Abstract
Cerebellar malformations cause changes to the sleep-wake cycle, resulting in sleep disturbance. However, it is unclear how the cerebellum contributes to the sleep-wake cycle. To examine the neural connections between the cerebellum and the nuclei involved in the sleep-wake cycle, we investigated the axonal projections of Purkinje cells in the mouse posterior vermis by using an adeno-associated virus (AAV) vector (serotype rh10) as an anterograde tracer. When an AAV vector expressing humanized renilla green fluorescent protein was injected into the cerebellar lobule IX, hrGFP and synaptophysin double-positive axonal terminals were observed in the region of medial parabrachial nucleus (MPB). The MPB is involved in the phase transition from rapid eye movement (REM) sleep to Non-REM sleep and vice versa, and the cardiovascular and respiratory responses. The hrGFP-positive axons from lobule IX went through the ventral spinocerebellar tract and finally reached the MPB. By contrast, when the AAV vector was injected into cerebellar lobule VI, no hrGFP-positive axons were observed in the MPB. To examine neurons projecting to the MPB, we unilaterally injected Fast Blue and AAV vector (retrograde serotype, rAAV2-retro) as retrograde tracers into the MPB. The cerebellar Purkinje cells in lobules VIII–X on the ipsilateral side of the Fast Blue-injected MPB were retrogradely labeled by Fast Blue and AAV vector (retrograde serotype), but no retrograde-labeled Purkinje cells were observed in lobules VI–VII and the cerebellar hemispheres. These results indicated that Purkinje cells in lobules VIII–X directly project their axons to the ipsilateral MPB but not lobules VI–VII. The direct connection between lobules VIII–X and the MPB suggests that the cerebellum participates in the neural network controlling the sleep-wake cycle, and cardiovascular and respiratory responses, by modulating the physiological function of the MPB.
Highlights
The parabrachial nucleus is located in the surrounding region of the superior cerebellar peduncle and is divided into the dorsolateral region, the lateral parabrachial nucleus (LPB) and the ventromedial region, the medial parabrachial nucleus (MPB)
Using anterograde labeling with an associated virus (AAV) vector, AAV-CMVhrGFP, and retrograde labeling by Fast Blue and an AAV vector, AAV2retro-CAG-enhanced green fluorescent protein (EGFP), we found a direct connection between lobule IX of the mouse cerebellar vermis and the MPB
The direct connection between lobule IX and the MPB is a special neuronal circuit in the cerebellum, and this suggests that the cerebellum participates in regulating the sleep-wake cycle and the cardiovascular and respiratory responses by modulating the neural activity of the MPB
Summary
The parabrachial nucleus is located in the surrounding region of the superior cerebellar peduncle (scp) and is divided into the dorsolateral region, the lateral parabrachial nucleus (LPB) and the ventromedial region, the medial parabrachial nucleus (MPB). Purkinje cells in cerebellar lobule III, the lateral-most region of cerebellar lobule IX, and the flocculus (FL) directly project to the LPB, and are involved in the modulation of cardiovascular and Abbreviations: 3v, third ventricle; 4v, fourth ventricle; 7n, root of facial nucleus; Aq, aqueduct; cbc, cerebellar commissure; CGRP, calcitonin gene-related peptide; cont, contralateral; Cop, copula pyramidis; Crus, crus of ansiform lobule; Cu, cuneate nucleus; DMSp5, dorsomedial spinal trigeminal nucleus; DTg, dorsal tegmental nucleus; ECu, external cuneate nucleus; FL, flocculus; g7, genu of facial nucleus; Gi, gigantocellular reticular nucleus; GL, granular layers; hrGFP, humanized renilla green fluorescent protein; icp, inferior cerebellar peduncle; ipsi, ipsilateral; IntA, anterior interposed cerebellar nucleus; IntP, posterior interposed cerebellar nucleus; IO, inferior olive; Lat, lateral (dentate) cerebellar nucleus; LC, locus coeruleus; LPB, lateral parabrachial nucleus; LVe, lateral vestibular nucleus; LRt, lateral reticular nucleus; mcp, medial cerebellar peduncle; MdD, dorsal part of medullary reticular nucleus; MdV, ventral part of medullary reticular nucleus; Med, medial (fastigial) cerebellar nucleus; ML, molecular layer; Mo5, motor trigeminal nucleus; MPB, medial parabrachial nucleus; mscp, the medial-most region of superior cerebellar peduncle; MVe, medial vestibular nucleus; MVeMC, magnocellular part of medial vestibular nucleus; MVePC, parvocellular part of medial vestibular nucleus; Pa5, paratrigeminal nucleus; PAG, ventrolateral region of periaqueductal gray; PCGS, paracochlear glial substance; pcn, precentral fissure; pcuf, preculminate fissure; PCR, parvocellular reticular nucleus; PF, paraflocculus; plf, posterolateral fissure; Pn, pontine nucleus; PVN, paraventricular hypothalamic nucleus; ppf, prepyramidal fissure; Pr, prepositus nucleus; py, pyramidal tract; Pr5, principal sensory trigeminal nucleus; psf, posterior superior fissureRPC, parvocellular part of red nucleus; RVL, rostroventrolateral medulla; s5, sensory root of trigeminal nucleus; scp, superior cerebellar peduncle; sf, secondary fissure; Sol, nucleus of the solitary tract; Sp5C, caudal part of spinal trigeminal nucleus; SP5I, interpolar part of spinal trigeminal nucleus; spt, spinal trigeminal tract; SpVe, spinal vestibular nucleus; Su5, supratrigeminal nucleus; SuVe, superior vestibular nucleus; SYP, synaptophysin; TH, tyrosine hydroxylase; unc, uncinate fasciculus of cerebellum; VGLUT2, vesicular glutamate transporter 2; vsc, ventral spinocerebellar tract; XN, X nucleus
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