RESUMEN

Caudate nucleus (CN) neurons in camels and humans were examined using modified Golgi impregnation methods. Neurons were classified based on soma morphology, dendritic characteristics, and spine distribution. Three primary neuron types were identified in both species: rich-spiny (Type I), sparsely-spiny (Type II), and aspiny (Type III), each comprising subtypes with specific features. Comparative analysis revealed significant differences in soma size, dendritic morphology, and spine distribution between camels and humans. The study contributes to our understanding of structural diversity in CN neurons and provides insights into evolutionary neural adaptations.

RESUMEN

A recent study by Cheung, Pauler, Koppensteiner et al. combining lineage tracing with single-cell RNA sequencing (scRNA-seq) has revealed unexpected features of the developing superior colliculus (SC). Extremely multipotent individual progenitors generate all types of SC neurons and glial cells that were found to localize in a non-predetermined pattern, demonstrating a remarkable degree of unpredictability in SC development.

Asunto(s)

RESUMEN

How our brain generates diverse neuron types that assemble into precise neural circuits remains unclear. Using Drosophila lamina neuron types (L1-L5), we show that the primary homeodomain transcription factor (HDTF) brain-specific homeobox (Bsh) is initiated in progenitors and maintained in L4/L5 neurons to adulthood. Bsh activates secondary HDTFs Ap (L4) and Pdm3 (L5) and specifies L4/L5 neuronal fates while repressing the HDTF Zfh1 to prevent ectopic L1/L3 fates (control: L1-L5; Bsh-knockdown: L1-L3), thereby generating lamina neuronal diversity for normal visual sensitivity. Subsequently, in L4 neurons, Bsh and Ap function in a feed-forward loop to activate the synapse recognition molecule DIP-ß, thereby bridging neuronal fate decision to synaptic connectivity. Expression of a Bsh:Dam, specifically in L4, reveals Bsh binding to the DIP-ß locus and additional candidate L4 functional identity genes. We propose that HDTFs function hierarchically to coordinate neuronal molecular identity, circuit formation, and function. Hierarchical HDTFs may represent a conserved mechanism for linking neuronal diversity to circuit assembly and function.

Asunto(s)

RESUMEN

In terrestrial vertebrates, the olfactory system is divided into main (MOS) and accessory (AOS) components that process both volatile and nonvolatile cues to generate appropriate behavioral responses. While much is known regarding the molecular diversity of neurons that comprise the MOS, less is known about the AOS. Here, focusing on the vomeronasal organ (VNO), the accessory olfactory bulb (AOB), and the medial amygdala (MeA), we reveal that populations of neurons in the AOS can be molecularly subdivided based on their ongoing or prior expression of the transcription factors Foxp2 or Dbx1, which delineate separate populations of GABAergic output neurons in the MeA. We show that a majority of AOB neurons that project directly to the MeA are of the Foxp2 lineage. Using single-neuron patch-clamp electrophysiology, we further reveal that in addition to sex-specific differences across lineage, the frequency of excitatory input to MeA Dbx1- and Foxp2-lineage neurons differs between sexes. Together, this work uncovers a novel molecular diversity of AOS neurons, and lineage and sex differences in patterns of connectivity.

Asunto(s)

RESUMEN

Reproducible definition and identification of cell types is essential to enable investigations into their biological function, and understanding their relevance in the context of development, disease and evolution. Current approaches model variability in data as continuous latent factors, followed by clustering as a separate step, or immediately apply clustering on the data. We show that such approaches can suffer from qualitative mistakes in identifying cell types robustly, particularly when the number of such cell types is in the hundreds or even thousands. Here, we propose an unsupervised method, MMIDAS, which combines a generalized mixture model with a multi-armed deep neural network, to jointly infer the discrete type and continuous type-specific variability. Using four recent datasets of brain cells spanning different technologies, species, and conditions, we demonstrate that MMIDAS can identify reproducible cell types and infer cell type-dependent continuous variability in both uni-modal and multi-modal datasets.

RESUMEN

Investigation of translation in rare cell types or subcellular contexts is challenging due to large input requirements for standard approaches. Here, we present "nanoRibo-seq" an optimized approach using 102- to 103-fold less input material than bulk approaches. nanoRibo-seq exhibits rigorous quality control features consistent with quantification of ribosome protected fragments with as few as 1,000 cells. We compare translatomes of two closely related cortical neuron subtypes, callosal projection neurons (CPN) and subcerebral projection neurons (SCPN), during their early postnatal development. We find that, while translational efficiency is highly correlated between CPN and SCPN, several dozen mRNAs are differentially translated. We further examine upstream open reading frame (uORF) translation and identify that mRNAs involved in synapse organization and axon development are highly enriched for uORF translation in both subtypes. nanoRibo-seq enables investigation of translational regulation of rare cell types in vivo and offers a flexible approach for globally quantifying translation from limited input material.

Asunto(s)

RESUMEN

Heterogeneity is the norm in biology. The brain is no different: Neuronal cell types are myriad, reflected through their cellular morphology, type, excitability, connectivity motifs, and ion channel distributions. While this biophysical diversity enriches neural systems' dynamical repertoire, it remains challenging to reconcile with the robustness and persistence of brain function over time (resilience). To better understand the relationship between excitability heterogeneity (variability in excitability within a population of neurons) and resilience, we analyzed both analytically and numerically a nonlinear sparse neural network with balanced excitatory and inhibitory connections evolving over long time scales. Homogeneous networks demonstrated increases in excitability, and strong firing rate correlations-signs of instability-in response to a slowly varying modulatory fluctuation. Excitability heterogeneity tuned network stability in a context-dependent way by restraining responses to modulatory challenges and limiting firing rate correlations, while enriching dynamics during states of low modulatory drive. Excitability heterogeneity was found to implement a homeostatic control mechanism enhancing network resilience to changes in population size, connection probability, strength and variability of synaptic weights, by quenching the volatility (i.e., its susceptibility to critical transitions) of its dynamics. Together, these results highlight the fundamental role played by cell-to-cell heterogeneity in the robustness of brain function in the face of change.

Asunto(s)

RESUMEN

The generation of neuronal diversity involves temporal patterning mechanisms by which a given progenitor sequentially produces multiple cell types. Several parallels are evident between the brain development programs of Drosophila and vertebrates, such as the successive emergence of specific cell types and the use of combinations of transcription factors to specify cell fates. Furthermore, cell-extrinsic cues such as hormones and signaling pathways have also been shown to be regulatory modules of temporal patterning. Recently, transcriptomic and epigenomic studies using large single-cell sequencing datasets have provided insights into the transcriptional dynamics of neurogenesis in the Drosophila and mammalian central nervous systems. We review these commonalities in the specification of neuronal identity and highlight the conserved or convergent strategies of brain development by discussing temporal patterning mechanisms found in flies and vertebrates.

Asunto(s)

RESUMEN

The development of the central nervous system (CNS) in flies and mammals requires the production of distinct neurons in different locations and times. Here we review progress on how Drosophila stem cells (neuroblasts; NBs) generate distinct neurons over time. There are two types of NBs: type I and type II NBs (defined below); here we focus on type I NBs; type II NBs are reviewed elsewhere in this issue. Type I NBs generate neural diversity via the cascading expression of specific temporal transcription factors (TTFs). TTFs are sequentially expressed in neuroblasts and required for the identity of neurons born during each TTF expression window. In this way TTFs specify the "temporal identity" or birth-order dependent identity of neurons. Recent studies have shown that TTF expression in neuroblasts alter the identity of their progeny, including directing motor neurons to form proper connectivity to the proper muscle targets, independent of their birth-order. Similarly, optic lobe (OL) type I NBs express a series of TTFs that promote proper neuron morphology and targeting to the four OL neuropils. Together, these studies demonstrate how temporal identity is crucial in promoting proper circuit assembly within the Drosophila CNS. In addition, TTF orthologs in mouse are good candidates for specifying neuron types in the neocortex and retina. In this review we highlight the recent advances in understanding the role of TTFs in CNS circuit assembly in Drosophila and reflect on the conservation of these mechanisms in mammalian CNS development.

Asunto(s)

RESUMEN

To understand how the nervous system develops from a small pool of progenitors during early embryonic development, it is fundamentally important to identify the diversity of neuronal subtypes, decode the origin of neuronal diversity, and uncover the principles governing neuronal specification across different regions. Recent single-cell analyses have systematically identified neuronal diversity at unprecedented scale and speed, leaving the deconstruction of spatiotemporal mechanisms for generating neuronal diversity an imperative and paramount challenge. In this review, we highlight three distinct strategies deployed by neural progenitors to produce diverse neuronal subtypes, including predetermined, stochastic, and cascade diversifying models, and elaborate how these strategies are implemented in distinct regions such as the neocortex, spinal cord, retina, and hypothalamus. Importantly, the identity of neural progenitors is defined by their spatial position and temporal patterning factors, and each type of progenitor cell gives rise to distinguishable cohorts of neuronal subtypes. Microenvironmental cues, spontaneous activity, and connectional pattern further reshape and diversify the fate of unspecialized neurons in particular regions. The illumination of how neuronal diversity is generated will pave the way for producing specific brain organoids to model human disease and desired neuronal subtypes for cell therapy, as well as understanding the organization of functional neural circuits and the evolution of the nervous system.

Asunto(s)

RESUMEN

To understand how the nervous system develops from a small pool of progenitors during early embryonic development, it is fundamentally important to identify the diversity of neuronal subtypes, decode the origin of neuronal diversity, and uncover the principles governing neuronal specification across different regions. Recent single-cell analyses have systematically identified neuronal diversity at unprecedented scale and speed, leaving the deconstruction of spatiotemporal mechanisms for generating neuronal diversity an imperative and paramount challenge. In this review, we highlight three distinct strategies deployed by neural progenitors to produce diverse neuronal subtypes, including predetermined, stochastic, and cascade diversifying models, and elaborate how these strategies are implemented in distinct regions such as the neocortex, spinal cord, retina, and hypothalamus. Importantly, the identity of neural progenitors is defined by their spatial position and temporal patterning factors, and each type of progenitor cell gives rise to distinguishable cohorts of neuronal subtypes. Microenvironmental cues, spontaneous activity, and connectional pattern further reshape and diversify the fate of unspecialized neurons in particular regions. The illumination of how neuronal diversity is generated will pave the way for producing specific brain organoids to model human disease and desired neuronal subtypes for cell therapy, as well as understanding the organization of functional neural circuits and the evolution of the nervous system.

Asunto(s)

RESUMEN

A liquid state machine (LSM) is a biologically plausible model of a cortical microcircuit. It exists of a random, sparse reservoir of recurrently connected spiking neurons with fixed synapses and a trainable readout layer. The LSM exhibits low training complexity and enables backpropagation-free learning in a powerful, yet simple computing paradigm. In this work, the liquid state machine is enhanced by a set of bio-inspired extensions to create the extended liquid state machine (ELSM), which is evaluated on a set of speech data sets. Firstly, we ensure excitatory/inhibitory (E/I) balance to enable the LSM to operate in edge-of-chaos regime. Secondly, spike-frequency adaptation (SFA) is introduced in the LSM to improve the memory capabilities. Lastly, neuronal heterogeneity, by means of a differentiation in time constants, is introduced to extract a richer dynamical LSM response. By including E/I balance, SFA, and neuronal heterogeneity, we show that the ELSM consistently improves upon the LSM while retaining the benefits of the straightforward LSM structure and training procedure. The proposed extensions led up to an 5.2% increase in accuracy while decreasing the number of spikes in the ELSM up to 20.2% on benchmark speech data sets. On some benchmarks, the ELSM can even attain similar performances as the current state-of-the-art in spiking neural networks. Furthermore, we illustrate that the ELSM input-liquid and recurrent synaptic weights can be reduced to 4-bit resolution without any significant loss in classification performance. We thus show that the ELSM is a powerful, biologically plausible and hardware-friendly spiking neural network model that can attain near state-of-the-art accuracy on speech recognition benchmarks for spiking neural networks.

RESUMEN

Realizing the full utility of brain organoids to study human development requires understanding whether organoids precisely replicate endogenous cellular and molecular events, particularly since acquisition of cell identity in organoids can be impaired by abnormal metabolic states. We present a comprehensive single-cell transcriptomic, epigenetic, and spatial atlas of human cortical organoid development, comprising over 610,000 cells, from generation of neural progenitors through production of differentiated neuronal and glial subtypes. We show that processes of cellular diversification correlate closely to endogenous ones, irrespective of metabolic state, empowering the use of this atlas to study human fate specification. We define longitudinal molecular trajectories of cortical cell types during organoid development, identify genes with predicted human-specific roles in lineage establishment, and uncover early transcriptional diversity of human callosal neurons. The findings validate this comprehensive atlas of human corticogenesis in vitro as a resource to prime investigation into the mechanisms of human cortical development.

Asunto(s)

RESUMEN

Defining the origin of neuronal diversity is a major challenge in developmental neurobiology. The Drosophila visual system is an excellent paradigm to study how cellular diversity is generated. Photoreceptors from the eye disc grow their axons into the optic lobe and secrete Hedgehog (Hh) to induce the lamina, such that for every unit eye there is a corresponding lamina unit made up of post-mitotic precursors stacked into columns. Each differentiated column contains five lamina neuron types (L1-L5), making it the simplest neuropil in the optic lobe, yet how this diversity is generated was unknown. Here, we found that Hh pathway activity is graded along the distal-proximal axis of lamina columns, and further determined that this gradient in pathway activity arises from a gradient of Hh ligand. We manipulated Hh pathway activity cell autonomously in lamina precursors and non-cell autonomously by inactivating the Hh ligand and by knocking it down in photoreceptors. These manipulations showed that different thresholds of activity specify unique cell identities, with more proximal cell types specified in response to progressively lower Hh levels. Thus, our data establish that Hh acts as a morphogen to pattern the lamina. Although this is the first such report during Drosophila nervous system development, our work uncovers a remarkable similarity with the vertebrate neural tube, which is patterned by Sonic Hh. Altogether, we show that differentiating neurons can regulate the neuronal diversity of their distant target fields through morphogen gradients.

Asunto(s)

RESUMEN

The nervous system is one of the most sophisticated animal tissues, consisting of thousands of interconnected cell types. How the nervous system develops its diversity from a few neural stem cells remains a challenging question. Spatial and temporal patterning mechanisms provide an efficient model through which diversity can be generated. The molecular mechanism of spatiotemporal patterning has been studied extensively in Drosophila melanogaster, where distinct sets of transcription factors define the spatial domains and temporal windows that give rise to different cell types. Similarly, in vertebrates, spatial domains defined by transcription factors produce different types of neurons in the brain and neural tube. At the same time, different cortical neuronal types are generated within the same cell lineage with a specific birth order. However, we still do not understand how the orthogonal information of spatial and temporal patterning is integrated into the progenitor and post-mitotic cells to combinatorially give rise to different neurons. In this review, after introducing spatial and temporal patterning in Drosophila and mice, we discuss possible mechanisms that neural progenitors may use to integrate spatial and temporal information. We finally review the functional implications of spatial and temporal patterning and conclude envisaging how small alterations of these mechanisms can lead to the evolution of new neuronal cell types.

RESUMEN

Cellular diversity supports the computational capacity and flexibility of cortical circuits. Accordingly, principal neurons at the CA1 output node of the murine hippocampus are increasingly recognized as a heterogeneous population. Their genes, molecular content, intrinsic morpho-physiology, connectivity, and function seem to segregate along the main anatomical axes of the hippocampus. Since these axes reflect the temporal order of principal cell neurogenesis, we directly examined the relationship between birthdate and CA1 pyramidal neuron diversity, focusing on the ventral hippocampus. We used a genetic fate-mapping approach that allowed tagging three groups of age-matched principal neurons: pioneer, early-, and late-born. Using a combination of neuroanatomy, slice physiology, connectivity tracing, and cFos staining in mice, we show that birthdate is a strong predictor of CA1 principal cell diversity. We unravel a subpopulation of pioneer neurons recruited in familiar environments with remarkable positioning, morpho-physiological features, and connectivity. Therefore, despite the expected plasticity of hippocampal circuits, given their role in learning and memory, the diversity of their main components is also partly determined at the earliest steps of development.

Asunto(s)

RESUMEN

Understanding how neurons of the striatum are formed and integrate into complex synaptic circuits is essential to provide insight into striatal function in health and disease. In this review, we summarize our current understanding of the development of striatal neurons and associated circuits with a focus on their embryonic origin. Specifically, we address the role of distinct types of embryonic progenitors, found in the proliferative zones of the ganglionic eminences in the ventral telencephalon, in the generation of diverse striatal interneurons and projection neurons. Indeed, recent evidence would suggest that embryonic progenitor origin dictates key characteristics of postnatal cells, including their neurochemical content, their location within striatum, and their long-range synaptic inputs. We also integrate recent observations regarding embryonic progenitors in cortical and other regions and discuss how this might inform future research on the ganglionic eminences. Last, we examine how embryonic progenitor dysfunction can alter striatal formation, as exemplified in Huntington's disease and autism spectrum disorder, and how increased understanding of embryonic progenitors can have significant implications for future research directions and the development of improved therapeutic options.SIGNIFICANCE STATEMENT This review highlights recently defined novel roles for embryonic progenitor cells in shaping the functional properties of both projection neurons and interneurons of the striatum. It outlines the developmental mechanisms that guide neuronal development from progenitors in the embryonic ganglionic eminences to progeny in the striatum. Where questions remain open, we integrate observations from cortex and other regions to present possible avenues for future research. Last, we provide a progenitor-centric perspective onto both Huntington's disease and autism spectrum disorder. We suggest that future investigations and manipulations of embryonic progenitor cells in both research and clinical settings will likely require careful consideration of their great intrinsic diversity and neurogenic potential.

Asunto(s)

RESUMEN

For precise motor control, distinct subpopulations of corticospinal neurons (CSN) must extend axons to distinct spinal segments, from proximal targets in the brainstem and cervical cord to distal targets in thoracic and lumbar spinal segments. We find that developing CSN subpopulations exhibit striking axon targeting specificity in spinal white matter, which establishes the foundation for durable specificity of adult corticospinal circuitry. Employing developmental retrograde and anterograde labeling, and their distinct neocortical locations, we purified developing CSN subpopulations using fluorescence-activated cell sorting to identify genes differentially expressed between bulbar-cervical and thoracolumbar-projecting CSN subpopulations at critical developmental times. These segmentally distinct CSN subpopulations are molecularly distinct from the earliest stages of axon extension, enabling prospective identification even before eventual axon targeting decisions are evident in the spinal cord. This molecular delineation extends beyond simple spatial separation of these subpopulations in the cortex. Together, these results identify candidate molecular controls over segmentally specific corticospinal axon projection targeting.

Asunto(s)

RESUMEN

The cerebral cortex executes highly skilled movement, necessitating that it connects accurately with specific brainstem and spinal motor circuitry. Corticospinal neurons (CSN) must correctly target specific spinal segments, but the basis for this targeting remains unknown. In the accompanying report, we show that segmentally distinct CSN subpopulations are molecularly distinct from early development, identifying candidate molecular controls over segmentally specific axon targeting. Here, we functionally investigate two of these candidate molecular controls, Crim1 and Kelch-like 14 (Klhl14), identifying their critical roles in directing CSN axons to appropriate spinal segmental levels in the white matter prior to axon collateralization. Crim1 and Klhl14 are specifically expressed by distinct CSN subpopulations and regulate their differental white matter projection targeting-Crim1 directs thoracolumbar axon extension, while Klhl14 limits axon extension to bulbar-cervical segments. These molecular regulators of descending spinal projections constitute the first stages of a dual-directional set of complementary controls over CSN diversity for segmentally and functionally distinct circuitry.

Asunto(s)

RESUMEN

Midbrain dopaminergic (mDA) neurons are diverse in their projection targets, effect on behavior, and susceptibility to neurodegeneration. Little is known about the molecular mechanisms establishing this diversity during development. We show that the transcription factor BCL11A is expressed in a subset of mDA neurons in the developing and adult murine brain and in a subpopulation of pluripotent-stem-cell-derived human mDA neurons. By combining intersectional labeling and viral-mediated tracing, we demonstrate that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the murine dopaminergic system. In the substantia nigra, the Bcl11a-expressing mDA subset is particularly vulnerable to neurodegeneration upon α-synuclein overexpression or oxidative stress. Inactivation of Bcl11a in murine mDA neurons increases this susceptibility further, alters the distribution of mDA neurons, and results in deficits in skilled motor behavior. In summary, BCL11A defines mDA subpopulations with highly distinctive characteristics and is required for establishing and maintaining their normal physiology.

Asunto(s)