Oxford open neuroscience最新文献

The mammalian neocortex is composed of diverse neuronal and glial cell classes that broadly arrange in six distinct laminae. Cortical layers emerge during development and defects in the developmental programs that orchestrate cortical lamination are associated with neurodevelopmental diseases. The developmental principle of cortical layer formation depends on concerted radial projection neuron migration, from their birthplace to their final target position. Radial migration occurs in defined sequential steps, regulated by a large array of signaling pathways. However, based on genetic loss-of-function experiments, most studies have thus far focused on the role of cell-autonomous gene function. Yet, cortical neuron migration in situ is a complex process and migrating neurons traverse along diverse cellular compartments and environments. The role of tissue-wide properties and genetic state in radial neuron migration is however not clear. Here we utilized mosaic analysis with double markers (MADM) technology to either sparsely or globally delete gene function, followed by quantitative single-cell phenotyping. The MADM-based gene ablation paradigms in combination with computational modeling demonstrated that global tissue-wide effects predominate cell-autonomous gene function albeit in a gene-specific manner. Our results thus suggest that the genetic landscape in a tissue critically affects the overall migration phenotype of individual cortical projection neurons. In a broader context, our findings imply that global tissue-wide effects represent an essential component of the underlying etiology associated with focal malformations of cortical development in particular, and neurological diseases in general.

The brain represents an organ with a particularly high diversity of genes that undergo post-transcriptional gene regulation through multiple mechanisms that affect RNA metabolism and, consequently, brain function. This vast regulatory process in the brain allows for a tight spatiotemporal control over protein expression, a necessary factor due to the unique morphologies of neurons. The numerous mechanisms of post-transcriptional regulation or translational control of gene expression in the brain include alternative splicing, RNA editing, mRNA stability and transport. A large number of trans-elements such as RNA-binding proteins and micro RNAs bind to specific cis-elements on transcripts to dictate the fate of mRNAs including its stability, localization, activation and degradation. Several trans-elements are exemplary regulators of translation, employing multiple cofactors and regulatory machinery so as to influence mRNA fate. Networks of regulatory trans-elements exert control over key neuronal processes such as neurogenesis, synaptic transmission and plasticity. Perturbations in these networks may directly or indirectly cause neuropsychiatric and neurodegenerative disorders. We will be reviewing multiple mechanisms of gene regulation by trans-elements occurring specifically in neurons.

Memory is the brain faculty to store and remember information. It is a sequential process in which four different phases can be distinguished: encoding or learning, consolidation, storage and reactivation. Since the discovery of the first Drosophila gene essential for memory formation in 1976, our knowledge of its mechanisms has progressed greatly. The current view considers the existence of engrams, ensembles of neuronal populations whose activity is temporally coordinated and represents the minimal correlate of experience in brain circuits. In order to form and maintain the engram, protein synthesis and, probably, specific transcriptional program(s) is required. The immediate early gene response during learning process has been extensively studied. However, a detailed description of the transcriptional response for later memory phases was technically challenging. Recent advances in transcriptomics have allowed us to tackle this biological problem. This review summarizes recent findings in this field, and discusses whether or not it is possible to identify a transcriptional trace for memory.

The initiation of nascent projections, or neurites, from the neuronal cell body is the first stage in the formation of axons and dendrites, and thus a critical step in the establishment of neuronal architecture and nervous system development. Neurite formation relies on the polarized remodelling of microtubules, which dynamically direct and reinforce cell shape, and provide tracks for cargo transport and force generation. Within neurons, microtubule behaviour and structure are tightly controlled by an array of regulatory factors. Although microtubule regulation in the later stages of axon development is relatively well understood, how microtubules are regulated during neurite initiation is rarely examined. Here, we discuss how factors that direct microtubule growth, remodelling, stability and positioning influence neurite formation. In addition, we consider microtubule organization by the centrosome and modulation by the actin and intermediate filament networks to provide an up-to-date picture of this vital stage in neuronal development.

The balance between proliferation and quiescence of stem cells is crucial in maintaining tissue homeostasis. Neural stem cells (NSCs) in the brain have the ability to be reactivated from a reversible quiescent state to generate new neurons. However, how NSCs transit between quiescence and reactivation remains largely elusive. Drosophila larval brain NSCs, also known as neuroblasts, have emerged as an excellent in vivo model to study molecular mechanisms underlying NSC quiescence and reactivation. Here, we discuss our current understanding of the molecular mechanisms underlying the reactivation of quiescent NSCs in Drosophila. We review the most recent advances on epigenetic regulations and microtubule cytoskeleton in Drosophila quiescent NSCs and their cross-talk with signaling pathways that are required in regulating NSC reactivation.

To faithfully transmit and decode signals released from presynaptic termini, postsynaptic compartments of neuronal synapses deploy hundreds of various proteins. In addition to distinct sets of proteins, excitatory and inhibitory postsynaptic apparatuses display very different organization features and regulatory properties. Decades of extensive studies have generated a wealth of knowledge on the molecular composition, assembly architecture and activity-dependent regulatory mechanisms of excitatory postsynaptic compartments. In comparison, our understanding of the inhibitory postsynaptic apparatus trails behind. Recent studies have demonstrated that phase separation is a new paradigm underlying the formation and plasticity of both excitatory and inhibitory postsynaptic molecular assemblies. In this review, we discuss molecular composition, organizational and regulatory features of inhibitory postsynaptic densities through the lens of the phase separation concept and in comparison with the excitatory postsynaptic densities.

Synaptic plasticity in the hippocampal Cornu Ammonis (CA) subfield, CA2, is tightly regulated. However, CA2 receives projections from several extra-hippocampal modulatory nuclei that release modulators that could serve to fine-tune plasticity at CA2 synapses. Considering that there are afferent projections from the serotonergic median raphe to hippocampal CA2, we hypothesized that the neuromodulator serotonin (5-hydroxytryptamine; 5-HT) could modulate CA2 synaptic plasticity. Here, we show that bath-application of serotonin facilitates the persistence of long-term depression (LTD) at the CA3 Schaffer collateral inputs to CA2 neurons (SC-CA2) when coupled to a weak low frequency electrical stimulation, in acute rat hippocampal slices. The observed late-LTD at SC-CA2 synapses was protein synthesis- and N-methyl-D-aspartate receptor (NMDAR)-dependent. Moreover, this late-LTD at SC-CA2 synapses paves way for the associative persistence of transient forms of LTD as well as long-term potentiation to long-lasting late forms of plasticity through synaptic tagging and cross-tagging respectively, at the entorhinal cortical synapses of CA2. We further observe that the 5-HT-mediated persistence of activity-dependent LTD at SC-CA2 synapses is blocked in the presence of the brain-derived neurotrophic factor scavenger, TrkB/Fc.

The formation of a functional circuitry in the central nervous system (CNS) requires the correct number and subtypes of neural cells. In the developing brain, neural stem cells (NSCs) self-renew while giving rise to progenitors that in turn generate differentiated progeny. As such, the size and the diversity of cells that make up the functional CNS depend on the proliferative properties of NSCs. In the fruit fly Drosophila, where the process of neurogenesis has been extensively investigated, extrinsic factors such as the microenvironment of NSCs, nutrients, oxygen levels and systemic signals have been identified as regulators of NSC proliferation. Here, we review decades of work that explores how extrinsic signals non-autonomously regulate key NSC characteristics such as quiescence, proliferation and termination in the fly.

Translational neuroscience is committed to generating discoveries in the laboratory that ultimately can improve human lives. Optogenetics has received considerable attention because of its demonstrated promise in rodent brains to manipulate cells and circuits. In a recent report, Tremblay et al. [28] introduce an open resource detailing optogenetic studies of the nonhuman primate (NHP) brain and make robust claims about the translatability of the technology. We propose that their quantitative (e.g. a 91% success rate) and theoretical claims are questionable because the data were analyzed at a level relevant to the rodent but not NHP brain. Injections were clustered within a few monkeys in a few studies in a few brain regions, and their definitions of success were not clearly relevant to human neuropsychiatric disease. A reanalysis of the data with a modified definition of success that included a behavioral and biological effect revealed a 62.5% success rate that was lower when considering only strong outcomes (53.1%). This calls into question the current efficacy of optogenetic techniques in the NHP brain and suggests that we are a long way from being able to leverage them in 'the service of patients with neurological or psychiatric conditions' as the Tremblay report claims.