Open Frontiers in Neural Cell Type Investigations; Lessons From Caenorhabditis elegans and Beyond, Toward a Multimodal Integration

Nervous system cells, the building blocks of circuits, have been studied with ever-progressing resolution, yet neural circuits appear still resistant to schemes of reductionist classification. Due to their sheer numbers, complexity and diversity, their systematic study requires concrete classifications that can serve reduced dimensionality, reproducibility, and information integration. Conventional hierarchical schemes transformed through the history of neuroscience by prioritizing criteria of morphology, (electro)physiological activity, molecular content, and circuit function, influenced by prevailing methodologies of the time. Since the molecular biology revolution and the recent advents in transcriptomics, molecular profiling gains ground toward the classification of neurons and glial cell types. Yet, transcriptomics entails technical challenges and more importantly uncovers unforeseen spatiotemporal heterogeneity, in complex and simpler nervous systems. Cells change states dynamically in space and time, in response to stimuli or throughout their developmental trajectory. Mapping cell type and state heterogeneity uncovers uncharted terrains in neurons and especially in glial cell biology, that remains understudied in many aspects. Examining neurons and glial cells from the perspectives of molecular neuroscience, physiology, development and evolution highlights the advantage of multifaceted classification schemes. Among the amalgam of models contributing to neuroscience research, Caenorhabditis elegans combines nervous system anatomy, lineage, connectivity and molecular content, all mapped at single-cell resolution, and can provide valuable insights for the workflow and challenges of the multimodal integration of cell type features. This review reflects on concepts and practices of neuron and glial cells classification and how research, in C. elegans and beyond, guides nervous system experimentation through integrated multidimensional schemes. It highlights underlying principles, emerging themes, and open frontiers in the study of nervous system development, regulatory logic and evolution. It proposes unified platforms to allow integrated annotation of large-scale datasets, gene-function studies, published or unpublished findings and community feedback. Neuroscience is moving fast toward interdisciplinary, high-throughput approaches for combined mapping of the morphology, physiology, connectivity, molecular function, and the integration of information in multifaceted schemes. A closer look in mapped neural circuits and understudied terrains offers insights for the best implementation of these approaches.