Knowledge of connectivity in the nervous system is essential to understanding its function. Here we describe connectomes for both adult sexes of the nematode Caenorhabditis elegans, an important model organism for neuroscience research. We present quantitative connectivity matrices that encompass all connections from sensory input to end-organ output across the entire animal, information that is necessary to model behaviour. Serial electron microscopy reconstructions that are based on the analysis of both new and previously published electron micrographs update previous results and include data on the male head. The nervous system differs between sexes at multiple levels. Several sex-shared neurons that function in circuits for sexual behaviour are sexually dimorphic in structure and connectivity. Inputs from sex-specific circuitry to central circuitry reveal points at which sexual and non-sexual pathways converge. In sex-shared central pathways, a substantial number of connections differ in strength between the sexes. Quantitative connectomes that include all connections serve as the basis for understanding how complex, adaptive behavior is generated.

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SummaryNervous systems are constructed from a deep repertoire of neuron types but the underlying gene expression programs that specify individual neuron identities are poorly understood. To address this deficit, we have produced an expression profile of all 302 neurons of the C. elegans nervous system that matches the single cell resolution of its anatomy and wiring diagram. Our results suggest that individual neuron classes can be solely identified by combinatorial expression of specific gene families. For example, each neuron class expresses unique codes of ∼23 neuropeptide-encoding genes and ∼36 neuropeptide receptors thus pointing to an expansive “wireless” signaling network. To demonstrate the utility of this uniquely comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression across the nervous system and (2) reveal adhesion proteins with potential roles in synaptic specificity and process placement. These data are available at cengen.org and can be interrogated at the web application CengenApp. We expect that this neuron-specific directory of gene expression will spur investigations of underlying mechanisms that define anatomy, connectivity and function throughout the C. elegans nervous system.

A fluorescent biosensor reports the localization of CDC-42 activity in the C. elegans embryo and was used to identify regulators of CDC-42 activity, one of which is involved in a novel regulatory loop that maintains cortical PAR polarity. CDC-42 activity regulates myosin II recruitment during the maintenance phase via the kinase MRCK-1.

Sex differences in behaviour extend to cognitive-like processes such as learning but the underlying dimorphisms in neural circuit development and organization that generate these behavioural differences are largely unknown. Here we define at the single-cell level, from development, through neural circuit connectivity, to function, the neural basis of a sex-specific learning in the nematode C. elegans. We show that sexual conditioning, a form of associative learning, requires a pair of male-specific interneurons whose progenitors are fully differentiated glia. These neurons are born during sexual maturation and incorporated into pre-exisiting sex-shared circuits to couple chemotactic responses to reproductive priorities. Our findings reveal a general role for glia as neural progenitors across metazoan taxa and demonstrate that the addition of sex-specific neuron types to brain circuits during sexual maturation is an important mechanism for the generation of sexually dimorphic plasticity in learning.

A single neuron and its synapses define the fundamental structural motif of the brain but the underlying gene expression programs that specify individual neuron types are poorly understood.To address this question in a model organism, we have produced a gene expression profile of >90% of the individual neuron classes in the C. elegans nervous system, an ensemble of neurons for which both the anatomy and connectivity are uniquely defined at single cell resolution. We generated single cell transcriptomes for 52,412 neurons that resolve as clusters corresponding to 109 of the canonical 118 neuron classes in the mature hermaphrodite nervous system. Detailed analysis revealed molecular signatures that further subdivide identified classes into specific neuronal subtypes. Notably, neuropeptide-related genes are often differentially expressed between subtypes of the given neuron class which points to distinct functional characteristics.All of these data are publicly available at our website (http://www.cengen.org) and can be interrogated at the web application SCeNGEA (https://cengen.shinyapps.io/SCeNGEA). We expect that this gene expression catalog will spur the goal of delineating the underlying mechanisms that define the developmental lineage, detailed anatomy, synaptic connectivity and function of each type of C. elegans neuron.

Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.endocytic trafficking | survival motor neuron | spinal muscular atrophy | C. elegans | infection S pinal muscular atrophy (SMA) is one of the most severe neuromuscular diseases of childhood, with an incidence of 1 in 10,000 live births and a high carrier frequency of roughly 1 in 40 Caucasians (1-3). SMA is caused by reduced levels of the ubiquitously expressed survival of motor neuron (SMN) protein and results in degeneration of α-spinal cord motor neurons, muscle weakness, and/or death. Two human genes encode the SMN protein, SMN1 and SMN2. SMA alleles arise at relatively high frequency due to small intrachromosomal de novo rearrangements including the SMN1 locus (4). Patients often carry homozygous SMN1 deletions, although missense and nonsense alleles exist (5). Multiple copies of SMN2 rarely compensate for loss of SMN1 due to a C > T nucleotide change in SMN2 exon 7 that perturbs pre-mRNA splicing and results in a truncated protein of diminished function and stability (SMNΔ7) (5-9).SMN has numerous roles and interacts with various proteins, yet it remains unclear which interactions are most pertinent to SMA pathogenesis. As a component of the Gemin complex, SMN is required for biogenesis of small nuclear ribonucleoprotein (snRNP) particles critical for pre-mRNA splicing (10-12). Furthermore, SMN is needed for stress granule formation (13,14), is found in RNP granules moving through neuronal processes, and is part of RNP complexes implicated in synaptic local translation (15)(16)(17)(18)(19)(20). Additional roles for SMN, in transcription (21), in the PTEN-mediated protein synthesis pathway (22), in translational control (23), and in cell proliferation/differentiation (24), have been described. Importantly, no consensus has been reached regarding the cellular and molecular pathways wh...

This is a repository copy of A multi-scale brain map derived from whole-brain volumetric reconstructions.