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Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by a number of environmental and cell-intrinsic factors to adapt to environmental changes. Accumulating evidence suggests that adult-born neurons may play distinct physiological roles in hippocampus-dependent functions, such as memory encoding and mood regulation. In addition, several brain diseases, such as neurological diseases and mood disorders, have deleterious effects on adult hippocampal neurogenesis, and some symptoms of those diseases can be partially explained by the dysregulation of adult hippocampal neurogenesis. Here we review a possible link between the physiological functions of adult-born neurons and their roles in pathological conditions.

The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD.

Human cerebral organoids undergo vascularization and maturation in the mouse brain. Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.

Key Points Since the discovery of induced pluripotent stem cell (iPSC) reprograming, many protocols to generate human neural cells, including specific neuronal subtypes, astrocytes and other glial cells have emerged. Guided differentiation protocols for the production of specific brain cell subtypes from human pluripotent stem cells (hPSCs) follow known developmental pathways. The precise combination of molecular cues allows scientists to guide neural commitment, early regionalization and cell type specification to develop cultures enriched for specific neuronal subtypes. The generation of functional neurons and glia from hPSCs can be markedly improved by controlling the cellular environment in vitro , and advances in developing optimized culture scaffolds, culture media and 3D neural organoid cultures enhance our ability to provide more sophisticated tissue models of the brain. Authentic models of physiological human neuronal tissue in vitro will provide novel means to study human neuronal development and disease. Functional neural cell cultures can also be obtained by converting primary human somatic cells, such as skin fibroblasts, directly into neurons or glia. Direct conversion into induced neurons (iNs) is typically achieved through the overexpression of pro-neuronal transcription factors; alternative methods based on RNA interference or small molecules are also being developed. Direct conversion of human somatic cells into defined neuronal subtypes can be achieved through combined overexpression of general pro-neuronal drivers and secondary lineage-specifying transcription factors. The increasing number of available methods to generate different neural cell types from human skin cells demands a careful consideration of practical as well as conceptual differences between hPSC differentiation and direct conversion methods. Practical concerns may include duration, difficulty, costs, efficiency, available cell numbers and subtypes that can be generated by a certain method; conceptual differences encompass the influence of the respective reprogramming method on the genomic identity of the derived cell culture (for example, clonal or mosaic), their epigenetic state (for example, rejuvenation), as well as whether a certain method recapitulates relevant neurodevelopmental and maturation. Cultures of human neural cells can be generated from skin cells that have been reprogrammed to produce induced pluripotent stem cells (iPSCs) or subjected to direct conversion. Gage and colleagues describe advances in differentiation protocols that allow specific subtypes of neural cell to be produced and consider the advantages and disadvantages of different approaches. The scarcity of live human brain cells for experimental access has for a long time limited our ability to study complex human neurological disorders and elucidate basic neuroscientific mechanisms. A decade ago, the development of methods to reprogramme somatic human cells into induced pluripotent stem cells enabled the in vitro generation of a wide range of neural cells from virtually any human individual. The growth of methods to generate more robust and defined neural cell types through reprogramming and direct conversion into induced neurons has led to the establishment of various human reprogramming-based neural disease models.

Mice genomes contain many mobile retrotransposons. Bedrosian et al. analyzed DNA from the mouse hippocampus during development (see the Perspective by Song and Gleeson). They found that the amount of maternal care in the first few weeks of a mouse pup's life affected the number of copies of the L1 retrotransposon. The experience of maternal care was thus “recorded” in the DNA of these mice pups during a time when the brain was still actively developing. Science , this issue p. 1395 ; see also p. 1330 Natural variations in maternal care alter neuronal DNA sequences through mobilization of L1 retrotransposons. The brain is a genomic mosaic owing to somatic mutations that arise throughout development. Mobile genetic elements, including retrotransposons, are one source of somatic mosaicism in the brain. Retrotransposition may represent a form of plasticity in response to experience. Here, we use droplet digital polymerase chain reaction to show that natural variations in maternal care mediate the mobilization of long interspersed nuclear element–1 (LINE-1 or L1) retrotransposons in the hippocampus of the mouse brain. Increasing the amount of maternal care blocks the accumulation of L1. Maternal care also alters DNA methylation at YY1 binding sites implicated in L1 activation and affects expression of the de novo methyltransferase DNMT3a. Our observations indicate that early life experience drives somatic variation in the genome via L1 retrotransposons.

Alzheimer's disease (AD) pathology destroys neurons and synapses in the brain, leading to dementia. The brain generates new neurons throughout life in the hippocampus, a process called adult hippocampal neurogenesis (AHN). Choi et al. found that blocking AHN exacerbated cognitive impairment in an AD mouse model (see the Perspective by Spires-Jones and Ritchie). Inducing neurogenesis alone did not improve cognition in AD mice, whereas inducing neurogenesis while simultaneously ameliorating the neuronal environment via exercise did. The use of genetic or pharmacological treatments that simultaneously induced neurogenesis and increased levels of brain-derived neurotrophic factor (BDNF) mimicked the benefits of exercise on cognition. Thus, inducing both neurogenesis and providing BDNF may be useful as an AD therapeutic. Science , this issue p. eaan8821 ; see also p. 975 Adult neurogenesis plays a critical role in neurodegeneration and cognition in a mouse model of Alzheimer’s disease. Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer’s disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.

Microglia are immune system cells that function in protecting and maintaining the brain. Gosselin et al. examined the epigenetics and RNA transcripts from single microglial cells and observed consistent profiles among samples despite differences in age, sex, and diagnosis. Mouse and human microglia demonstrated similar microglia-specific gene expression profiles, as well as a shared environmental response among microglia collected either immediately after surgery (ex vivo) or after culturing (in vitro). Interestingly, those genes exhibiting differences in expression between humans and mice or after culturing were often implicated in neurodegenerative diseases. Science , this issue p. eaal3222 Single-cell sequencing of brain microglia reveals ex vivo and in vitro differences in transcription. Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. However, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue ex vivo and after transition to an in vitro environment. Transfer to a tissue culture environment resulted in rapid and extensive down-regulation of microglia-specific genes that were induced in primitive mouse macrophages after migration into the fetal brain. Substantial subsets of these genes exhibited altered expression in neurodegenerative and behavioral diseases and were associated with noncoding risk variants. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and facilitate efforts to understand the roles of microglia in human brain diseases.

Telomeres are the protective nucleoprotein structures at the end of linear eukaryotic chromosomes. Telomeres’ repetitive nature and length have traditionally challenged the precise assessment of the composition and length of individual human telomeres. Here, we present Telo-seq to resolve bulk, chromosome arm-specific and allele-specific human telomere lengths using Oxford Nanopore Technologies’ native long-read sequencing. Telo-seq resolves telomere shortening in five population doubling increments and reveals intrasample, chromosome arm-specific, allele-specific telomere length heterogeneity. Telo-seq can reliably discriminate between telomerase- and ALT-positive cancer cell lines. Thus, Telo-seq is a tool to study telomere biology during development, aging, and cancer at unprecedented resolution. Here, the authors developed a method to precisely measure bulk, chromosome arm- and allele-specific human telomere length using nanopore sequencing. They resolve telomere shortening and differences between telomerase- and ALT-positive cancer cells

How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size. Structures called mitochondria act like the batteries of cells, and use several different metabolic processes to release energy. For example, neurons rely on a metabolic process called oxidative phosphorylation, while neural progenitor cells (which develop, or differentiate, into neurons) use a process called aerobic glycolysis instead. Little is known about why neurons prefer to use oxidative phosphorylation to provide them with energy, and it is also not clear why problems that affect this process are often seen in neurological disorders and neurodegenerative diseases. Zheng, Boyer et al. have now used human neural progenitor cells to explore the metabolic changes that occur as these cells develop into neurons. It appears that the loss of two metabolic enzymes, called hexokinase and lactate dehydrogenase, marks the transition from aerobic glycolysis to oxidative phosphorylation. In addition, the instructions to produce an enzyme called pyruvate kinase are altered or “alternatively spliced” when progenitor cells differentiate, which in turn changes the structure of the enzyme. The levels of the proteins that activate and regulate the production of these three metabolic enzymes also decrease dramatically during this transition. Further experiments showed that neurons that produce hexokinase and lactate dehydrogenase while they differentiate die, which means that neurons must shut off aerobic glycolysis in order to survive. The amounts of two proteins that regulate metabolism (called PGC-1α and ERRγ) increase significantly when a neuron differentiates. This sustains a constant level of activity for several metabolic and mitochondrial genes as neural progenitor cells differentiate to form neurons. Zheng, Boyer et al. also found that neurons build more mitochondria as they grow; this suggests that an unknown mechanism exists that links the creation of mitochondria to the size of the neuron. Zheng, Boyer et al. have mainly focused on how much of each metabolic enzyme is produced inside cells, but these levels may not completely reflect the actual level of enzyme activity. The next steps are therefore to investigate whether any other processes or modifications play a part in regulating the enzymes. Further investigation is also needed to determine the effects of changes in mitochondrial structure that occur as a neuron develops from a neural progenitor cell.

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type–specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.