The subgranular zone (SGZ) of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs) that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body.

Histone variants were recently discovered to regulate neural plasticity, with H2A.Z emerging as a memory suppressor. Using whole-genome sequencing of the mouse hippocampus, we show that basal H2A.Z occupancy is positively associated with steady-state transcription, whereas learning-induced H2A.Z removal is associated with learning-induced gene expression. AAV-mediated H2A.Z depletion enhanced fear memory and resulted in gene-specific alterations of learning-induced transcription, reinforcing the role of H2A.Z as a memory suppressor. H2A.Z accumulated with age, although it remained sensitive to learning-induced eviction. Learning-related H2A.Z removal occurred at largely distinct genes in young versus aged mice, suggesting that H2A.Z is subject to regulatory shifts in the aged brain despite similar memory performance. When combined with prior evidence of H3.3 accumulation in neurons, our data suggest that nucleosome composition in the brain is reorganized with age.

The suprachiasmatic nucleus (SCN) acts as the central clock to coordinate circadian oscillations in mammalian behavior, physiology and gene expression. Despite our knowledge of the circadian transcriptome of the SCN, how it impacts genome-wide protein expression is not well understood. Here, we interrogated the murine SCN proteome across the circadian cycle using SILAC-based quantitative mass spectrometry. Of the 2112 proteins that were accurately quantified, 20% (421 proteins) displayed a time-of-day-dependent expression profile. Within this time-of-day proteome, 11% (48 proteins) were further defined as circadian based on a sinusoidal expression pattern with a ∼24 h period. Nine circadianly expressed proteins exhibited 24 h rhythms at the transcript level, with an average time lag that exceeded 8 h. A substantial proportion of the time-of-day proteome exhibited abrupt fluctuations at the anticipated light-to-dark and dark-to-light transitions, and was enriched for proteins involved in several key biological pathways, most notably, mitochondrial oxidative phosphorylation. Additionally, predicted targets of miR-133ab were enriched in specific hierarchical clusters and were inversely correlated with miR133ab expression in the SCN. These insights into the proteomic landscape of the SCN will facilitate a more integrative understanding of cellular control within the SCN clock. The suprachiasmatic nucleus (SCN) serves as the master circadian pacemaker in mammals, coordinating the physiological responses of a myriad of peripheral clocks throughout the body and linking their rhythms to the environmental light-dark cycle. In this study, we interrogated the murine SCN proteome across the circadian cycle using stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative mass spectrometry. Among 3275 identified proteins in the SCN, 421 displayed a time-of-day-dependent expression profile, 48 fit a circadian expression profile with a ∼24 h period, and a surprising number of proteins were ultradianly expressed. Nine circadianly expressed proteins were accompanied by transcripts that were also 24 h rhythmic, but with a significant time lag (>8 h) between the phases of peak mRNA vs. protein expression. A substantial proportion of the time-of-day proteome exhibited abrupt fluctuations at the anticipated dawn and dusk, and was involved in mitochondrial oxidative phosphorylation. Additionally, predicted targets of miR-133ab were enriched in specific hierarchical clusters and were inversely correlated with miR133ab expression in the SCN. Our study underscores the significance of post-transcriptional regulation, the surprising prevalence of ultradian protein expression, and the functional implications on mitochondrial energy metabolism.

Significance: Naked mole rats exhibit the most profound case of socially induced infertility among mammals. They live in sizable colonies where breeding is monopolized by two to four dominant animals; all other colony members retain prepubertal gonadal quiescence until death or removal from the colony. Proximate mechanisms underlying this phenomenon are unknown but presumably involve integration of environmental cues by the brain into neuroendocrine signals that impact the gonadotropin-releasing hormone (GnRH) system. The role of RFamide-related peptide-3 (RFRP-3) in modulating the reproductive axis in vertebrates has been well documented, making it a prime candidate as a gatekeeper for puberty onset. Here, we present evidence for RFRP-3–mediated social delay of puberty and define a previously unidentified neuroendocrine component of social control of sexual maturation.

The central circadian pacemaker, the suprachiasmatic nucleus (SCN), encodes day length information by mechanisms that are not well understood. Here, we report that genetic ablation of miR-132/212 alters entrainment to different day lengths and non-24 hr day-night cycles, as well as photoperiodic regulation of Period2 expression in the SCN. SCN neurons from miR-132/212-deficient mice have significantly reduced dendritic spine density, along with altered methyl CpG-binding protein (MeCP2) rhythms. In Syrian hamsters, a model seasonal rodent, day length regulates spine density on SCN neurons in a melatonin-independent manner, as well as expression of miR-132, miR-212, and their direct target, MeCP2. Genetic disruption of Mecp2 fully restores the level of dendritic spines of miR-132/212-deficient SCN neurons. Our results reveal that, by regulating the dendritic structure of SCN neurons through a MeCP2-dependent mechanism, miR-132/212 affects the capacity of the SCN to encode seasonal time.