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Nature Neuroscience Feb 2024
Topics: Cerebellum; Organoids
PubMed: 38326430
DOI: 10.1038/s41593-024-01583-w -
Neuron Aug 2023Information transmission between neural populations could occur through either coordinated changes in firing rates or the precise transmission of spike timing. We...
Information transmission between neural populations could occur through either coordinated changes in firing rates or the precise transmission of spike timing. We investigate the code for information transmission from a part of the cerebellar cortex that is crucial for the accurate execution of a quantifiable motor behavior. Simultaneous recordings from Purkinje cell pairs in the cerebellum of rhesus macaques reveal how these cells coordinate their activity to drive smooth pursuit eye movements. Purkinje cells show millisecond-scale coordination of spikes (synchrony), but the level of synchrony is small and insufficient to impact the firing of downstream vestibular nucleus neurons. Analysis of previous metrics that purported to reveal Purkinje cell synchrony demonstrates that these metrics conflate changes in firing rate and neuron-neuron covariance. We conclude that the output of the cerebellar cortex uses primarily a rate rather than a synchrony code to drive the activity of downstream neurons and thus control motor behavior.
Topics: Animals; Macaca mulatta; Cerebellum; Purkinje Cells; Neurons; Pursuit, Smooth; Action Potentials
PubMed: 37536289
DOI: 10.1016/j.neuron.2023.07.002 -
JCI Insight Oct 2023BACKGROUNDThe locus coeruleus (LC) is the primary source of norepinephrine in the brain and regulates arousal and sleep. Animal research shows that it plays important...
BACKGROUNDThe locus coeruleus (LC) is the primary source of norepinephrine in the brain and regulates arousal and sleep. Animal research shows that it plays important roles in the transition between sleep and wakefulness, and between slow wave sleep and rapid eye movement sleep (REMS). It is unclear, however, whether the activity of the LC predicts sleep variability in humans.METHODSWe used 7-Tesla functional MRI, sleep electroencephalography (EEG), and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 33 healthy younger (~22 years old; 28 women, 5 men) and 19 older (~61 years old; 14 women, 5 men) individuals.RESULTSWe found that, in older but not in younger participants, higher LC activity, as probed during an auditory attentional task, was associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS. The results remained robust even when accounting for the age-related changes in the integrity of the LC.CONCLUSIONThese findings suggest that LC activity correlates with the perception of the sleep quality and an essential oscillatory mode of REMS, and we found that the LC may be an important target in the treatment of sleep- and age-related diseases.FUNDINGThis work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, T.0242.19 & J. 0222.20), Action de Recherche Concertée - Fédération Wallonie-Bruxelles (ARC SLEEPDEM 17/27-09), Fondation Recherche Alzheimer (SAO-FRA 2019/0025), ULiège, and European Regional Development Fund (Radiomed & Biomed-Hub).
Topics: Male; Animals; Humans; Female; Aged; Young Adult; Adult; Middle Aged; Sleep, REM; Locus Coeruleus; Wakefulness; Sleep Quality; Sleep
PubMed: 37698926
DOI: 10.1172/jci.insight.172008 -
Cerebellum (London, England) Oct 2023The cerebellum plays an important role in movement disorders, specifically in symptoms of ataxia, tremor, and dystonia. Understanding the physiological signals of the... (Review)
Review
The cerebellum plays an important role in movement disorders, specifically in symptoms of ataxia, tremor, and dystonia. Understanding the physiological signals of the cerebellum contributes to insights into the pathophysiology of these movement disorders and holds promise in advancing therapeutic development. Non-invasive techniques such as electroencephalogram and magnetoencephalogram can record neural signals with high temporal resolution at the millisecond level, which is uniquely suitable to interrogate cerebellar physiology. These techniques have recently been implemented to study cerebellar physiology in healthy subjects as well as individuals with movement disorders. In the present review, we focus on the current understanding of cerebellar physiology using these techniques to study movement disorders.
Topics: Humans; Movement Disorders; Cerebellum; Tremor; Cerebellar Ataxia; Dystonic Disorders
PubMed: 36070135
DOI: 10.1007/s12311-022-01473-6 -
Science Advances Apr 2024Temporally coordinated neural activity is central to nervous system function and purposeful behavior. Still, there is a paucity of evidence demonstrating how this...
Temporally coordinated neural activity is central to nervous system function and purposeful behavior. Still, there is a paucity of evidence demonstrating how this coordinated activity within cortical and subcortical regions governs behavior. We investigated this between the primary motor (M1) and contralateral cerebellar cortex as rats learned a neuroprosthetic/brain-machine interface (BMI) task. In neuroprosthetic task, actuator movements are causally linked to M1 "direct" neurons that drive the decoder for successful task execution. However, it is unknown how task-related M1 activity interacts with the cerebellum. We observed a notable 3 to 6 hertz coherence that emerged between these regions' local field potentials (LFPs) with learning that also modulated task-related spiking. We identified robust task-related indirect modulation in the cerebellum, which developed a preferential relationship with M1 task-related activity. Inhibiting cerebellar cortical and deep nuclei activity through optogenetics led to performance impairments in M1-driven neuroprosthetic control. Together, these results demonstrate that cerebellar influence is necessary for M1-driven neuroprosthetic control.
Topics: Animals; Rats; Cerebellum; Brain-Computer Interfaces; Cell Nucleus; Learning; Movement
PubMed: 38608024
DOI: 10.1126/sciadv.adm8246 -
Cerebellum (London, England) Dec 2023In 1967, Andén, Fuxe, and Ungerstedt demonstrated the presence of monoamine-containing fibers in the rat cerebellum. Over the past 50 years, this finding has provided...
In 1967, Andén, Fuxe, and Ungerstedt demonstrated the presence of monoamine-containing fibers in the rat cerebellum. Over the past 50 years, this finding has provided clinical relevance of the noradrenergic system to the cerebellum. Cerebellar dysfunction and noradrenergic system may relate to tremor in Parkinson disease and essential tremor, motor learning, and the vestibulo-ocular reflex in spinocerebellar ataxias. Cognition and emotion may also be linked to the cerebellar noradrenergic system, in relation to the symptoms of Alzheimer disease, dementia with Lewy bodies, and attention-deficit/hyperactivity disorder. Despite recent technological advances in neuroimaging for evaluating the noradrenergic system, we need more evidence to understand the precise pathophysiological relationship between the cerebellum and the noradrenergic system and its clinical implications.
Topics: Rats; Animals; Cerebellum; Norepinephrine; Cerebellar Diseases; Tremor; Parkinson Disease
PubMed: 36149525
DOI: 10.1007/s12311-022-01479-0 -
Science (New York, N.Y.) Jul 2023Canonically, each Purkinje cell (PC) in the adult cerebellum receives only one climbing fiber (CF) from the inferior olive. Underlying current theories of cerebellar...
Canonically, each Purkinje cell (PC) in the adult cerebellum receives only one climbing fiber (CF) from the inferior olive. Underlying current theories of cerebellar function is the notion that this highly conserved one-to-one relationship renders Purkinje dendrites into a single computational compartment. However, we discovered that multiple primary dendrites are a near-universal morphological feature in humans. Using tract tracing, immunolabeling, and in vitro electrophysiology, we found that in mice ~25% of mature multibranched cells receive more than one CF input. Two-photon calcium imaging in vivo revealed that separate dendrites can exhibit distinct response properties to sensory stimulation, indicating that some multibranched cells integrate functionally independent CF-receptive fields. These findings indicate that PCs are morphologically and functionally more diverse than previously thought.
Topics: Animals; Humans; Mice; Axons; Dendrites; Purkinje Cells; Synapses
PubMed: 37499000
DOI: 10.1126/science.adi1024 -
Neuron Mar 2024The coupling between Ca channels and release sensors is a key factor defining the signaling properties of a synapse. However, the coupling nanotopography at many...
The coupling between Ca channels and release sensors is a key factor defining the signaling properties of a synapse. However, the coupling nanotopography at many synapses remains unknown, and it is unclear how it changes during development. To address these questions, we examined coupling at the cerebellar inhibitory basket cell (BC)-Purkinje cell (PC) synapse. Biophysical analysis of transmission by paired recording and intracellular pipette perfusion revealed that the effects of exogenous Ca chelators decreased during development, despite constant reliance of release on P/Q-type Ca channels. Structural analysis by freeze-fracture replica labeling (FRL) and transmission electron microscopy (EM) indicated that presynaptic P/Q-type Ca channels formed nanoclusters throughout development, whereas docked vesicles were only clustered at later developmental stages. Modeling suggested a developmental transformation from a more random to a more clustered coupling nanotopography. Thus, presynaptic signaling developmentally approaches a point-to-point configuration, optimizing speed, reliability, and energy efficiency of synaptic transmission.
Topics: Reproducibility of Results; Synapses; Synaptic Transmission; Purkinje Cells; Presynaptic Terminals; Calcium
PubMed: 38215739
DOI: 10.1016/j.neuron.2023.12.002 -
Nature Communications Feb 2024In the central nervous system, astrocytes enable appropriate synapse function through glutamate clearance from the synaptic cleft; however, it remains unclear how...
In the central nervous system, astrocytes enable appropriate synapse function through glutamate clearance from the synaptic cleft; however, it remains unclear how astrocytic glutamate transporters function at peri-synaptic contact. Here, we report that Down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls synapse formation and function in the developing cerebellum. Dscam-mutant mice show defects in CF synapse translocation as is observed in loss of function mutations in the astrocytic glutamate transporter GLAST expressed in Bergmann glia. These mice show impaired glutamate clearance and the delocalization of GLAST away from the cleft of parallel fibre (PF) synapse. GLAST complexes with the extracellular domain of DSCAM. Riluzole, as an activator of GLAST-mediated uptake, rescues the proximal impairment in CF synapse formation in Purkinje cell-selective Dscam-deficient mice. DSCAM is required for motor learning, but not gross motor coordination. In conclusion, the intercellular association of synaptic and astrocyte proteins is important for synapse formation and function in neural transmission.
Topics: Animals; Mice; Amino Acid Transport System X-AG; Cerebellum; Glutamic Acid; Neuroglia; Neurons; Purkinje Cells; Synapses
PubMed: 38302444
DOI: 10.1038/s41467-023-44579-z -
Life Science Alliance Sep 2023Niemann-Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Its key pathogenic events remain largely...
Niemann-Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Its key pathogenic events remain largely unknown. We have, herein, found that neonatal BM-derived cell transplantation can ameliorate Purkinje cell degeneration in NPC1 mice. We subsequently addressed the impact of the peripheral immune system on the neuropathogenesis observed in NPC1 mice. The depletion of mature lymphocytes promoted NPC1 phenotypes, thereby suggesting a neuroprotective effect of lymphocytes. Moreover, the peripheral infusion of CD4-positive cells (specifically, of regulatory T cells) from normal healthy donor ameliorated the cerebellar ataxic phenotype and enhanced the survival of Purkinje cells. Conversely, the depletion of regulatory T cells enhanced the onset of the neurological phenotype. On the other hand, circulating inflammatory monocytes were found to be involved in the progression of Purkinje cell degeneration, whereas the depletion of resident microglia had little effect. Our findings reveal a novel role of the adaptive and the innate immune systems in NPC1 neuropathology.
Topics: Mice; Animals; Purkinje Cells; Niemann-Pick Disease, Type C; Cerebellum; Immune System; Microglia
PubMed: 37369603
DOI: 10.26508/lsa.202201881