Emerging Topics in Life Sciences最新文献

Until recently, understanding the neurobiology of dreaming has relied upon on correlating a subjective dream report with a measure of brain activity or function sampled from a different occasion. As such, most assumptions about dreaming come from the neuroscience of rapid eye-movement (REM) sleep from which many, but not all, dream reports are recalled. Core features of REM sleep (intense emotional activation, a reduction in activity in most frontal regions, particularly the dorsolateral prefrontal cortex, along with increased dopamine, acetylcholine, cholinergic activation) align with typical dream characteristics (characterised by fear, reduced reality monitoring, increased bizarreness and hyperassociativity, respectively). The default mode network offers a way of understanding the nature of dreaming more independently from a REM sleep context, and electroencephalography methods paired with serial awakenings to elicit dream reports demonstrate how high-frequency activity in posterior regions may be associated with dreaming. Nevertheless, all measures of dreaming rely fundamentally on recall processes, so our understanding of dreaming must embrace and address memory's crucial involvement in dream report production.

Sleep promotes memory consolidation: the process by which newly acquired memories are stabilised, strengthened, and integrated into long-term storage. Pioneering research in rodents has revealed that memory reactivation in sleep is a primary mechanism underpinning sleep's beneficial effect on memory. In this review, we consider evidence for memory reactivation processes occurring in human sleep. Converging lines of research support the view that memory reactivation occurs during human sleep, and is functionally relevant for consolidation. Electrophysiology studies have shown that memory reactivation is tightly coupled to the cardinal neural oscillations of non-rapid eye movement sleep, namely slow oscillation-spindle events. In addition, functional imaging studies have found that brain regions recruited during learning become reactivated during post-learning sleep. In sum, the current evidence paints a strong case for a mechanistic role of neural reactivation in promoting memory consolidation during human sleep.

Gastrulation represents a pivotal phase of development and aberrations during this period can have major consequences, from minor anatomical deviations to severe congenital defects. Animal models are used to study gastrulation, however, there is considerable morphological and molecular diversity of gastrula across mammalian species. Here, we provide an overview of the latest research on interspecies developmental control across mammals. This includes single-cell atlases of several mammalian gastrula which have enabled comparisons of the temporal and molecular dynamics of differentiation. These studies highlight conserved cell differentiation regulators and both absolute and relative differences in differentiation dynamics between species. Recent advances in in vitro culture techniques have facilitated the derivation, maintenance and differentiation of cell lines from a range of species and the creation of multi-species models of gastrulation. Gastruloids are three-dimensional aggregates capable of self-organising and recapitulating aspects of gastrulation. Such models enable species comparisons outside the confines of the embryo. We highlight recent in vitro evidence that differentiation processes such as somitogenesis and neuronal maturation scale with known in vivo differences in developmental tempo across species. This scaling is likely due to intrinsic differences in cell biochemistry. We also highlight several studies which provide examples of cell differentiation dynamics being influenced by extrinsic factors, including culture conditions, chimeric co-culture, and xenotransplantation. These collective studies underscore the complexity of gastrulation across species, highlighting the necessity of additional datasets and studies to decipher the intricate balance between intrinsic cellular programs and extrinsic signals in shaping embryogenesis.

During mammalian gastrulation, a mass of pluripotent cells surrounded by extraembryonic tissues differentiates into germ layers, mesoderm, endoderm, and ectoderm. The three germ layers are then organized into a body plan with organ rudiments via morphogenetic gastrulation movements of emboly, epiboly, convergence, and extension. Emboly is the most conserved gastrulation movement, whereby mesodermal and endodermal progenitors undergo epithelial-to-mesenchymal transition (EMT) and move via a blastopore/primitive streak beneath the ectoderm. Decades of embryologic, genetic, and molecular studies in invertebrates and vertebrates, delineated a BMP > WNT > NODAL signaling cascade underlying mesoderm and endoderm specification. Advances have been made in the research animals in understanding the cellular and molecular mechanisms underlying gastrulation morphogenesis. In contrast, little is known about human gastrulation, which occurs in utero during the third week of gestation and its investigations face ethical and methodological limitations. This is changing with the unprecedented progress in modeling aspects of human development, using human pluripotent stem cells (hPSCs), including embryonic stem cells (hESC)-based embryo-like models (SCEMs). In one approach, hESCs of various pluripotency are aggregated to self-assemble into structures that resemble pre-implantation or post-implantation embryo-like structures that progress to early gastrulation, and some even reach segmentation and neurulation stages. Another approach entails coaxing hESCs with biochemical signals to generate germ layers and model aspects of gastrulation morphogenesis, such as EMT. Here, we review the recent advances in understanding signaling cascades that direct germ layers specification and the early stages of gastrulation morphogenesis in these models. We discuss outstanding questions, challenges, and opportunities for this promising area of developmental biology.

Neurulation is a critical step in early embryonic development, giving rise to the neural tube, the primordium of the central nervous system in amniotes. Understanding this complex, multi-scale, multi-tissue morphogenetic process is essential to provide insights into normal development and the etiology of neural tube defects. Innovations in tissue engineering have fostered the generation of pluripotent stem cell-based in vitro models, including organoids, that are emerging as unique tools for delving into neurulation mechanisms, especially in the context of human development. Each model captures specific aspects of neural tube morphogenesis, from epithelialization to neural tissue elongation, folding and cavitation. In particular, the recent models of human and mouse trunk morphogenesis, such as gastruloids, that form a spinal neural plate-like or neural tube-like structure are opening new avenues to study normal and pathological neurulation. Here, we review the morphogenetic events generating the neural tube in the mammalian embryo and questions that remain unanswered. We discuss the advantages and limitations of existing in vitro models of neurulation and possible future technical developments.

Haematopoietic stem cells (HSCs) are the most extensively studied adult stem cells. Yet, six decades after their first description, reproducible and translatable generation of HSC in vitro remains an unmet challenge. HSC production in vitro is confounded by the multi-stage nature of blood production during development. Specification of HSC is a late event in embryonic blood production and depends on physical and chemical cues which remain incompletely characterised. The precise molecular composition of the HSC themselves is incompletely understood, limiting approaches to track their origin in situ in the appropriate cellular, chemical and mechanical context. Embryonic material at the point of HSC emergence is limiting, highlighting the need for an in vitro model of embryonic haematopoietic development in which current knowledge gaps can be addressed and exploited to enable HSC production. Gastruloids are pluripotent stem cell-derived 3-dimensional (3D) cellular aggregates which recapitulate developmental events in gastrulation and early organogenesis with spatial and temporal precision. Gastruloids self-organise multi-tissue structures upon minimal and controlled external cues, and are amenable to live imaging, screening, scaling and physicochemical manipulation to understand and translate tissue formation. In this review, we consider the haematopoietic potential of gastruloids and review early strategies to enhance blood progenitor and HSC production. We highlight possible strategies to achieve HSC production from gastruloids, and discuss the potential of gastruloid systems in illuminating current knowledge gaps in HSC specification.

The young field of gastruloids brings promise to modeling and understanding early embryonic development. However, being a complex model, gastruloids are prone to variability at different levels. In this perspective, we define the different levels of gastruloid variability, and parameters over which it can be measured. We discuss potential sources for variability, and then propose methods to better control and reduce it. We provide an example from definitive endoderm progression in gastruloids, where we harness gastruloid-to-gastruloid variation in early parameters to identify key driving factors for endoderm morphology. We then devise interventions that steer morphological outcome. A better control over the developmental progression of gastruloids will enhance their utility in both basic research and biomedical applications.

Metabolic networks are well placed to orchestrate the coordination of multiple cellular processes associated with embryonic development such as cell growth, proliferation, differentiation and cell movement. Here, we discuss the advantages that gastruloids, aggregates of mammalian embryonic stem cells that self-assemble a rudimentary body plan, have for uncovering the instructive role of metabolic pathways play in directing developmental processes. We emphasise the importance of using such reductionist systems to link specific pathways to defined events of early mammalian development and their utility for obtaining enough material for metabolomic studies. Finally, we review the ways in which the basic gastruloid protocol can be adapted to obtain specific models of embryonic cell types, tissues and regions. Together, we propose that gastruloids are an ideal system to rapidly uncover new mechanistic links between developmental signalling pathways and metabolic networks, which can then inform precise in vivo studies to confirm their function in the embryo.

Gastruloids acquire their organization and shape through cell biochemical and mechanical activities. Such activities determine the physical forces and changes in material properties that transform simple spherical aggregates into organized tissues. In this Perspective, we discuss why the concepts and approaches of mechanobiology, a discipline that focuses on cell and tissue mechanics and its contribution to the organization and functions of living systems, are essential to the gastruloid field and, in turn, what gastruloids may teach us about mechanobiology.

Spinocerebellar ataxias (SCAs) are a heterogenous group of neurodegenerative disorders which commonly inherited in an autosomal dominant manner. They cause muscle incoordination due to degeneration of the cerebellum and other parts of nervous system. Out of all the characterized (>50) SCAs, 14 SCAs are caused due to microsatellite repeat expansion mutations. Repeat expansions can result in toxic protein gain-of-function, protein loss-of-function, and/or RNA gain-of-function effects. The location and the nature of mutation modulate the underlying disease pathophysiology resulting in varying disease manifestations. Potential toxic effects of these mutations likely affect key major cellular processes such as transcriptional regulation, mitochondrial functioning, ion channel dysfunction and synaptic transmission. Involvement of several common pathways suggests interlinked function of genes implicated in the disease pathogenesis. A better understanding of the shared and distinct molecular pathogenic mechanisms in these diseases is required to develop targeted therapeutic tools and interventions for disease management. The prime focus of this review is to elaborate on how expanded 'CAG' repeats contribute to the common modes of neurotoxicity and their possible therapeutic targets in management of such devastating disorders.