Abstract
The neural network, including the interstitial nucleus of Cajal (INC), functions as an oculomotor neural integrator involved in the control of vertical gaze holding. Impairment of the vestibulocerebellum (VC), including the flocculus (FL), has been shown to affect vertical gaze holding, indicating that the INC cooperates with the VC in controlling this function. However, a network between the INC and VC has not been identified. In this study, we aimed to obtain anatomical evidence of a neural pathway from the INC to the VC (the INC-VC pathway) in rats. Injection of dextran-conjugated Alexa 488 or adeno-associated virus 2-retro (AAV2retro) expressing GFP into the FL or another VC region (uvula/nodulus) did not reveal any retrogradely labeled neurons in the INC, suggesting that INC neurons do not project directly to the VC. Rabies virus-based transsynaptic tracing experiments revealed that the INC-VC pathway is mediated via synaptic connections with the prepositus hypoglossi nucleus (PHN) and medial vestibular nucleus (MVN). The INC neurons in the INC-VC pathway were mainly localized bilaterally within the rostral region of the INC. Transsynaptic tracing experiments involving the INC-FL pathway revealed that INC neurons connected to the FL via the bilateral PHN and MVN. These results indicate that the INC-VC pathway is not a direct pathway but is mediated via the PHN and MVN. These findings can provide clues for understanding the network mechanisms responsible for vertical gaze holding.
Significance Statement Gaze holding is crucial for achieving clear vision. However, the mechanism underlying vertical gaze holding is not fully understood owing to our limited knowledge of the neural connections between the interstitial nucleus of Cajal (INC) and the vestibulocerebellum (VC). In this study, we aimed to identify the neural pathway from the INC to the VC. Retrograde tract-tracing experiments using tracers and viruses revealed that INC neurons do not directly project to the VC; rather, the pathway from the INC to the VC is mediated via synaptic connections with the PHN and MVN. This finding clarifies a new indirect pathway from the INC to the VC that is responsible for vertical gaze holding.
Footnotes
Author Contributions: T.S. and Y.S. designed research; T.S., T.M., M.Y. and K.K. performed research; T.S. analyzed data; T.S., Y.Y. and Y.S. wrote the paper.
We thank the members of our laboratory for their technical assistance and comments. We also thank the staff of the Institutes of Experimental Animal Research at Nara Medical University for their technical support.
The authors declare that they have no competing financial interests.
This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (22K15229 to T.S.) and the Cooperative Study Program (22NIPS126, 23NIPS125) of the National Institute for Physiological Sciences.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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