Dataset Information

Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis.

ABSTRACT: The cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output neurons in the mouse fastigial (medial cerebellar) nucleus, we identify five major classes of glutamatergic projection neurons distinguished by gene expression, morphology, distribution, and input-output connectivity. Each fastigial cell type is connected with a specific set of Purkinje cells and inferior olive neurons and in turn innervates a distinct collection of downstream targets. Transsynaptic tracing indicates extensive disynaptic links with cognitive, affective, and motor forebrain circuits. These results indicate that diverse cerebellar vermis functions could be mediated by modular synaptic connections of distinct fastigial cell types with posturomotor, oromotor, positional-autonomic, orienting, and vigilance circuits.

SUBMITTER: Fujita H

PROVIDER: S-EPMC7438114 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis.

Fujita Hirofumi H Kodama Takashi T du Lac Sascha S

eLife 20200708

The cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output neurons in the mouse fastigial (medial cerebellar) nucleus, we identify five major classes of glu ...[more]

PMID: 32639229

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Project description:Background Electrical 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. Objective This 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). Methods This 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. Results The 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. Conclusion By 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

Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis.

Publications

Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis.

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