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Disease Models & Mechanisms Jun 2024Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation....
Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxic mouse model generated by silencing Purkinje cell neurotransmission (L7Cre;Vgatfx/fx) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity was unaltered in the mutant mice, although their sleep parameters and ECoG patterns were modified. The L7Cre;Vgatfx/fx mutant mice had decreased wakefulness and rapid eye movement (REM) sleep, whereas non-REM sleep was increased. The mutants had an extended latency to REM sleep, which is also observed in human patients with ataxia. Spectral analysis of ECoG signals revealed alterations in the power distribution across different frequency bands defining sleep. Therefore, Purkinje cell dysfunction may influence wakefulness and equilibrium of distinct sleep stages in ataxia. Our findings posit a connection between cerebellar dysfunction and disrupted sleep and underscore the importance of examining cerebellar circuit function in sleep disorders.
Topics: Animals; Purkinje Cells; Wakefulness; Ataxia; Sleep; Sleep, REM; Mice; Circadian Rhythm; Disease Models, Animal; Male
PubMed: 38563553
DOI: 10.1242/dmm.050379 -
Journal of Neuropathology and... Apr 2024Two aspects of the neuropathology of early Huntington disease (HD) are examined. Neurons of the neostriatum are counted to determine relative loss in striosomes versus...
Two aspects of the neuropathology of early Huntington disease (HD) are examined. Neurons of the neostriatum are counted to determine relative loss in striosomes versus matrix at early stages, including for the first time in preclinical cases. An immunohistochemical procedure is described that tentatively distinguishes early HD from HD mimic disorders in postmortem brains. Counts of striatal projection neurons (SPNs) in striosomes defined by calbindin immunohistochemistry versus counts in the surrounding matrix are reported for 8 Vonsattel grade 0 (including 5 premanifest), 8 grade 1, 2 grade 2 HD, and for 8 control postmortem brains. Mean counts of striosome and matrix SPNs were significantly lower in premanifest grade 0 versus controls, with striosome counts significantly lower than matrix. In 8 grade 1 and 2 grade 2 brains, no striosomes with higher SPN counts than in the surrounding matrix were observed. Comparing dorsal versus ventral neostriatum, SPNs in dorsal striosomes and matrix declined more than ventral, making clear the importance of the dorsoventral site of tissue selection for research studies. A characteristic pattern of expanded polyglutamine-immunopositive inclusions was seen in all HD cases. Inclusions were always present in some SPNs and some pontine nucleus neurons and were absent in Purkinje cells, which showed no obvious cell loss.
Topics: Humans; Huntington Disease; Corpus Striatum; Neostriatum; Neurons; Calbindins
PubMed: 38553027
DOI: 10.1093/jnen/nlae022 -
Brain Research Jul 2024A Disintegrin And Metalloprotease 10 (ADAM10), is able to control several important physiopathological processes through the shedding of a large number of protein...
A Disintegrin And Metalloprotease 10 (ADAM10), is able to control several important physiopathological processes through the shedding of a large number of protein substrates. Although ADAM10 plays a crucial role in the central nervous system (CNS) development and function, its protein distribution in the CNS has not been fully addressed. Here, we described the regional and cellular ADAM10 protein expression in C57BL/6 mice examined by immunofluorescence 1) throughout the adult mouse brain, cerebellum and spinal cord in vivo and 2) in different cell types as neurons, astrocytes, oligodendrocytes and microglia in vitro. We observed ADAM10 expression through the whole CNS, with a strong expression in the hippocampus, in the hypothalamus and in the cerebral and piriform cortex in the brain, in the Purkinje and in granular cell layers in the cerebellum and in the spinal cord to a lower extent. In vivo, ADAM10 protein expression was mainly found in neurons and in some oligodendroglial cell populations. However, in primary cultures we observed ADAM10 expression in neurons, oligodendrocytes, astrocytes and microglia. Interestingly, ADAM10 was not only found in the membrane but also in cytoplasmic vesicles and in the nucleus of primary cultured cells. Overall, this work highlights a wide distribution of ADAM10 throughout the CNS. The nuclear localization of ADAM10, probably due to its intracellular domain, emphasizes its role in cell signalling in physiological and pathological conditions. Further investigations are required to better elucidate the role of ADAM10 in glial cells.
Topics: Animals; ADAM10 Protein; Mice, Inbred C57BL; Neurons; Mice; Membrane Proteins; Central Nervous System; Spinal Cord; Amyloid Precursor Protein Secretases; Astrocytes; Microglia; Cells, Cultured; Oligodendroglia; Male; Brain; Cerebellum
PubMed: 38548249
DOI: 10.1016/j.brainres.2024.148888 -
ELife Mar 2024The cell-type-specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here, we...
The cell-type-specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here, we determine a functional relevance of the long-established mutually exclusive expression of the receptor tyrosine kinase Kit and the trans-membrane protein Kit Ligand by discrete populations of neurons in the mammalian brain. Kit is enriched in molecular layer interneurons (MLIs) of the cerebellar cortex (i.e., stellate and basket cells), while cerebellar Kit Ligand is selectively expressed by a target of their inhibition, Purkinje cells (PCs). By in vivo genetic manipulation spanning embryonic development through adulthood, we demonstrate that PC Kit Ligand and MLI Kit are required for, and capable of driving changes in, the inhibition of PCs. Collectively, these works in mice demonstrate that the Kit Ligand/Kit receptor dyad sustains mammalian central synapse function and suggest a rationale for the affiliation of Kit mutation with neurodevelopmental disorders.
Topics: Mice; Animals; Purkinje Cells; Stem Cell Factor; Cerebellum; Cerebellar Cortex; Interneurons; Receptor Protein-Tyrosine Kinases; Mammals
PubMed: 38536959
DOI: 10.7554/eLife.89792 -
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 -
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 -
Cells Feb 2024Fetal alcohol spectrum disorders (FASD) caused by developmental ethanol exposure lead to cerebellar impairments, including motor problems, decreased cerebellar weight,...
Fetal alcohol spectrum disorders (FASD) caused by developmental ethanol exposure lead to cerebellar impairments, including motor problems, decreased cerebellar weight, and cell death. Alterations in the sole output of the cerebellar cortex, Purkinje cells, and central nervous system immune cells, microglia, have been reported in animal models of FASD. To determine how developmental ethanol exposure affects adult cerebellar microglia and Purkinje cells, we used a human third-trimester binge exposure model in which mice received ethanol or saline from postnatal (P) days 4-9. In adolescence, cerebellar cranial windows were implanted and mice were aged to young adulthood for examination of microglia and Purkinje cells in vivo with two-photon imaging or in fixed tissue. Ethanol had no effect on microglia density, morphology, dynamics, or injury response. However, Purkinje cell linear frequency was reduced by ethanol. Microglia-Purkinje cell interactions in the Purkinje Cell Layer were altered in females compared to males. Overall, developmental ethanol exposure had few effects on cerebellar microglia in young adulthood and Purkinje cells appeared to be more susceptible to its effects.
Topics: Pregnancy; Male; Humans; Female; Animals; Mice; Young Adult; Adult; Aged; Ethanol; Purkinje Cells; Fetal Alcohol Spectrum Disorders; Microglia; Cerebellum; Disease Models, Animal
PubMed: 38474350
DOI: 10.3390/cells13050386 -
Ecotoxicology and Environmental Safety Apr 2024Deltamethrin (DM) is a highly effective and widely used pyrethroid pesticide. It is an environmental factor affecting public and occupational health and exerts direct...
Deltamethrin (DM) is a highly effective and widely used pyrethroid pesticide. It is an environmental factor affecting public and occupational health and exerts direct toxic effects on the central nervous system. As the major target organs for neurotoxicity of DM, the hippocampus and the cerebellum are critical to the learning and motor function. Pregnant Wistar rats were randomly divided into four groups and gavaged at doses of 0, 1, 4or 10 mg/kg/d DM from gestational day (GD) 0 to postnatal day (PN) 21. The PC12 cells were selected to further verify the regulatory mechanisms of DM on the neurodevelopmental injury. We found that maternal exposure to DM caused learning, memory and motor dysfunction in male offspring. Maternal exposure to DM induced the decrease in the density of hippocampal dendritic spines in male offspring through the reduced expression of M1 mAchRs, which in turn reduced the mediated AKT/mTOR signaling pathway, contributing to the inhibition of dynamic changes of GluA1. Meanwhile, DM exposure inhibited the BDNF/TrkB signaling pathway, thereby reducing phosphorylation of stathmin and impairing cerebellar purkinje cell dendrite growth and development. Taken together, maternal exposure to DM during pregnancy and lactation could impair neurodevelopment of male offspring.
Topics: Pregnancy; Rats; Animals; Humans; Female; Male; Maternal Exposure; Rats, Wistar; Prenatal Exposure Delayed Effects; Lactation; Hippocampus; Nitriles; Pyrethrins
PubMed: 38461575
DOI: 10.1016/j.ecoenv.2024.116196 -
Development (Cambridge, England) Apr 2024Cerebellar neurons, such as GABAergic Purkinje cells (PCs), interneurons (INs) and glutamatergic granule cells (GCs) are differentiated from neural progenitors...
Cerebellar neurons, such as GABAergic Purkinje cells (PCs), interneurons (INs) and glutamatergic granule cells (GCs) are differentiated from neural progenitors expressing proneural genes, including ptf1a, neurog1 and atoh1a/b/c. Studies in mammals previously suggested that these genes determine cerebellar neuron cell fate. However, our studies on ptf1a;neurog1 zebrafish mutants and lineage tracing of ptf1a-expressing progenitors have revealed that the ptf1a/neurog1-expressing progenitors can generate diverse cerebellar neurons, including PCs, INs and a subset of GCs in zebrafish. The precise mechanisms of how each cerebellar neuron type is specified remains elusive. We found that genes encoding the transcriptional regulators Foxp1b, Foxp4, Skor1b and Skor2, which are reportedly expressed in PCs, were absent in ptf1a;neurog1 mutants. foxp1b;foxp4 mutants showed a strong reduction in PCs, whereas skor1b;skor2 mutants completely lacked PCs, and displayed an increase in immature GCs. Misexpression of skor2 in GC progenitors expressing atoh1c suppressed GC fate. These data indicate that Foxp1b/4 and Skor1b/2 function as key transcriptional regulators in the initial step of PC differentiation from ptf1a/neurog1-expressing neural progenitors, and that Skor1b and Skor2 control PC differentiation by suppressing their differentiation into GCs.
Topics: Animals; Cell Differentiation; Cerebellum; Co-Repressor Proteins; Forkhead Transcription Factors; Mammals; Neurons; Purkinje Cells; Zebrafish; Zebrafish Proteins
PubMed: 38456494
DOI: 10.1242/dev.202546