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BioRxiv : the Preprint Server For... Sep 2023The cerebellar cortex contributes to diverse behaviors by transforming mossy fiber inputs into predictions in the form of Purkinje cell (PC) outputs, and then refining...
The cerebellar cortex contributes to diverse behaviors by transforming mossy fiber inputs into predictions in the form of Purkinje cell (PC) outputs, and then refining those predictions. Molecular layer interneurons (MLIs) account for approximately 80% of the inhibitory interneurons in the cerebellar cortex, and are vital to cerebellar processing. MLIs are thought to primarily inhibit PCs and suppress the plasticity of excitatory synapses onto PCs. MLIs also inhibit, and are electrically coupled to, other MLIs, but the functional significance of these connections is not known. Behavioral studies suggest that cerebellar-dependent learning is gated by disinhibition of PCs, but the source of such disinhibition has not been identified. Here we find that two recently recognized MLI subtypes, MLI1 and MLI2, have highly specialized connectivity that allows them to serve very different functional roles. MLI1s primarily inhibit PCs, are electrically coupled to each other, fire synchronously with other MLI1s on the millisecond time scale , and synchronously pause PC firing. MLI2s are not electrically coupled, they primarily inhibit MLI1s and disinhibit PCs, and are well suited to gating cerebellar-dependent learning. These findings require a major reevaluation of processing within the cerebellum in which disinhibition, a powerful circuit motif present in the cerebral cortex and elsewhere, greatly increases the computational power and flexibility of the cerebellum. They also suggest that millisecond time scale synchronous firing of electrically-coupled MLI1s helps regulate the output of the cerebellar cortex by synchronously pausing PC firing, which has been shown to evoke precisely-timed firing in PC targets.
PubMed: 37745401
DOI: 10.1101/2023.09.15.557934 -
Development (Cambridge, England) Nov 2023Reciprocal interactions between non-myocytes and cardiomyocytes regulate cardiac growth and differentiation. Here, we report that the transcription factor Ebf1 is highly...
Reciprocal interactions between non-myocytes and cardiomyocytes regulate cardiac growth and differentiation. Here, we report that the transcription factor Ebf1 is highly expressed in non-myocytes and potently regulates heart development. Ebf1-deficient hearts display myocardial hypercellularity and reduced cardiomyocyte size, ventricular conduction system hypoplasia, and conduction system disease. Growth abnormalities in Ebf1 knockout hearts are observed as early as embryonic day 13.5. Transcriptional profiling of Ebf1-deficient embryonic cardiac non-myocytes demonstrates dysregulation of Polycomb repressive complex 2 targets, and ATAC-Seq reveals altered chromatin accessibility near many of these same genes. Gene set enrichment analysis of differentially expressed genes in cardiomyocytes isolated from E13.5 hearts of wild-type and mutant mice reveals significant enrichment of MYC targets and, consistent with this finding, we observe increased abundance of MYC in mutant hearts. EBF1-deficient non-myocytes, but not wild-type non-myocytes, are sufficient to induce excessive accumulation of MYC in co-cultured wild-type cardiomyocytes. Finally, we demonstrate that BMP signaling induces Ebf1 expression in embryonic heart cultures and controls a gene program enriched in EBF1 targets. These data reveal a previously unreported non-cell-autonomous pathway controlling cardiac growth and differentiation.
Topics: Animals; Mice; Cell Differentiation; Gene Expression Regulation; Myocardium; Myocytes, Cardiac; Transcription Factors
PubMed: 37787076
DOI: 10.1242/dev.202054 -
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 -
Cell Discovery Feb 2024Human cerebellum encompasses numerous neurons, exhibiting a distinct developmental paradigm from cerebrum. Here we conducted scRNA-seq, scATAC-seq and spatial...
Human cerebellum encompasses numerous neurons, exhibiting a distinct developmental paradigm from cerebrum. Here we conducted scRNA-seq, scATAC-seq and spatial transcriptomic analyses of fetal samples from gestational week (GW) 13 to 18 to explore the emergence of cellular diversity and developmental programs in the developing human cerebellum. We identified transitory granule cell progenitors that are conserved across species. Special patterns in both granule cells and Purkinje cells were dissected multidimensionally. Species-specific gene expression patterns of cerebellar lobes were characterized and we found that PARM1 exhibited inconsistent distribution in human and mouse granule cells. A novel cluster of potential neuroepithelium at the rhombic lip was identified. We also resolved various subtypes of Purkinje cells and unipolar brush cells and revealed gene regulatory networks controlling their diversification. Therefore, our study offers a valuable multi-omics landscape of human fetal cerebellum and advances our understanding of development and spatial organization of human cerebellum.
PubMed: 38409116
DOI: 10.1038/s41421-024-00656-1 -
Neuroscience Research May 2024Anger transition is often abrupt. In this study, we investigated the mechanisms responsible for switching and modulating aggression levels. The cerebellum is considered...
Anger transition is often abrupt. In this study, we investigated the mechanisms responsible for switching and modulating aggression levels. The cerebellum is considered a center for motor coordination and learning; however, its connection to social behavior has long been observed. Here, we used the resident-intruder paradigm in male mice and examined local field potential (LFP) changes, glial cytosolic ion fluctuations, and vascular dynamics in the cerebellar vermis throughout various phases of a combat sequence. Notably, we observed the emergence of theta band oscillations in the LFP and sustained elevations in glial Ca levels during combat breakups. When astrocytes, including Bergmann glial cells, were photoactivated using channelrhodopsin-2, the theta band emerged and an early combat breakup occurred. Within a single combat sequence, rapid alteration of offensive (fight) and passive (flight) responses were observed, which roughly correlated with decreases and increases in glial Ca, respectively. Neuron-glial interactions in the cerebellar vermis may play a role in adjusting Purkinje cell excitability and setting the tone of aggression. Future anger management strategies and clinical control of excessive aggression and violent behavior may be realized by developing a therapeutic strategy that adjusts glial activity in the cerebellum.
Topics: Animals; Aggression; Male; Neuroglia; Mice; Cerebellum; Astrocytes; Mice, Inbred C57BL; Calcium
PubMed: 38007191
DOI: 10.1016/j.neures.2023.11.008 -
Current Opinion in Neurobiology Oct 2023The cerebellum has been a popular topic for theoretical studies because its structure was thought to be simple. Since David Marr and James Albus related its function to... (Review)
Review
The cerebellum has been a popular topic for theoretical studies because its structure was thought to be simple. Since David Marr and James Albus related its function to motor skill learning and proposed the Marr-Albus cerebellar learning model, this theory has guided and inspired cerebellar research. In this review, we summarize the theoretical progress that has been made within this framework of error-based supervised learning. We discuss the experimental progress that demonstrates more complicated molecular and cellular mechanisms in the cerebellum as well as new cell types and recurrent connections. We also cover its involvement in diverse non-motor functions and evidence of other forms of learning. Finally, we highlight the need to explain these new experimental findings into an integrated cerebellar model that can unify its diverse computational functions.
Topics: Cerebellum; Learning; Motor Skills
PubMed: 37591124
DOI: 10.1016/j.conb.2023.102765 -
Scientific Reports Oct 2023The C1Q complement protein C1QL1 is highly conserved in mammals where it is expressed in various tissues including the brain. This secreted protein interacts with...
The C1Q complement protein C1QL1 is highly conserved in mammals where it is expressed in various tissues including the brain. This secreted protein interacts with Brain-specific Angiogenesis Inhibitor 3, BAI3/ADGRB3, and controls synapse formation and maintenance. C1ql1 is expressed in the inferior olivary neurons that send projections to cerebellar Purkinje cells, but its expression in the rest of the brain is less documented. To map C1ql1 expression and enable the specific targeting of C1ql1-expressing cells, we generated a knockin mouse model expressing the Cre recombinase under the control of C1ql1 regulatory sequences. We characterized the capacity for Cre-driven recombination in the brain and mapped Cre expression in various neuron types using reporter mouse lines. Using an intersectional strategy with viral particle injections, we show that this mouse line can be used to target specific afferents of Purkinje cells. As C1ql1 is also expressed in other regions of the brain, as well as in other tissues such as adrenal glands and colon, our mouse model is a useful tool to target C1ql1-expressing cells in a broad variety of tissues.
Topics: Mice; Animals; Neurons; Brain; Purkinje Cells; Mice, Transgenic; Integrases; Mammals; Complement C1q
PubMed: 37845276
DOI: 10.1038/s41598-023-42924-2 -
Biomedicines Sep 2023Neuroinflammation is a complex biological process that typically originates as a protective response in the brain. This inflammatory process is triggered by the release... (Review)
Review
Neuroinflammation is a complex biological process that typically originates as a protective response in the brain. This inflammatory process is triggered by the release of pro-inflammatory substances like cytokines, prostaglandins, and reactive oxygen and nitrogen species from stimulated endothelial and glial cells, including those with pro-inflammatory functions, in the outer regions. While neuronal inflammation is common in various central nervous system disorders, the specific inflammatory pathways linked with different immune-mediated cell types and the various factors influencing the blood-brain barrier significantly contribute to disease-specific characteristics. The endocannabinoid system consists of cannabinoid receptors, endogenous cannabinoids, and enzymes responsible for synthesizing and metabolizing endocannabinoids. The primary cannabinoid receptor is CB1, predominantly found in specific brain regions such as the brainstem, cerebellum, hippocampus, and cortex. The presence of CB2 receptors in certain brain components, like cultured cerebellar granular cells, Purkinje fibers, and microglia, as well as in the areas like the cerebral cortex, hippocampus, and cerebellum is also evidenced by immunoblotting assays, radioligand binding, and autoradiography studies. Both CB1 and CB2 cannabinoid receptors exhibit noteworthy physiological responses and possess diverse neuromodulatory capabilities. This review primarily aims to outline the distribution of CB1 and CB2 receptors across different brain regions and explore their potential roles in regulating neuroinflammatory processes.
PubMed: 37893016
DOI: 10.3390/biomedicines11102642 -
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 -
Experimental Neurology Nov 2023Purkinje cells are the sole output neurons of the cerebellar cortex and play central roles in the integration of cerebellum-related motor coordination and memory. The...
Purkinje cells are the sole output neurons of the cerebellar cortex and play central roles in the integration of cerebellum-related motor coordination and memory. The loss or dysfunction of Purkinje cells due to cerebellar atrophy leads to severe ataxia. Here we used in vivo transplantation to examine the function of human iPS cell-derived cerebellar progenitors in adult transgenic mice in which Purkinje-specific cell death occurs due to cytotoxicity of polyglutamines. Transplantation using cerebellar organoids (42-48 days in culture), which are rich in neural progenitors, showed a viability of >50% 4 weeks after transplantation. STEM121 grafted cells extended their processes toward the deep cerebellar nuclei, superior cerebellar peduncle, and vestibulocerebellar nuclei. The transplanted cells were mostly located in the white matter, and they were not found in the Purkinje cell layer. MAP2-positive fibers seen in the molecular layer of cerebellar cortex received VGluT2 inputs from climbing fibers. Transplanted neural progenitors overgrew in the host cerebellum but were suppressed by pretreatment with the γ-secretase inhibitor DAPT. Hyperproliferation was also suppressed by transplantation with more differentiated organoids (86 days in culture) or KIRREL2-positive cells purified by FACS sorting. Transplanted cells expressed Purkinje cell markers, GABA, CALB1 and L7, though they did not show fan-shaped morphology. We attempted to improve neuronal integration of stem cell-derived cerebellar progenitors by transplantation into the adult mouse, but this was not successfully achieved. Our findings in the present study contribute to regenerative medical application for cerebellar degeneration and provide new insights into cerebellar development in future.
Topics: Humans; Mice; Animals; Purkinje Cells; Induced Pluripotent Stem Cells; Cerebellum; Cerebellar Cortex; Mice, Transgenic
PubMed: 37634697
DOI: 10.1016/j.expneurol.2023.114511