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The Journal of Neuroscience : the... Apr 2024Throughout life, the cerebellum plays a central role in the coordination and optimization of movements, using cellular plasticity to adapt a range of behaviors. Whether...
Throughout life, the cerebellum plays a central role in the coordination and optimization of movements, using cellular plasticity to adapt a range of behaviors. Whether these plasticity processes establish a fixed setpoint during development, or continuously adjust behaviors throughout life, is currently unclear. Here, by spatiotemporally manipulating the activity of protein phosphatase 2B (PP2B), an enzyme critical for cerebellar plasticity in male and female mice, we examined the consequences of disrupted plasticity on the performance and adaptation of the vestibulo-ocular reflex (VOR). We find that, in contrast to Purkinje cell (PC)-specific deletion starting early postnatally, acute pharmacological as well as adult-onset genetic deletion of PP2B affects all forms of VOR adaptation but not the level of VOR itself. Next, we show that PC-specific genetic deletion of PP2B in juvenile mice leads to a progressive loss of the protein PP2B and a concurrent change in the VOR, in addition to the loss of adaptive abilities. Finally, re-expressing PP2B in adult mice that lack PP2B expression from early development rescues VOR adaptation but does not affect the performance of the reflex. Together, our results indicate that chronic or acute, genetic, or pharmacological block of PP2B disrupts the adaptation of the VOR. In contrast, only the absence of plasticity during cerebellar development affects the setpoint of VOR, an effect that cannot be corrected after maturation of the cerebellum. These findings suggest that PP2B-dependent cerebellar plasticity is required during a specific period to achieve the correct setpoint of the VOR.
Topics: Animals; Reflex, Vestibulo-Ocular; Neuronal Plasticity; Mice; Cerebellum; Male; Female; Purkinje Cells; Adaptation, Physiological; Mice, Inbred C57BL; Mice, Knockout
PubMed: 38527808
DOI: 10.1523/JNEUROSCI.1211-23.2024 -
Nature Communications Mar 2024Consensus is rapidly building to support a role for the cerebellum beyond motor function, but its contributions to non-motor learning remain poorly understood. Here, we...
Consensus is rapidly building to support a role for the cerebellum beyond motor function, but its contributions to non-motor learning remain poorly understood. Here, we provide behavioral, anatomical and computational evidence to demonstrate a causal role for the primate posterior lateral cerebellum in learning new visuomotor associations. Reversible inactivation of the posterior lateral cerebellum of male monkeys impeded the learning of new visuomotor associations, but had no effect on movement parameters, or on well-practiced performance of the same task. Using retrograde transneuronal transport of rabies virus, we identified a distinct cerebro-cerebellar network linking Purkinje cells in the posterior lateral cerebellum with a region of the prefrontal cortex that is critical in learning visuomotor associations. Together, these results demonstrate a causal role for the primate posterior lateral cerebellum in non-motor, reinforcement learning.
Topics: Animals; Male; Cerebellum; Learning; Purkinje Cells; Prefrontal Cortex; Primates
PubMed: 38514616
DOI: 10.1038/s41467-024-46281-0 -
Developmental Neurobiology Apr 2024The organization of neurons into distinct layers, known as lamination, is a common feature of the nervous system. This process, which arises from the direct coupling of...
The organization of neurons into distinct layers, known as lamination, is a common feature of the nervous system. This process, which arises from the direct coupling of neurogenesis and neuronal migration, plays a crucial role in the development of the cerebellum, a structure exhibiting a distinct folding cytoarchitecture with cells arranged in discrete layers. Disruptions to neuronal migration can lead to various neurodevelopmental disorders, highlighting the significance of understanding the molecular regulation of lamination. We report a role Mllt11/Af1q/Tcf7c (myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 fused gene from chromosome 1q, also known as Mllt11 transcriptional cofactor 7; henceforth referred to Mllt11) in the migration of cerebellar granule cells (GCs). We now show that Mllt11 plays a role in both the tangential and radial migration of GCs. Loss of Mllt11 led to an accumulation of GC precursors in the rhombic lip region and a reduction in the number of GCs successfully populating developing folia. Consequently, this results in smaller folia and an overall reduction in cerebellar size. Furthermore, analysis of the anchoring centers reveals disruptions in the perinatal folia cytoarchitecture, including alterations in the Bergmann glia fiber orientation and reduced infolding of the Purkinje cell plate. Lastly, we demonstrate that Mllt11 interacts with non-muscle myosin IIB (NMIIB) and Mllt11 loss-reduced NMIIB expression. We propose that the dysregulation of NMIIB underlies altered GC migratory behavior. Taken together, the findings reported herein demonstrate a role for Mllt11 in regulating neuronal migration within the developing cerebellum, which is necessary for its proper neuroanatomical organization.
Topics: Pregnancy; Female; Humans; Neurons; Cerebellum; Neuroglia; Cell Movement; Embryonic Structures; Metencephalon
PubMed: 38509451
DOI: 10.1002/dneu.22936 -
Handbook of Clinical Neurology 2024Gynecologic and breast malignancies are the cancers most commonly associated with paraneoplastic neurologic syndromes, of which the foremost is Yo [Purkinje cell... (Review)
Review
Gynecologic and breast malignancies are the cancers most commonly associated with paraneoplastic neurologic syndromes, of which the foremost is Yo [Purkinje cell antibody, type 1 (PCA-1)] paraneoplastic cerebellar degeneration. Yo syndrome affects women in the sixth decade and manifests as a subacute severe cerebellar ataxia. The association of the typical clinical picture with the detection of Yo antibodies in a patient's serum or CSF defines the diagnosis. Yo syndrome is always associated with a cancer, and the search for the underlying tumor should focus on ovarian and breast cancers and be repeated overtime if negative. The Yo autoantibodies are directed against the Yo antigens, aberrantly overexpressed by tumor cells with frequent somatic mutations and gene amplifications. The massive infiltration of these tumors by immune cells suggests that they are the site of the immune tolerance breakdown, leading to the destruction of Purkinje cells harboring the Yo antigens. Despite a growing understanding of the immunologic mechanisms, efficient therapeutic options are still lacking. Anti-Ri and antiamphiphysin syndromes are rarer and associated with breast cancers; a wide variety of other rare paraneoplastic neurologic syndromes have been described in association with gynecologic and breast malignancies that, though sharing some similarities, may have specific immune and genetics features leading to the immune tolerance breakdown.
Topics: Female; Humans; Breast Neoplasms; Paraneoplastic Cerebellar Degeneration; Autoantibodies; Purkinje Cells
PubMed: 38494293
DOI: 10.1016/B978-0-12-823912-4.00014-1 -
Handbook of Clinical Neurology 2024Paraneoplastic neurologic syndromes (PNS) represent a rare group of immune-mediated complications associated with an underlying tumor. Ectopic protein expression in... (Review)
Review
Paraneoplastic neurologic syndromes (PNS) represent a rare group of immune-mediated complications associated with an underlying tumor. Ectopic protein expression in neoplastic cells or an aberrant immune regulation in the course of hematooncologic diseases or thymomas trigger an autoimmune response that may affect any part of the central and/or peripheral nervous system. Recent advances in drug therapies as well as novel animal models and neuropathologic studies have led to further insights on the immune pathomechanisms of PNS. Although the syndromes share common paths in pathogenesis, they may differ in the disease course, prognosis, and therapy targets, depending on the localization and type of antibody epitope. Neuropathologic hallmarks of PNS associated with antibodies directed against intracellular epitopes are characterized by T cell-dominated inflammation, reactive gliosis including microglial nodules, and neuronal degeneration. By contrast, the neuropathology of cell surface antibody-mediated PNS strongly depends on the targeted antigen and varies from B cell/plasma cell-dominated inflammation and well-preserved neurons together with a reduced expression of the target antigen in anti-NMDAR encephalitis to irreversible Purkinje cell loss in anti-P/Q-type VGCC antibody-associated paraneoplastic cerebellar degeneration. The understanding of different pathomechanisms in PNS is important because they strongly correspond with therapy response and prognosis, and should guide treatment decisions.
Topics: Animals; Humans; Autoantibodies; Paraneoplastic Syndromes, Nervous System; Nervous System Diseases; Neoplasms; Inflammation
PubMed: 38494287
DOI: 10.1016/B978-0-12-823912-4.00027-X -
Neuroscience Letters Mar 2024Etomidate (ET) is a widely used intravenous imidazole general anesthetic, which depresses the cerebellar neuronal activity by modulating various receptors activity and...
Etomidate (ET) is a widely used intravenous imidazole general anesthetic, which depresses the cerebellar neuronal activity by modulating various receptors activity and synaptic transmission. In this study, we investigated the effects of ET on the cerebellar climbing fiber-Purkinje cells (CF-PC) plasticity in vitro in mice using whole-cell recording technique and pharmacological methods. Our results demonstrated that CF tetanic stimulation produced a mGluR1-dependent long-term depression (LTD) of CF-PC excitatory postsynaptic currents (EPSCs), which was enhanced by bath application of ET (10 µM). Blockade of mGluR1 receptor with JNJ16259685, ET triggered the tetanic stimulation to induce a CF-PC LTD accompanied with an increase in paired-pulse ratio (PPR). The ET-triggered CF-PC LTD was abolished by extracellular administration of an N-methyl-(D)-aspartate (NMDA) receptor antagonist, D-APV, as well as by intracellular blockade of NMDA receptors activity with MK801. Furthermore, blocking cannabinoids 1 (CB1) receptor with AM251 or chelating intracellular Ca with BAPTA, ET failed to trigger the CF-PC LTD. Moreover, the ET-triggered CF-PC LTD was abolished by inhibition of protein kinase A (PKA), but not by inhibition of protein kinase C inhibiter. The present results suggest that ET acts on postsynaptic NMDA receptor resulting in an enhancement of the cerebellar CF-PC LTD through CB1 receptor/PKA cascade in vitro in mice. These results provide new evidence and possible mechanism for ET anesthesia to affect motor learning and motor coordination by regulating cerebellar CF-PC LTD.
Topics: Mice; Animals; Etomidate; Receptor, Cannabinoid, CB1; Cyclic AMP-Dependent Protein Kinases; Long-Term Synaptic Depression; Synapses; Cerebellum; Neuronal Plasticity; Purkinje Cells; Synaptic Transmission; Anesthetics, Intravenous
PubMed: 38492880
DOI: 10.1016/j.neulet.2024.137733 -
Neuron Jun 2024Whisker stimulation in awake mice evokes transient suppression of simple spike probability in crus I/II Purkinje cells. Here, we investigated how simple spike...
Whisker stimulation in awake mice evokes transient suppression of simple spike probability in crus I/II Purkinje cells. Here, we investigated how simple spike suppression arises synaptically, what it encodes, and how it affects cerebellar output. In vitro, monosynaptic parallel fiber (PF)-excitatory postsynaptic currents (EPSCs) facilitated strongly, whereas disynaptic inhibitory postsynaptic currents (IPSCs) remained stable, maximizing relative inhibitory strength at the onset of PF activity. Short-term plasticity thus favors the inhibition of Purkinje spikes before PFs facilitate. In vivo, whisker stimulation evoked a 2-6 ms synchronous spike suppression, just 6-8 ms (∼4 synaptic delays) after sensory onset, whereas active whisker movements elicited broadly timed spike rate increases that did not modulate sensory-evoked suppression. Firing in the cerebellar nuclei (CbN) inversely correlated with disinhibition from sensory-evoked simple spike suppressions but was decoupled from slow, non-synchronous movement-associated elevations of Purkinje firing rates. Synchrony thus allows the CbN to high-pass filter Purkinje inputs, facilitating sensory-evoked cerebellar outputs that can drive movements.
Topics: Animals; Purkinje Cells; Cerebellar Nuclei; Mice; Action Potentials; Synapses; Vibrissae; Excitatory Postsynaptic Potentials; Mice, Inbred C57BL; Inhibitory Postsynaptic Potentials; Male
PubMed: 38492575
DOI: 10.1016/j.neuron.2024.02.014 -
CNS Neuroscience & Therapeutics Mar 2024The open-loop nature of conventional deep brain stimulation (DBS) produces continuous and excessive stimulation to patients which contributes largely to increased...
Real-time field-programmable gate array-based closed-loop deep brain stimulation platform targeting cerebellar circuitry rescues motor deficits in a mouse model of cerebellar ataxia.
AIMS
The open-loop nature of conventional deep brain stimulation (DBS) produces continuous and excessive stimulation to patients which contributes largely to increased prevalence of adverse side effects. Cerebellar ataxia is characterized by abnormal Purkinje cells (PCs) dendritic arborization, loss of PCs and motor coordination, and muscle weakness with no effective treatment. We aim to develop a real-time field-programmable gate array (FPGA) prototype targeting the deep cerebellar nuclei (DCN) to close the loop for ataxia using conditional double knockout mice with deletion of PC-specific LIM homeobox (Lhx)1 and Lhx5, resulting in abnormal dendritic arborization and motor deficits.
METHODS
We implanted multielectrode array in the DCN and muscles of ataxia mice. The beneficial effect of open-loop DCN-DBS or closed-loop DCN-DBS was compared by motor behavioral assessments, electromyography (EMG), and neural activities (neurospike and electroencephalogram) in freely moving mice. FPGA board, which performed complex real-time computation, was used for closed-loop DCN-DBS system.
RESULTS
Closed-loop DCN-DBS was triggered only when symptomatic muscle EMG was detected in a real-time manner, which restored motor activities, electroencephalogram activities and neurospike properties completely in ataxia mice. Closed-loop DCN-DBS was more effective than an open-loop paradigm as it reduced the frequency of DBS.
CONCLUSION
Our real-time FPGA-based DCN-DBS system could be a potential clinical strategy for alleviating cerebellar ataxia and other movement disorders.
Topics: Humans; Mice; Animals; Cerebellar Ataxia; Deep Brain Stimulation; Cerebellum; Purkinje Cells; Movement Disorders; Cerebellar Nuclei
PubMed: 38488445
DOI: 10.1111/cns.14638 -
The Journal of Physiology Apr 2024Mapping neuronal activation using calcium imaging in vivo during behavioural tasks has advanced our understanding of nervous system function. In almost all of these...
Mapping neuronal activation using calcium imaging in vivo during behavioural tasks has advanced our understanding of nervous system function. In almost all of these studies, calcium imaging is used to infer spike probabilities because action potentials activate voltage-gated calcium channels and increase intracellular calcium levels. However, neurons not only fire action potentials, but also convey information via intrinsic dynamics such as by generating bistable membrane potential states. Although a number of tools for spike inference have been developed and are currently being used, no tool exists for converting calcium imaging signals to maps of cellular state in bistable neurons. Purkinje neurons in the larval zebrafish cerebellum exhibit membrane potential bistability, firing either tonically or in bursts. Several studies have implicated the role of a population code in cerebellar function, with bistability adding an extra layer of complexity to this code. In the present study, we develop a tool, CaMLSort, which uses convolutional recurrent neural networks to classify calcium imaging traces as arising from either tonic or bursting cells. We validate this classifier using a number of different methods and find that it performs well on simulated event rasters as well as real biological data that it had not previously seen. Moreover, we find that CaMLsort generalizes to other bistable neurons, such as dopaminergic neurons in the ventral tegmental area of mice. Thus, this tool offers a new way of analysing calcium imaging data from bistable neurons to understand how they participate in network computation and natural behaviours. KEY POINTS: Calcium imaging, compriising the gold standard of inferring neuronal activity, does not report cellular state in neurons that are bistable, such as Purkinje neurons in the cerebellum of larval zebrafish. We model the relationship between Purkinje neuron electrical activity and its corresponding calcium signal to compile a dataset of state-labelled simulated calcium signals. We apply machine-learning methods to this dataset to develop a tool that can classify the state of a Purkinje neuron using only its calcium signal, which works well on real data even though it was trained only on simulated data. CaMLsort (Calcium imaging and Machine Learning based tool to sort intracellular state) also generalizes well to bistable neurons in a different brain region (ventral tegmental area) in a different model organism (mouse). This tool can facilitate our understanding of how these neurons carry out their functions in a circuit.
Topics: Mice; Animals; Calcium; Zebrafish; Purkinje Cells; Membrane Potentials; Action Potentials; Calcium, Dietary
PubMed: 38482722
DOI: 10.1113/JP284373