Jointly profiling the transcriptome, chromatin accessibility and other molecular properties of single cells offers a powerful way to study cellular diversity. Here we present MultiVI, a probabilistic ...model to analyze such multiomic data and leverage it to enhance single-modality datasets. MultiVI creates a joint representation that allows an analysis of all modalities included in the multiomic input data, even for cells for which one or more modalities are missing. It is available at scvi-tools.org .
Animals generate movement by engaging spinal circuits that direct precise sequences of muscle contraction, but the identity and organizational logic of local interneurons that lie at the core of ...these circuits remain unresolved. Here, we show that V1 interneurons, a major inhibitory population that controls motor output, fractionate into highly diverse subsets on the basis of the expression of 19 transcription factors. Transcriptionally defined V1 subsets exhibit distinct physiological signatures and highly structured spatial distributions with mediolateral and dorsoventral positional biases. These positional distinctions constrain patterns of input from sensory and motor neurons and, as such, suggest that interneuron position is a determinant of microcircuit organization. Moreover, V1 diversity indicates that different inhibitory microcircuits exist for motor pools controlling hip, ankle, and foot muscles, revealing a variable circuit architecture for interneurons that control limb movement.
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•V1 inhibitory interneurons exhibit extensive transcriptional heterogeneity•V1 subsets have stereotyped positions and divergent physiological properties•Interneuron settling position constrains neuronal input specificity•Distinct inhibitory circuits act on motor pools innervating proximo-distal muscles
Subsets of spinal inhibitory interneurons differ in position, electrophysiological properties, and synaptic connectivity, showing that inhibitory microcircuits are tailored to individual limb muscles.
One of the hallmarks of the cerebral cortex is the extreme diversity of interneurons
. The two largest subtypes of cortical interneurons, parvalbumin- and somatostatin-positive cells, are ...morphologically and functionally distinct in adulthood but arise from common lineages within the medial ganglionic eminence
. This makes them an attractive model for studying the generation of cell diversity. Here we examine how developmental changes in transcription and chromatin structure enable these cells to acquire distinct identities in the mouse cortex. Generic interneuron features are first detected upon cell cycle exit through the opening of chromatin at distal elements. By constructing cell-type-specific gene regulatory networks, we observed that parvalbumin- and somatostatin-positive cells initiate distinct programs upon settling within the cortex. We used these networks to model the differential transcriptional requirement of a shared regulator, Mef2c, and confirmed the accuracy of our predictions through experimental loss-of-function experiments. We therefore reveal how a common molecular program diverges to enable these neuronal subtypes to acquire highly specialized properties by adulthood. Our methods provide a framework for examining the emergence of cellular diversity, as well as for quantifying and predicting the effect of candidate genes on cell-type-specific development.
Space agencies have announced plans for human missions to the Moon to prepare for Mars. However, the space environment presents stressors that include radiation, microgravity, and isolation. ...Understanding how these factors affect biology is crucial for safe and effective crewed space exploration. There is a need to develop countermeasures, to adapt plants and microbes for nutrient sources and bioregenerative life support, and to limit pathogen infection. Scientists across the world are conducting space omics experiments on model organisms and, more recently, on humans. Optimal extraction of actionable scientific discoveries from these precious datasets will only occur at the collective level with improved standardization. To address this shortcoming, we established ISSOP (International Standards for Space Omics Processing), an international consortium of scientists who aim to enhance standard guidelines between space biologists at a global level. Here we introduce our consortium and share past lessons learned and future challenges related to spaceflight omics.
With the rise of commercial spaceflight and prospective human missions to Mars, a wider health range of humans will enter space for longer spans and at higher exposure to environmental stressors than ever before. Numerous adverse health effects have been observed in space, including bone demineralization and skeletal muscle atrophy, among others. Scientists across the world are conducting space omics studies to develop countermeasures for safe and effective crewed space missions. However, optimal extraction of scientific insight from such data is contingent on improved standardization. In response, we founded ISSOP (International Standards for Space Omics Processing), an international consortium of scientists who aim to enhance guidelines between space biologists globally. This paper informs scientists and data scientists from many fields about the challenges and future avenues of space omics and can serve as an introductory reference for new members in the space biology discipline.
Humans will be entering space for longer spans and at higher exposure to environmental stressors than ever before. Numerous adverse health effects have been observed in space, including bone demineralization and skeletal muscle atrophy. We have formed an international consortium of scientists who aim to develop better standardization guidelines of space biology (especially omics) data. Maximum extraction of scientific knowledge from these rare data can lead to countermeasures needed for safe and effective crewed space missions.
ATAC-seq has become a leading technology for probing the chromatin landscape of single and aggregated cells. Distilling functional regions from ATAC-seq presents diverse analysis challenges. Methods ...commonly used to analyze chromatin accessibility datasets are adapted from algorithms designed to process different experimental technologies, disregarding the statistical and biological differences intrinsic to the ATAC-seq technology. Here, we present a Bayesian statistical approach that uses latent space models to better model accessible regions, termed ChromA. ChromA annotates chromatin landscape by integrating information from replicates, producing a consensus de-noised annotation of chromatin accessibility. ChromA can analyze single cell ATAC-seq data, correcting many biases generated by the sparse sampling inherent in single cell technologies. We validate ChromA on multiple technologies and biological systems, including mouse and human immune cells, establishing ChromA as a top performing general platform for mapping the chromatin landscape in different cellular populations from diverse experimental designs.
Documenting the extent of cellular diversity is a critical step in defining the functional organization of tissues and organs. To infer cell-type diversity from partial or incomplete transcription ...factor expression data, we devised a sparse Bayesian framework that is able to handle estimation uncertainty and can incorporate diverse cellular characteristics to optimize experimental design. Focusing on spinal V1 inhibitory interneurons, for which the spatial expression of 19 transcription factors has been mapped, we infer the existence of ∼50 candidate V1 neuronal types, many of which localize in compact spatial domains in the ventral spinal cord. We have validated the existence of inferred cell types by direct experimental measurement, establishing this Bayesian framework as an effective platform for cell-type characterization in the nervous system and elsewhere.
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•Bayesian framework identifies cell types using a variety of information sources•Spinal V1 inhibitory interneurons are genetically diverse•Spinal V1 cell types cluster into localized spatial domains•Experimental validation confirms model predictions
A statistical approach based on limited protein expression data and neuronal position provides estimates of cell-type diversity, revealing some 50 discrete types of spinal V1 inhibitory interneurons.
The taste system is one of our fundamental senses, responsible for detecting and responding to sweet, bitter, umami, salty, and sour stimuli. In the tongue, the five basic tastes are mediated by ...separate classes of taste receptor cells each finely tuned to a single taste quality. We explored the logic of taste coding in the brain by examining how sweet, bitter, umami, and salty qualities are represented in the primary taste cortex of mice. We used in vivo two-photon calcium imaging to demonstrate topographic segregation in the functional architecture of the gustatory cortex. Each taste quality is represented in its own separate cortical field, revealing the existence of a gustotopic map in the brain. These results expose the basic logic for the central representation of taste.
Motor output varies along the rostro-caudal axis of the tetrapod spinal cord. At limb levels, ∼60 motor pools control the alternation of flexor and extensor muscles about each joint, whereas at ...thoracic levels as few as 10 motor pools supply muscle groups that support posture, inspiration, and expiration. Whether such differences in motor neuron identity and muscle number are associated with segmental distinctions in interneuron diversity has not been resolved. We show that select combinations of nineteen transcription factors that specify lumbar V1 inhibitory interneurons generate subpopulations enriched at limb and thoracic levels. Specification of limb and thoracic V1 interneurons involves the Hox gene Hoxc9 independently of motor neurons. Thus, early Hox patterning of the spinal cord determines the identity of V1 interneurons and motor neurons. These studies reveal a developmental program of V1 interneuron diversity, providing insight into the organization of inhibitory interneurons associated with differential motor output.
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•Two transcription factors define limb and thoracic inhibitory V1 interneurons•Computational model predicts and compares thoracic and limb V1 cell-type diversity•Motor neurons are not required for limb and thoracic interneuron specification•Hox genes specify interneuron identity in limb and thoracic spinal cord
Sweeney et al. show that the diversity of spinal inhibitory interneurons, defined by combinatorial transcription factor expression, differs along the body axis in correspondence with limb and thoracic motor output. Hox genes, not motor neurons, specify segmental differences in inhibitory interneuron identity.
Cortical neurons form specific circuits, but the functional structure of this microarchitecture and its relation to behaviour are poorly understood. Two-photon calcium imaging can monitor activity of ...spatially defined neuronal ensembles in the mammalian cortex. Here we applied this technique to the motor cortex of mice performing a choice behaviour. Head-fixed mice were trained to lick in response to one of two odours, and to withhold licking for the other odour. Mice routinely showed significant learning within the first behavioural session and across sessions. Microstimulation and trans-synaptic tracing identified two non-overlapping candidate tongue motor cortical areas. Inactivating either area impaired voluntary licking. Imaging in layer 2/3 showed neurons with diverse response types in both areas. Activity in approximately half of the imaged neurons distinguished trial types associated with different actions. Many neurons showed modulation coinciding with or preceding the action, consistent with their involvement in motor control. Neurons with different response types were spatially intermingled. Nearby neurons (within approximately 150 mum) showed pronounced coincident activity. These temporal correlations increased with learning within and across behavioural sessions, specifically for neuron pairs with similar response types. We propose that correlated activity in specific ensembles of functionally related neurons is a signature of learning-related circuit plasticity. Our findings reveal a fine-scale and dynamic organization of the frontal cortex that probably underlies flexible behaviour.
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