of adult neurogenesis. These results indicate a dorsal-ventral asymmetry in transcription and methylation that parallels well-known functional and anatomical differences, and that may be enhanced by environmental enrichment. Environmental enrichment has functional and molecular effects on mammalian hippocampus. Here, Zhang and colleagues show that environmental enrichment of mice is correlated with dorsal-ventral asymmetry in transcription and DNA methylation of the dentate gyrus.

Increasing evidence suggests that regular exercise improves brain health and promotes synaptic plasticity and hippocampal neurogenesis. Exercise improves learning, but specific mechanisms of information processing influenced by physical activity are unknown. Here, we report that voluntary running enhanced the ability of adult (3 months old) male C57BL/6 mice to discriminate between the locations of two adjacent identical stimuli. Improved spatial pattern separation in adult runners was tightly correlated with increased neurogenesis. In contrast, very aged (22 months old) mice had impaired spatial discrimination and low basal cell genesis that was refractory to running. These findings suggest that the addition of newly born neurons may bolster dentate gyrus-mediated encoding of fine spatial distinctions.

Newly generated dentate granule cells in the hippocampus at 4 weeks after their 'birth' are more plastic than existing neurons. The authors use a combined retroviral and optogenetic approach to show that silencing these 4-week-old cells, but not cells of other ages, impaired retrieval of hippocampal memory. Accumulating evidence suggests that global depletion of adult hippocampal neurogenesis influences its function and that the timing of the depletion affects the deficits. However, the behavioral roles of adult-born neurons during their establishment of projections to CA3 pyramidal neurons remain largely unknown. We used a combination of retroviral and optogenetic approaches to birth date and reversibly control a group of adult-born neurons in adult mice. Adult-born neurons formed functional synapses on CA3 pyramidal neurons as early as 2 weeks after birth, and this projection to the CA3 area became stable by 4 weeks in age. Newborn neurons at this age were more plastic than neurons at other stages. Notably, we found that reversibly silencing this cohort of ∼4-week-old cells after training, but not cells of other ages, substantially disrupted retrieval of hippocampal memory. Our results identify a restricted time window for adult-born neurons essential in hippocampal memory retrieval.

Background Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light/dark variations of the mitotic index and DNA synthesis occur in many tissues, we wanted to unravel the role of the clock-controlled Period2 gene ( mPer2 ) in timing cell cycle kinetics and neurogenesis in the adult DG. Results In contrast to the suprachiasmatic nucleus, we observed a non-rhythmic constitutive expression of mPER2 in the dentate gyrus. We provide evidence that mPER2 is expressed in proliferating neural stem/progenitor cells (NPCs) and persists in early post-mitotic and mature newborn neurons from the adult DG. In vitro and in vivo analysis of a mouse line mutant in the mPer2 gene ( Per2 Brdm1 ), revealed a higher density of dividing NPCs together with an increased number of immature newborn neurons populating the DG. However, we showed that the lack of mPer2 does not change the total amount of mature adult-generated hippocampal neurons, because of a compensatory increase in neuronal cell death. Conclusion Taken together, these data demonstrated a functional link between the constitutive expression of mPER2 and the intrinsic control of neural stem/progenitor cells proliferation, cell death and neurogenesis in the dentate gyrus of adult mice.

Lifelong neurogenesis in the dentate gyrus (DG) of the hippocampus supports cognitive and emotional functions in most adult mammals. The subgranular zone (SGZ) of the DG contains dense vasculature where neural stem and progenitor cells (NSPCs) reside in close proximity to local capillaries. This arrangement likely supports NSPCs by providing access to oxygen, circulating molecules, and endothelial-derived factors. While SGZ vessel density and NSPC association with vessels are well established in adulthood, when these niche attributes emerge in development remains unclear. Here, we show that while blood vessel density in the SGZ remained stable from initial layer formation (2 weeks of age) into young adulthood (9 weeks of age) in male and female mice, the average distance from NSPC somas to the nearest blood vessel decreased progressively over postnatal development. This finding was accompanied by a symmetrical compression of proliferating cells within the SGZ, and a gradual shift of quiescent neural stem cell somas towards the granule cell layer of the DG. Our findings imply that the DG neurogenic vascular niche continues to refine postnatally, suggesting that the NSPC vascular niche has a unique functional role in supporting mature adult neurogenesis.

RationaleAutism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders characterized by deficits in social communication and interaction, repetitive stereotyped behaviors, and cognitive impairments. Curcumin has been indicated to be neuroprotective against neurological and psychological disorders. However, the role of curcumin in autistic phenotypes remains unclear.ObjectivesIn the current study, we evaluated the effects of neonatal curcumin treatment on behavior and hippocampal neurogenesis in BTBRT+ltpr3tf/J (BTBR) mice, a model of autism.MethodsC57BL/6J (C57) and BTBR mouse pups were treated with 0.1% dimethyl sulfoxide (DMSO) or curcumin (20 mg/kg) from postnatal day 6 (P6) to P8. Neural progenitor cells (NPCs) in the hippocampal dentate gyrus (DG) were evaluated on P8, and neurogenesis was measured on P24 by immunofluorescence. A battery of behavioral tests was carried out when the mice were 8 weeks of age.ResultsNeonatal curcumin treatment improved autism-related symptoms in BTBR mice, enhancing sociability, reducing repetitive behaviors, and ameliorating cognitive impairments. Furthermore, the suppression of hippocampal neurogenesis in BTBR mice was greatly rescued after neonatal curcumin treatment, leading to an increase in neurogenic processes and an increase in NPC proliferation concomitant with an expansion of the NPC pool on P8, and NPC differentiation towards the neuronal lineage was promoted in the DG of BTBR mice on P24.ConclusionsOur findings suggest that neonatal curcumin treatment elicits a therapeutic response through the restoration of hippocampal neurogenesis in BTBR mice and thus may represent a promising novel pharmacological strategy for ASD treatment.

Associative memory develops into adulthood and critically depends on the hippocampus. The hippocampus is a complex structure composed of subfields that are functionally-distinct, and anterior-posterior divisions along the length of the hippocampal horizontal axis that may also differ by cognitive correlates. Although each of these aspects has been considered independently, here we evaluate their relative contributions as correlates of age-related improvement in memory. Volumes of hippocampal subfields (subiculum, CA1-2, CA3-dentate gyrus) and anterior-posterior divisions (hippocampal head, body, tail) were manually segmented from high-resolution images in a sample of healthy participants (age 8–25 years). Adults had smaller CA3-dentate gyrus volume as compared to children, which accounted for 67% of the indirect effect of age predicting better associative memory via hippocampal volumes. Whereas hippocampal body volume demonstrated non-linear age differences, larger hippocampal body volume was weakly related to better associative memory only when accounting for the mutual correlation with subfields measured within that region. Thus, typical development of associative memory was largely explained by age-related differences in CA3-dentate gyrus. •Hippocampal subfield and subregion volumes were measured in children and adults.•Adults had smaller CA3-dentate gyrus volumes as compared to children.•Non-linear age differences were identified in CA1-2 and hippocampal body volumes.•Smaller CA3-dentate gyrus volume explained better associative memory with age.

Early life stress predisposes to mental illness and behavioral dysfunction in adulthood, but the mechanisms underlying these persistent effects are poorly understood. Stress throughout life impairs the structure and function of the hippocampus, a brain system undergoing considerable development in early life. The long-term behavioral consequences of early life stress may therefore be due in part to interference with hippocampal development, in particular with assembly of the dentate gyrus (DG) region of the hippocampus. We investigated how early life stress produces long-term alterations in DG structure by examining DG assembly and the generation of a stable adult stem cell pool in routine housing and after stress induced by the limited bedding/nesting paradigm in mice. We found that early life stress leads to a more immature, proliferative DG than would be expected for the animal’s age immediately after stress exposure, suggesting that early life stress delays DG development. Adult animals exposed to early life stress exhibited a reduction in the number of DG stem cells, but unchanged neurogenesis suggesting a depletion of the stem cell pool with compensation in the birth and survival of adult-born neurons. These results suggest a developmental mechanism by which early life stress can induce long-term changes in hippocampal function by interfering with DG assembly and ultimately diminishing the adult stem cell pool.

Adult stem cell niches relays in the acquisition of a reversible state of quiescence to ensure long-lasting DNA integrity and cell expansion. Neural stem cells (NSCs) in the dentate gyrus (DG) enter quiescence before the adult hippocampal neurogenic niche is fully established. However, the mechanisms controlling NSC first quiescence entry and quiescence deepness are largely unknown. Using conditional mutant mouse during embryonic or postnatal stages, we have determined that transcription factor Sox5 is required to restrict first entry in quiescence. Moreover, we have found a critical window during the second postnatal week when NSCs build up a shallow quiescent state. Loss of Sox5 leads to an excess of NSCs in shallow quiescence, which are prone to activate, leading to a neurogenic burst in the adult DG and precocious depletion of the NSC pool. Mechanistically, Sox5 prevents an excess of BMP canonical signaling, a pathway that is required to maintain the correct levels of NSC quiescence during the second postnatal week. In conclusion, our results demonstrate that Sox5 is required to control the correct balance between shallow and deep quiescence during the first postnatal weeks of DG development, a balance which is essential for establishing long-lasting adult neurogenesis.