Explore the vast range of titles available.

Adult hippocampal neurogenesis is increased by antidepressants, and is required for some of their behavioral effects. However, it remains unclear whether expanding the population of adult-born neurons is sufficient to affect anxiety and depression-related behavior. Here, we use an inducible transgenic mouse model in which the pro-apoptotic gene Bax is deleted from neural stem cells and their progeny in the adult brain, and thereby increases adult neurogenesis. We find no effects on baseline anxiety and depression-related behavior; however, we find that increasing adult neurogenesis is sufficient to reduce anxiety and depression-related behaviors in mice treated chronically with corticosterone (CORT), a mouse model of stress. Thus, neurogenesis differentially affects behavior under baseline conditions and in a model of chronic stress. Moreover, we find no effect of increased adult hippocampal neurogenesis on hypothalamic-pituitary-adrenal (HPA) axis regulation, either at baseline or following chronic CORT administration, suggesting that increasing adult hippocampal neurogenesis can affect anxiety and depression-related behavior through a mechanism independent of the HPA axis. The use of future techniques to specifically inhibit BAX in the hippocampus could be used to augment adult neurogenesis, and may therefore represent a novel strategy to promote antidepressant-like behavioral effects.

Adult hippocampal neurogenesis contributes to learning and memory, and is sensitive to a variety of environmental stimuli. Exposure to a hypomagnetic field (HMF) influences the cognitive processes of various animals, from insects to human beings. However, whether HMF exposure affect adult hippocampal neurogenesis and hippocampus-dependent cognitions is still an enigma. Here, we showed that male C57BL/6 J mice exposed to HMF by means of near elimination of the geomagnetic field (GMF) exhibit significant impairments of adult hippocampal neurogenesis and hippocampus-dependent learning, which is strongly correlated with a reduction in the content of reactive oxygen species (ROS). However, these deficits seen in HMF-exposed mice could be rescued either by elevating ROS levels through pharmacological inhibition of ROS removal or by returning them back to GMF. Therefore, our results suggest that GMF plays an important role in adult hippocampal neurogenesis through maintaining appropriate endogenous ROS levels. Exposure to a hypomagnetic field (HMF) influences the cognitive processes of various animals, from insects to human beings. The authors show that in mice exposed to HMF, adult hippocampal neurogenesis and hippocampusdependent learning are impaired and could be rescued by restoring ROS levels.

Neurogenesis persists in adult mammals in specific brain areas, known as neurogenic niches. Adult neurogenesis is highly dynamic and is modulated by multiple physiological stimuli and pathological states. There is a strong interest in understanding how this process is regulated, particularly since active neuronal production has been demonstrated in both the hippocampus and the subventricular zone (SVZ) of adult humans. The molecular mechanisms that control neurogenesis have been extensively studied during embryonic development. Therefore, we have a broad knowledge of the intrinsic factors and extracellular signaling pathways driving proliferation and differentiation of embryonic neural precursors. Many of these factors also play important roles during adult neurogenesis, but essential differences exist in the biological responses of neural precursors in the embryonic and adult contexts. Because adult neural stem cells (NSCs) are normally found in a quiescent state, regulatory pathways can affect adult neurogenesis in ways that have no clear counterpart during embryogenesis. BMP signaling, for instance, regulates NSC behavior both during embryonic and adult neurogenesis. However, this pathway maintains stem cell proliferation in the embryo, while it promotes quiescence to prevent stem cell exhaustion in the adult brain. In this review, we will compare and contrast the functions of transcription factors (TFs) and other regulatory molecules in the embryonic brain and in adult neurogenic regions of the adult brain in the mouse, with a special focus on the hippocampal niche and on the regulation of the balance between quiescence and activation of adult NSCs in this region.

Brain organoids derived from human pluripotent stem cells provide a highly valuable in vitro model to recapitulate human brain development and neurological diseases. However, the current systems for brain organoid culture require further improvement for the reliable production of high-quality organoids. Here, we demonstrate two engineering elements to improve human brain organoid culture, (1) a human brain extracellular matrix to provide brain-specific cues and (2) a microfluidic device with periodic flow to improve the survival and reduce the variability of organoids. A three-dimensional culture modified with brain extracellular matrix significantly enhanced neurogenesis in developing brain organoids from human induced pluripotent stem cells. Cortical layer development, volumetric augmentation, and electrophysiological function of human brain organoids were further improved in a reproducible manner by dynamic culture in microfluidic chamber devices. Our engineering concept of reconstituting brain-mimetic microenvironments facilitates the development of a reliable culture platform for brain organoids, enabling effective modeling and drug development for human brain diseases. Brain organoids derived from human pluripotent stem cells can model human brain development and disease, though current culture systems fail to ensure reliable production of high-quality organoids. Here the authors combine human brain extracellular matrix and culture in a microfluidic device to promote structural and functional maturation of human brain organoids.

The generation of new neurons in the adult brain is a currently accepted phenomenon. Over the past few decades, the subventricular zone and the hippocampal dentate gyrus have been described as the two main neurogenic niches. Neurogenic niches generate new neurons through an asymmetric division process involving several developmental steps. This process occurs throughout life in several species, including humans. These new neurons possess unique properties that contribute to the local circuitry. Despite several efforts, no other neurogenic zones have been observed in many years; the lack of observation is probably due to technical issues. However, in recent years, more brain niches have been described, once again breaking the current paradigms. Currently, a debate in the scientific community about new neurogenic areas of the brain, namely, human adult neurogenesis, is ongoing. Thus, several open questions regarding new neurogenic niches, as well as this phenomenon in adult humans, their functional relevance, and their mechanisms, remain to be answered. In this review, we discuss the literature and provide a compressive overview of the known neurogenic zones, traditional zones, and newly described zones. Additionally, we will review the regulatory roles of some molecular mechanisms, such as miRNAs, neurotrophic factors, and neurotrophins. We also join the debate on human adult neurogenesis, and we will identify similarities and differences in the literature and summarize the knowledge regarding these interesting topics.

Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on messenger RNA (mRNA) expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG dinucleotides and in the expression of 3,857 transcripts (false discovery rate [FDR] ≤ 0.1 and absolute fold change [FC] expression ≥ 1.15). HPC expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into 4 trajectories over HPC differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting expression changes but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a polyepigenetic score that predicted exposure to conditions associated with altered prenatal GCs in newborn’s cord blood DNA. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.

Intelligence, or general cognitive function, is phenotypically and genetically correlated with many traits, including a wide range of physical, and mental health variables. Education is strongly genetically correlated with intelligence (rg = 0.70). We used these findings as foundations for our use of a novel approach—multi-trait analysis of genome-wide association studies (MTAG; Turley et al. 2017)—to combine two large genome-wide association studies (GWASs) of education and intelligence, increasing statistical power and resulting in the largest GWAS of intelligence yet reported. Our study had four goals: first, to facilitate the discovery of new genetic loci associated with intelligence; second, to add to our understanding of the biology of intelligence differences; third, to examine whether combining genetically correlated traits in this way produces results consistent with the primary phenotype of intelligence; and, finally, to test how well this new meta-analytic data sample on intelligence predicts phenotypic intelligence in an independent sample. By combining datasets using MTAG, our functional sample size increased from 199,242 participants to 248,482. We found 187 independent loci associated with intelligence, implicating 538 genes, using both SNP-based and gene-based GWAS. We found evidence that neurogenesis and myelination—as well as genes expressed in the synapse, and those involved in the regulation of the nervous system—may explain some of the biological differences in intelligence. The results of our combined analysis demonstrated the same pattern of genetic correlations as those from previous GWASs of intelligence, providing support for the meta-analysis of these genetically-related phenotypes.

Although the main task of a neuroprogenitor is to produce more cells, it may not always produce the same cells. Some progenitors produce different daughter neurons as an embryo develops. Concurrently, these daughter neurons are also transitioning through states toward maturation. Telley et al. used single-cell RNA sequencing to survey the transcriptional identity of cells early in mouse brain development. As a neuroprogenitor transitioned to new states, it produced daughter neurons that reflect those new states. The neuron's own postmitotic differentiation program is apparently overlaid onto these parentally supplied programs, driving emergence of specialized neuronal cell types in the neocortex. Science , this issue p. eaav2522 During corticogenesis in the brain, temporally dynamic molecular birthmarks in progenitors act as seeds for later neuronal diversity. During corticogenesis, distinct subtypes of neurons are sequentially born from ventricular zone progenitors. How these cells are molecularly temporally patterned is poorly understood. We used single-cell RNA sequencing at high temporal resolution to trace the lineage of the molecular identities of successive generations of apical progenitors (APs) and their daughter neurons in mouse embryos. We identified a core set of evolutionarily conserved, temporally patterned genes that drive APs from internally driven to more exteroceptive states. We found that the Polycomb repressor complex 2 (PRC2) epigenetically regulates AP temporal progression. Embryonic age–dependent AP molecular states are transmitted to their progeny as successive ground states, onto which essentially conserved early postmitotic differentiation programs are applied, and are complemented by later-occurring environment-dependent signals. Thus, epigenetically regulated temporal molecular birthmarks present in progenitors act in their postmitotic progeny to seed adult neuronal diversity.

Key Points DNA methylation and DNA methyltransferases regulate neurogenesis through epigenetic control of gene expression. Dynamic DNA demethylation exerts temporal control over transcription control during neurogenesis. Cytosine modification derivatives and ten-eleven translocation (TET) proteins precisely coordinate neurogenesis. Histone modification dynamics and their regulators can exert a broad influence over neurogenic processes both directly and indirectly. The proliferation and differentiation of neural stem cells in the embryonic and adult brain are influenced by various processes, including epigenetic regulation. Song and colleagues review the epigenetic regulation of neurogenesis in health and in various brain disorders, placing their focus on DNA and histone modifications. In the embryonic and adult brain, neural stem cells proliferate and give rise to neurons and glia through highly regulated processes. Epigenetic mechanisms — including DNA and histone modifications, as well as regulation by non-coding RNAs — have pivotal roles in different stages of neurogenesis. Aberrant epigenetic regulation also contributes to the pathogenesis of various brain disorders. Here, we review recent advances in our understanding of epigenetic regulation in neurogenesis and its dysregulation in brain disorders, including discussion of newly identified DNA cytosine modifications. We also briefly cover the emerging field of epitranscriptomics, which involves modifications of mRNAs and long non-coding RNAs.