Dataset Information

BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination.

ABSTRACT: Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly understood. Through cell-type-specific manipulations, we discovered a novel GABAergic Purkinje cell (PC) circuit in the cerebellar IV/V lobe that projected to CaMKIIα⁺ neurons in the fastigial nucleus (FN), which regulated sensorimotor coordination. Furthermore, transcriptomics profiling analysis revealed various cerebellar neuronal identities, and we validated that biorientation defective 1 (BOD1) played an important role in the circuit of IV/V lobe to FN. BOD1 deficit in PCs of IV/V lobe attenuated the excitability and spine density of PCs, accompany with ataxia behaviors. Instead, BOD1 enrichment in PCs of IV/V lobe reversed the hyperexcitability of CaMKIIα⁺ neurons in the FN and ameliorated ataxia behaviors in L7-Cre; BOD1^f/f mice. Together, these findings further suggest that specific regulation of the cerebellar IV/V lobe^PCs→ FN^CaMKIIα+ circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.

SUBMITTER: Liu XX

PROVIDER: S-EPMC9156688 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination.

Liu Xiu-Xiu XX Chen Xing-Hui XH Zheng Zhi-Wei ZW Jiang Qin Q Li Chen C Yang Lin L Chen Xiang X Mao Xing-Feng XF Yuan Hao-Yang HY Feng Li-Li LL Jiang Quan Q Shi Wei-Xing WX Sasaki Takuya T Fukunaga Kohji K Chen Zhong Z Han Feng F Lu Ying-Mei YM

Signal transduction and targeted therapy 20220601 1

Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly understood. Through cell-type-specific manipulations, we discovered a novel GABAergic Purkinje cell (PC) circuit in the cerebellar IV/V lobe that projected to CaMKIIα<sup>+</sup> neurons in the fastigial nucleus (FN), which regulated sensorimotor coordination. Furthermore, transcriptomics profiling analysis revealed various cere ...[more]

PMID: 35641478

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Project description:BackgroundElectrical stimulation of the cerebellar fastigial nucleus (FNS) has been shown to protect animals against cerebral ischemic injury. However, the changes in cortical activation as a response to FNS have not been illustrated in humans.ObjectiveThis study aims to detect functional connectivity changes in the brain of stroke patients, and investigate the cortical activation caused by FNS through measuring the oxygenated hemoglobin concentration (HBO) in the cerebral cortex of stroke patients and healthy controls (HCs).MethodsThis study recruited 20 patients with stroke and 20 HCs with all the following factors matched: age, gender and BMI. The experiment session was made up of the pre-task baseline, FNS task period, and post-task baseline. FNS task period contains 5 blocks, each block encompassing the resting state (30 s) and the FNS state (30 s). HBO signals were acquired by functional near-infrared spectroscopy (fNIRS) from the Prefrontal Cortex (PFC), the Motor Cortex (MC) and the Occipital Cortex (OC) throughout the experiment. The Pearson correlation coefficient was used to calculate the resting-state functional connectivity strength between the two groups, and the general linear model (GLM) was used to calculate the activation of 39 fNIRS channels during FNS in stroke patients and HCs, respectively.ResultsThe coupling strength of stroke patients were significantly decreased in the following regions: right MC and left MC (t = 4.65, p = 0.0007), right MC and left OC (t = 2.93, p = 0.04), left MC and left OC (t = 2.81, p = 0.04). In stroke patients, the changes in cerebral oxygenated hemoglobin (ΔHBO) among 12 channels (CH) in the bilateral PFC and bilateral MC regions were significantly increased during the FNS state (FDR corrected p < 0.05) compared with the resting state. In HCs, only 1 channel was increased (FDR corrected p < 0.05) in the left PFC during FNS.ConclusionBy using the FNS and fNIRS techniques, the characteristics of functional connectivity were found to decrease in stroke patients. It was also noticed that FNS activates the PFC and MC regions. These findings may help to guide functional rehabilitation in stroke patients.

Project description:Despite being canonically considered a motor control structure, the cerebellum is increasingly recognized for important roles in processes beyond this traditional framework, including seizure suppression. Excitatory fastigial neurons project to a large number of downstream targets, and it is unclear whether this broad targeting underlies seizure suppression, or whether a specific output may be sufficient. To address this question, we used the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, male and female animals, and a dual-virus approach to selectively label and manipulate fastigial outputs. We examined fastigial neurons projecting to the superior colliculus, medullary reticular formation, and central lateral nucleus of the thalamus, and found that these comprise largely nonoverlapping populations of neurons that send collaterals to unique sets of additional, somewhat overlapping, thalamic and brainstem regions. We found that neither optogenetic stimulation of superior colliculus nor reticular formation output channels attenuated hippocampal seizures. In contrast, on-demand stimulation of fastigial neurons targeting the central lateral nucleus robustly inhibited seizures. Our results indicate that fastigial control of hippocampal seizures does not require simultaneous modulation of many fastigial output channels. Rather, selective modulation of the fastigial output channel to the central lateral thalamus, specifically, is sufficient for seizure control. More broadly, our data highlight the concept of specific cerebellar output channels, whereby discrete cerebellar nucleus neurons project to specific aggregates of downstream targets, with important consequences for therapeutic interventions.SIGNIFICANCE STATEMENT The cerebellum has an emerging relationship with nonmotor systems and may represent a powerful target for therapeutic intervention in temporal lobe epilepsy. We find, as previously reported, that fastigial neurons project to numerous brain regions via largely segregated output channels, and that projection targets cannot be predicted simply by somatic locations within the nucleus. We further find that on-demand optogenetic excitation of fastigial neurons projecting to the central lateral nucleus of the thalamus-but not fastigial neurons projecting to the reticular formation, superior colliculus, or ventral lateral thalamus-is sufficient to attenuate hippocampal seizures.

Dataset Information

BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination.

Publications

BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination.

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