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Science (New York, N.Y.) Dec 2020How have complex brains evolved from simple circuits? Here we investigated brain region evolution at cell-type resolution in the cerebellar nuclei, the output structures...
How have complex brains evolved from simple circuits? Here we investigated brain region evolution at cell-type resolution in the cerebellar nuclei, the output structures of the cerebellum. Using single-nucleus RNA sequencing in mice, chickens, and humans, as well as STARmap spatial transcriptomic analysis and whole-central nervous system projection tracing, we identified a conserved cell-type set containing two region-specific excitatory neuron classes and three region-invariant inhibitory neuron classes. This set constitutes an archetypal cerebellar nucleus that was repeatedly duplicated to form new regions. The excitatory cell class that preferentially funnels information to lateral frontal cortices in mice becomes predominant in the massively expanded human lateral nucleus. Our data suggest a model of brain region evolution by duplication and divergence of entire cell-type sets.
Topics: Animals; Biological Evolution; Cerebellar Nuclei; Chickens; Female; Humans; Male; Mice; Mice, Inbred C57BL; Neurons; RNA-Seq
PubMed: 33335034
DOI: 10.1126/science.abd5059 -
Science (New York, N.Y.) Jan 2019The cerebellum has been implicated in a number of nonmotor mental disorders such as autism spectrum disorder, schizophrenia, and addiction. However, its contribution to...
The cerebellum has been implicated in a number of nonmotor mental disorders such as autism spectrum disorder, schizophrenia, and addiction. However, its contribution to these disorders is not well understood. In mice, we found that the cerebellum sends direct excitatory projections to the ventral tegmental area (VTA), one of the brain regions that processes and encodes reward. Optogenetic activation of the cerebello-VTA projections was rewarding and, in a three-chamber social task, these projections were more active when the animal explored the social chamber. Intriguingly, activity in the cerebello-VTA pathway was required for the mice to show social preference in this task. Our data delineate a major, previously unappreciated role for the cerebellum in controlling the reward circuitry and social behavior.
Topics: Animals; Axons; Behavior, Animal; Cerebellar Nuclei; Dopaminergic Neurons; Female; Male; Mice; Mice, Inbred C57BL; Optogenetics; Reward; Social Behavior; Synapses; Ventral Tegmental Area
PubMed: 30655412
DOI: 10.1126/science.aav0581 -
Neuroscience Dec 2020Dexterous forelimb movements like reaching, grasping, and manipulating objects are fundamental building blocks of the mammalian motor repertoire. These behaviors are... (Review)
Review
Dexterous forelimb movements like reaching, grasping, and manipulating objects are fundamental building blocks of the mammalian motor repertoire. These behaviors are essential to everyday activities, and their elaboration underlies incredible accomplishments by human beings in art and sport. Moreover, the susceptibility of these behaviors to damage and disease of the nervous system can lead to debilitating deficits, highlighting a need for a better understanding of function and dysfunction in sensorimotor control. The cerebellum is central to coordinating limb movements, as defined in large part by Joseph Babinski and Gordon Holmes describing motor impairment in patients with cerebellar lesions over 100 years ago (Babinski, 1902; Holmes, 1917), and supported by many important human and animal studies that have been conducted since. Here, with a focus on output pathways of the cerebellar nuclei across mammalian species, we describe forelimb movement deficits observed when cerebellar circuits are perturbed, the mechanisms through which these circuits influence motor output, and key challenges in defining how the cerebellum refines limb movement.
Topics: Animals; Cerebellar Nuclei; Cerebellum; Forelimb; Hand Strength; Humans; Movement
PubMed: 32652173
DOI: 10.1016/j.neuroscience.2020.06.046 -
Cerebellum (London, England) Dec 2011
Topics: Animals; Cerebellar Nuclei; Cerebellum; Humans; Purkinje Cells; Vestibular Nuclei
PubMed: 21279491
DOI: 10.1007/s12311-010-0245-y -
Signal Transduction and Targeted Therapy Jun 2022Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly...
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 mice. Together, these findings further suggest that specific regulation of the cerebellar IV/V lobe→ FN circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.
Topics: Animals; Ataxia; Cerebellar Nuclei; Mice; Neurons; Purkinje Cells
PubMed: 35641478
DOI: 10.1038/s41392-022-00989-x -
AJNR. American Journal of Neuroradiology Jan 2016
Topics: Cerebellar Nuclei; Contrast Media; Cranial Irradiation; Female; Gadolinium; Humans; Image Enhancement; Magnetic Resonance Imaging; Male
PubMed: 26494696
DOI: 10.3174/ajnr.A4608 -
The Journal of Physiology Jul 2011The microcircuitry of cerebellar cortex and, in particular, the physiology of its main element, the Purkinje neuron, has been extensively investigated and described.... (Review)
Review
The microcircuitry of cerebellar cortex and, in particular, the physiology of its main element, the Purkinje neuron, has been extensively investigated and described. However, activity in Purkinje neurons, either as single cells or populations, does not directly mediate the cerebellar effects on the motor effector systems. Rather, the result of the entire cerebellar cortical computation is passed to the relatively small cerebellar nuclei that act as the final, integrative processing unit in the cerebellar circuitry. The nuclei ultimately control the temporal and spatial features of the cerebellar output. Given this key role, it is striking that the internal organization and the connectivity with afferent and efferent pathways in the cerebellar nuclei are rather poorly known. In the present review, we discuss some of the many critical shortcomings in the understanding of cerebellar nuclei microcircuitry: the extent of convergence and divergence of the cerebellar cortical pathway to the various cerebellar nuclei neurons and subareas, the possible (lack of) conservation of the finely-divided topographical organization in the cerebellar cortex at the level of the nuclei, as well as the absence of knowledge of the synaptic circuitry within the cerebellar nuclei. All these issues are important for predicting the pattern-extraction and encoding capabilities of the cerebellar nuclei and, until resolved, theories and models of cerebellar motor control and learning may err considerably.
Topics: Animals; Cerebellar Cortex; Cerebellar Nuclei; Humans; Motor Activity; Neural Pathways; Purkinje Cells; Synaptic Potentials
PubMed: 21521761
DOI: 10.1113/jphysiol.2010.201582 -
Cell Reports Jan 2023Cerebellar-thalamo-striatal synaptic communication has been implicated in a wide range of behaviors, including goal-directed actions, and is altered in cerebellar...
Cerebellar-thalamo-striatal synaptic communication has been implicated in a wide range of behaviors, including goal-directed actions, and is altered in cerebellar dystonia. However, its detailed connectivity through the thalamus and its contribution to the execution of forelimb movements is unclear. Here, we use trans-synaptic and retrograde tracing, ex vivo slice recordings, and optogenetic inhibitions during the execution of unidirectional or sequential joystick displacements to demonstrate that the deep cerebellar nuclei (DCN) influence the dorsal striatum with a very high probability. We show that this mainly occurs through the centrolateral (CL), parafascicular (PF), and ventrolateral (VL) nuclei of the thalamus, observing that the DCN→VL and DCN→CL pathways contribute to the execution of unidirectional forelimb displacements while the DCN→PF and DCN→thalamo→striatal pathways contribute to the appropriate execution of forelimb reaching and sequential displacements. These findings highlight specific contributions of the different cerebellar-thalamo-striatal paths to the control of skilled forelimb movement.
Topics: Animals; Cerebellar Nuclei; Corpus Striatum; Thalamus; Cerebellum; Movement; Forelimb
PubMed: 36656714
DOI: 10.1016/j.celrep.2023.112000 -
Tremor and Other Hyperkinetic Movements... Oct 2020Patients with essential tremor, vocal tremor, torticollis, myoclonus-dystonia and posthypoxic myoclonus often benefit in a surprisingly rapid and robust manner from... (Review)
Review
Patients with essential tremor, vocal tremor, torticollis, myoclonus-dystonia and posthypoxic myoclonus often benefit in a surprisingly rapid and robust manner from ingestion of a modest amount of alcohol (ethanol). Despite considerable investigation, the mechanism of ethanol's ability to produce this effect remains a mystery. In this paper, we review the pharmacology of ethanol and its analogue GHB (or sodium oxybate), summarize the published literature of alcohol-responsive hyperkinetic movement disorders, and demonstrate videos of patients we have treated over the last fifteen years with either an ethanol challenge or with chronic sodium oxybate therapy. We then propose a novel explanation for this phenomenon-namely, that ingestion of doses of ethanol (or sodium oxybate) normalizes the aberrant motor networks underling these disorders. We propose that alcohol and its analogues improve clinical symptoms and their physiologic correlate by restoring the normal firing pattern of the major outflow pathways of the cerebellum (the Purkinje cells and deep cerebellar nuclei), We present evidence to support this hypothesis in animal models and in affected patients, and suggest future investigations to test this model.
Topics: Adjuvants, Anesthesia; Alcoholic Beverages; Animals; Behavior, Animal; Central Nervous System Depressants; Cerebellar Nuclei; Dystonic Disorders; Essential Tremor; Ethanol; Humans; Hypoxia, Brain; Movement Disorders; Myoclonus; Neural Pathways; Purkinje Cells; Sodium Oxybate; Torticollis; Voice Disorders
PubMed: 33178485
DOI: 10.5334/tohm.560 -
Input and output organization of the mesodiencephalic junction for cerebro-cerebellar communication.Journal of Neuroscience Research Feb 2022Most studies investigating the impact of the cerebral cortex (CC) onto the cerebellum highlight the role of the pons, which provides the mossy fibers to the cerebellum....
Most studies investigating the impact of the cerebral cortex (CC) onto the cerebellum highlight the role of the pons, which provides the mossy fibers to the cerebellum. However, cerebro-cerebellar communication may also be mediated by the nuclei of the mesodiencephalic junction (MDJ) that project to the inferior olive (IO), which in turn provides the climbing fibers to the molecular layer. Here, we uncover the precise topographic relations of the inputs and outputs of the MDJ using multiple, classical, and transneuronal tracing methods as well as analyses of mesoscale cortical injections from Allen Mouse Brain. We show that the caudal parts of the CC predominantly project to the principal olive via the rostral MDJ and that the rostral parts of the CC predominantly project to the rostral medial accessory olive via the caudal MDJ. Moreover, using triple viral tracing technology, we show that the cerebellar nuclei directly innervate the neurons in the MDJ that receive input from CC and project to the IO. By unraveling these topographic and prominent, mono- and disynaptic projections through the MDJ, this work establishes that cerebro-cerebellar communication is not only mediated by the pontine mossy fiber system, but also by the climbing fiber system.
Topics: Animals; Cerebellar Nuclei; Cerebellum; Medulla Oblongata; Mice; Neural Pathways; Neurons; Olivary Nucleus
PubMed: 34850425
DOI: 10.1002/jnr.24993