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Developmental biology - Brain Function

Mapping nerve connections from brain-to-spinal cord

A new study has mapped mouse spinal nerves, and will now attempt developing new strategies to overcome spinal cord injuries and stroke...


In order to help people suffering from paralysis after spinal cord injuries, researchers mapped critical brain-to-spinal cord nerve connections that drive voluntary movement in mouse forelimbs. Yutaka Yoshida PhD, and colleagues at Cincinnati Children's Hospital Medical Center made this effort to help motor function recovery after damage to the central nervous system. Their work appears in Cell Reports.
"The map study should allow us to explore which cortico-spinal interneuron connections are good targets for repair and restoration of voluntary movement. More research is necessary before human therapies are possible, but this information is very helpful. We now know which circuits need to be repaired."

Yutaka Yoshida PhD, Assistant Professor, Department of Pediatrics, Division of Developmental Biology, University of Cincinnati, Ohio.

However, the scientists believe it will take more years of investigative work to make certain the current findings are therapeutically relevant. So, they are conducting more studies to build on this newly identified basic neural architecture.

The Schematics of Corticospinal Connections

Little has been known about how the corticospinal network of nerves between the brain and spinal cord are organized or function together. Simple tasks like reaching or grabbing require precise coordination between sensory and motor responses transmitted through neuronal connections. To map this connectivity, scientists studied these circuits in laboratory mice taking advantage of the similarity between corticospinal connections in primates, cats, and rodents.
Working from previous studies by his team and others, Yoshida and colleagues traced corticospinal connections from the cerebral cortex near the top of the head, down through the spinal cord. They also traced through mouse genetics, how corticospinal circuits connections are organized and function, with a viral tracer (a de-armed rabies virus) that allowed them to capture images of these links.

Connections traced through the brain's internal capsule, arrive at the caudal medulla of the brain just above the spinal cord. From there they enter the spinal cord, crisscrossing deep inside the spine as they continue to extend downward making more connections.

In his paper, Yoshida explains how his team was able to map corticospinal neurons controlling sensory nerve impulses, while also identifying neurons that affect finely tuned muscular response. In such areas, scientists saw how nerve fibers connect with certain premotor interneurons to transmit impulses to neurons triggering fine muscular responses. This includes nerve fibers that express a transcription factor called Chx10 a regulator gene which initiates the turning "on" or "off" of finely tuned muscular response. Chx10 is linked to nervous system function in areas such as the eyes. When researchers silenced (turned off) Chx10 in the cervical spinal cord, an animals' ability to reach for food became impaired.

The Importance of How We Sense

The map also highlights connections between the cortex and corticospinal neurons which control an animals' ability to sense and convert external stimuli into electrical impulses. This in contrast to corticospinal neurons in the motor cortex that directly trigger specific skilled movements. Corticospinal neurons in the sensory cortex do not connect directly to premotor neurons. Instead, they connect directly to other spinal interneurons that turn on a gene called Vglut3. When scientists inhibited neurons in the cervical spinal cord expressing Vglut3, it caused difficulty in an animals' ability to grab and release food pellets a goal-oriented task.

Highlights
Mouse CS axons from motor and sensory cortices project to distinct spinal regions
We map connectivity between CS neurons and various spinal interneurons
CS neurons in motor cortex control reaching via spinal Chx10+ interneurons
CS neurons in sensory cortex control food release via spinal Vglut3+ interneurons

Summary
Little is known about the organizational and functional connectivity of the corticospinal (CS) circuits that are essential for voluntary movement. Here, we map the connectivity between CS neurons in the forelimb motor and sensory cortices and various spinal interneurons, demonstrating that distinct CS-interneuron circuits control specific aspects of skilled movements. CS fibers originating in the mouse motor cortex directly synapse onto premotor interneurons, including those expressing Chx10. Lesions of the motor cortex or silencing of spinal Chx10+ interneurons produces deficits in skilled reaching. In contrast, CS neurons in the sensory cortex do not synapse directly onto premotor interneurons, and they preferentially connect to Vglut3+ spinal interneurons. Lesions to the sensory cortex or inhibition of Vglut3+ interneurons cause deficits in food pellet release movements in goal-oriented tasks. These findings reveal that CS neurons in the motor and sensory cortices differentially control skilled movements through distinct CS-spinal interneuron circuits.

Authors: Masaki Ueno, Yuka Nakamura, Jie Li, Zirong Gu, Jesse Niehaus, Mari Maezawa, Steven A. Crone, Martyn Goulding, Mark L. Baccei, Yutaka Yoshida. The authors declare no competing interests.


Thank you to L. Enquist and the Center for Neuroanatomy with Neurotropic Viruses (CNNV; NIH grant P40RR018604) at Princeton University for providing PRVs; E. Callaway for rabies viruses; A. Joyner, C. Wright, A. Pierani, Y. Nakagawa, L. Sussel, R. Johnson, A. Kania, J. Robbins, and G. Feng for providing mice; J. Martin, N. Serradj, and J. Kalambogias (CUNY School of Medicine) for instruction on ICMS; K. Katayama, F. Imai, P. Thanh, A. Epstein, and M. Sandy (CCHMC) for their technical assistance; M. Masujima (NRIFS) for helping with heatmap analyses; M. Kamoshita, J. Ito (Azabu Univ), X. Sun (CCHMC), and T. Daikoku (Kanazawa University) for help in sperm cryopreservation; T. Yamashita (Osaka University), K. Shibuki, and O. Onodera (Niigata University) for supporting materials; and J. Martin for critical reading of the manuscript. This work was supported by NINDS-NS093002 (Y.Y.); PRESTO (JST; JPMJPR13M8); JSPS KAKENHI 17H04985, 17H05556, and 17K19443; JSPS Postdoctoral Fellowships for Research Abroad; the KANAE Foundation for the Promotion of Medical Science; the Kato Memorial Bioscience Foundation; Grant-in-Aid from the Tokyo Biochemical Research Foundation; the Narishige Neuroscience Research Foundation; and a Japan Heart Foundation Research Grant (M.U.).

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May 18, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




This microscopic image shows corticospinal neurons and synaptic connections to the spinal cord in a mouse. Spinal interneurons (blue) show synaptic connections (in green) with corticospinal axons (red). Researchers report in Cell Reports the mapping of critical nerve connections to the spine that drive voluntary movement in forelimbs. The gridlines allow scientists to plot neuron locations along the spinal cord. Information useful to specific repair strategies for stroke and spinal cord injury.


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