Neural organoids have the potential to improve our understanding of human brain development and neurological disorders. However, it remains to be seen whether these tissues can model circuit formation with functional neuronal output. Here, we have adapted air-liquid interface culture to cerebral organoids leading to improved neuronal survival and axon outgrowth. The resulting thick axon tracts display various morphologies including long-range projection within and away from the organoid, growth cone turning, and decussation. Single-cell RNA-sequencing reveals various cortical neuronal identities, and retrograde tracing demonstrates tract morphologies that match proper molecular identities. These cultures exhibit active neuronal networks, and extracortical projecting tracts can innervate mouse spinal cord and evoke contractions of adjacent muscle in a manner dependent on intact organoid-derived innervating tracts. Overall, these results reveal a remarkable self-organization of corticofugal and callosal tracts with a functional output, providing new opportunities to examine relevant aspects of human CNS development and disease.
Movement is the behavioral output of neuronal activity in the spinal cord. Motor neurons are grouped into motor neuron pools, the functional units innervating individual muscles. Here we establish an anatomical rabies virus-based connectivity assay in early postnatal mice. We employ it to study the connectivity scheme of premotor neurons, the neuronal cohorts monosynaptically connected to motor neurons, unveiling three aspects of organization. First, motor neuron pools are connected to segmentally widely distributed yet stereotypic interneuron populations, differing for pools innervating functionally distinct muscles. Second, depending on subpopulation identity, interneurons take on local or segmentally distributed positions. Third, cholinergic partition cells involved in the regulation of motor neuron excitability segregate into ipsilaterally and bilaterally projecting populations, the latter exhibiting preferential connections to functionally equivalent motor neuron pools bilaterally. Our study visualizes the widespread yet precise nature of the connectivity matrix for premotor interneurons and reveals exquisite synaptic specificity for bilaterally projecting cholinergic partition cells.
Walking is a key motor behaviour of limbed animals, executed by contraction of functionally antagonistic muscle groups during swing and stance phases. Nevertheless, neuronal circuits regulating the activation of antagonistic extensor-flexor muscles remain poorly understood. Here we use monosynaptically restricted trans-synaptic viruses to elucidate premotor anatomical substrates for extensor-flexor control in mice. We observe a medio-lateral spatial segregation between extensor and flexor premotor interneurons in the dorsal spinal cord. These premotor interneuron populations are derived from common progenitor domains, but segregate by timing of neurogenesis. We find that proprioceptive sensory feedback from the periphery is targeted to medial extensor premotor populations and is required for extensor-specific connectivity profiles during development. Our findings provide evidence for a discriminating anatomical basis of antagonistic circuits at the level of premotor interneurons, and point to synaptic input and developmental ontogeny as key factors in the establishment of circuits regulating motor behavioural dichotomy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.