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PloS One 2024Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative diseases for which at present no cure is available. Despite the extensive... (Comparative Study)
Comparative Study
Understanding the relationship between cerebellum and the frontal-cortex region of C9orf72-related amyotrophic lateral sclerosis: A comparative analysis of genetic features.
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative diseases for which at present no cure is available. Despite the extensive research the progress from diagnosis to prognosis in ALS and frontotemporal dementia (FTD) has been slow which represents suboptimal understanding of disease pathophysiological processes. In recent studies, several genes have been associated with the ALS and FTD diseases such as SOD1, TDP43, and TBK1, whereas the hexanucleotide GGGGCC repeat expansion (HRE) in C9orf72 gene is a most frequent cause of ALS and FTD, that has changed the understanding of these diseases.
METHODS
The goal of this study was to identify and spatially determine differential gene expression signature differences between cerebellum and frontal cortex in C9orf72-associated ALS (C9-ALS), to study the network properties of these differentially expressed genes, and to identify miRNAs targeting the common differentially expressed genes in both the tissues. This study thus highlights underlying differential cell susceptibilities to the disease mechanisms in C9-ALS and suggesting therapeutic target selection in C9-ALS.
RESULTS
In this manuscript, we have identified that the genes involved in neuron development, protein localization and transcription are mostly enriched in cerebellum of C9-ALS patients, while the UPR-related genes are enriched in the frontal cortex. Of note, UPR pathway genes were mostly dysregulated both in the C9-ALS cerebellum and frontal cortex. Overall, the data presented here show that defects in normal RNA processing and the UPR pathway are the pathological hallmarks of C9-ALS. Interestingly, the cerebellum showed more strong transcriptome changes than the frontal cortex.
CONCLUSION
Interestingly, the cerebellum region showed more significant transcriptomic changes as compared to the frontal cortex region suggesting its active participation in the disease process. This nuanced understanding may offer valuable insights for the development of targeted therapeutic strategies aimed at mitigating disease progression in C9-ALS.
Topics: Aged; Female; Humans; Male; Middle Aged; Amyotrophic Lateral Sclerosis; C9orf72 Protein; Cerebellum; Frontal Lobe; Frontotemporal Dementia; MicroRNAs
PubMed: 38753768
DOI: 10.1371/journal.pone.0301267 -
Neurobiology of Disease Jul 2024Heterogeneity is one of the key features of the healthy brain and selective vulnerability characterizes many, if not all, neurodegenerative diseases. While cerebellum...
Heterogeneity is one of the key features of the healthy brain and selective vulnerability characterizes many, if not all, neurodegenerative diseases. While cerebellum contains majority of brain cells, neither its heterogeneity nor selective vulnerability in disease are well understood. Here we describe molecular, cellular and functional heterogeneity in the context of healthy cerebellum as well as in cerebellar disease Spinocerebellar Ataxia Type 1 (SCA1). We first compared disease pathology in cerebellar vermis and hemispheres across anterior to posterior axis in a knock-in SCA1 mouse model. Using immunohistochemistry, we demonstrated earlier and more severe pathology of PCs and glia in the posterior cerebellar vermis of SCA1 mice. We also demonstrate heterogeneity of Bergmann glia in the unaffected, wild-type mice. Then, using RNA sequencing, we found both shared, as well as, posterior cerebellum-specific molecular mechanisms of pathogenesis that include exacerbated gene dysregulation, increased number of altered signaling pathways, and decreased pathway activity scores in the posterior cerebellum of SCA1 mice. We demonstrated unexpectedly large differences in the gene expression between posterior and anterior cerebellar vermis of wild-type mice, indicative of robust intraregional heterogeneity of gene expression in the healthy cerebellum. Additionally, we found that SCA1 disease profoundly reduces intracerebellar heterogeneity of gene expression. Further, using fiber photometry, we found that population level PC calcium activity was altered in the posterior lobules in SCA1 mice during walking. We also identified regional differences in the population level activity of Purkinje cells (PCs) in unrestrained wild-type mice that were diminished in SCA1 mice.
Topics: Animals; Cerebellum; Spinocerebellar Ataxias; Mice; Ataxin-1; Purkinje Cells; Neuroglia; Disease Models, Animal; Mice, Transgenic; Mice, Inbred C57BL; Male
PubMed: 38750673
DOI: 10.1016/j.nbd.2024.106530 -
Science Translational Medicine May 2024Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency....
Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.
Topics: Essential Tremor; Animals; Humans; Neurons; Olivary Nucleus; Cerebellum; Mice; Male; Optogenetics; Female; Deep Brain Stimulation; Middle Aged; Electroencephalography; Aged
PubMed: 38748772
DOI: 10.1126/scitranslmed.adl1408 -
Radiology May 2024
Topics: Humans; Diffusion Tensor Imaging; Mutism; Male; Female; Cerebellar Diseases; Cerebellum; Child
PubMed: 38742972
DOI: 10.1148/radiol.240760 -
Cerebral Cortex (New York, N.Y. : 1991) May 2024This study investigates abnormalities in cerebellar-cerebral static and dynamic functional connectivity among patients with acute pontine infarction, examining the...
This study investigates abnormalities in cerebellar-cerebral static and dynamic functional connectivity among patients with acute pontine infarction, examining the relationship between these connectivity changes and behavioral dysfunction. Resting-state functional magnetic resonance imaging was utilized to collect data from 45 patients within seven days post-pontine infarction and 34 normal controls. Seed-based static and dynamic functional connectivity analyses identified divergences in cerebellar-cerebral connectivity features between pontine infarction patients and normal controls. Correlations between abnormal functional connectivity features and behavioral scores were explored. Compared to normal controls, left pontine infarction patients exhibited significantly increased static functional connectivity within the executive, affective-limbic, and motor networks. Conversely, right pontine infarction patients demonstrated decreased static functional connectivity in the executive, affective-limbic, and default mode networks, alongside an increase in the executive and motor networks. Decreased temporal variability of dynamic functional connectivity was observed in the executive and default mode networks among left pontine infarction patients. Furthermore, abnormalities in static and dynamic functional connectivity within the executive network correlated with motor and working memory performance in patients. These findings suggest that alterations in cerebellar-cerebral static and dynamic functional connectivity could underpin the behavioral dysfunctions observed in acute pontine infarction patients.
Topics: Humans; Male; Female; Middle Aged; Magnetic Resonance Imaging; Cerebellum; Neural Pathways; Pons; Brain Stem Infarctions; Aged; Adult; Cerebral Cortex; Nerve Net
PubMed: 38741271
DOI: 10.1093/cercor/bhae182 -
Brain Stimulation 2024Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation method that can modulate many brain functions including learning and memory. Recent...
BACKGROUND
Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation method that can modulate many brain functions including learning and memory. Recent evidence suggests that tDCS memory effects may be caused by co-stimulation of scalp nerves such as the trigeminal nerve (TN), and not the electric field in the brain. The TN gives input to brainstem nuclei, including the locus coeruleus that controls noradrenaline release across brain regions, including hippocampus. However, the effects of TN direct current stimulation (TN-DCS) are currently not well understood.
HYPOTHESIS
In this study we tested the hypothesis that stimulation of the trigeminal nerve with direct current manipulates hippocampal activity via an LC pathway.
METHODS
We recorded neural activity in rat hippocampus using multichannel silicon probes. We applied 3 min of 0.25 mA or 1 mA TN-DCS, monitored hippocampal activity for up to 1 h and calculated spikes-rate and spike-field coherence metrics. Subcutaneous injections of xylocaine were used to block TN, while intraperitoneal and intracerebral injection of clonidine were used to block the LC pathway.
RESULTS
We found that 1 mA TN-DCS caused a significant increase in hippocampal spike-rate lasting 45 min in addition to significant changes in spike-field coherence, while 0.25 mA TN-DCS did not. TN blockage prevented spike-rate increases, confirming effects were not caused by the electric field in the brain. When 1 mA TN-DCS was delivered during clonidine blockage no increase in spike-rate was observed, suggesting an important role for the LC-noradrenergic pathway.
CONCLUSION
These results support our hypothesis and provide a neural basis to understand the tDCS TN co-stimulation mechanism. TN-DCS emerges as an important tool to potentially modulate learning and memory.
Topics: Animals; Hippocampus; Rats; Male; Trigeminal Nerve; Rats, Sprague-Dawley; Transcranial Direct Current Stimulation; Locus Coeruleus
PubMed: 38740183
DOI: 10.1016/j.brs.2024.05.005 -
STAR Protocols Jun 2024GABAergic interneurons are inhibitory neurons of the CNS, playing a fundamental role in neural circuitry and activity. Here, we provide a robust protocol for the...
GABAergic interneurons are inhibitory neurons of the CNS, playing a fundamental role in neural circuitry and activity. Here, we provide a robust protocol for the successful enrichment of human cerebellar GABAergic interneurons from human induced pluripotent stem cells (iPSCs) and measuring intracellular calcium transients. We describe in detail steps for culturing iPSCs; generating embryoid bodies; and differentiating and enriching for cerebellar GABAergic neurons (cGNs), with precise steps for their molecular characterization. We then detail the procedure for adeno-associated virus-mediated transduction of cGNs with genetically encoded calcium indicators, followed by intracellular calcium imaging and analyses. For complete details on the use and execution of this protocol, please refer to Pilotto et al..
Topics: Induced Pluripotent Stem Cells; Humans; Calcium; GABAergic Neurons; Interneurons; Cell Differentiation; Cerebellum; Cell Culture Techniques; Cells, Cultured
PubMed: 38735042
DOI: 10.1016/j.xpro.2024.102936 -
Nature Communications May 2024Accurate perception and behavior rely on distinguishing sensory signals arising from unexpected events from those originating from our own voluntary actions. In the...
Accurate perception and behavior rely on distinguishing sensory signals arising from unexpected events from those originating from our own voluntary actions. In the vestibular system, sensory input that is the consequence of active self-motion is canceled early at the first central stage of processing to ensure postural and perceptual stability. However, the source of the required cancellation signal was unknown. Here, we show that the cerebellum combines sensory and motor-related information to predict the sensory consequences of active self-motion. Recordings during attempted but unrealized head movements in two male rhesus monkeys, revealed that the motor-related signals encoded by anterior vermis Purkinje cells explain their altered sensitivity to active versus passive self-motion. Further, a model combining responses from ~40 Purkinje cells accounted for the cancellation observed in early vestibular pathways. These findings establish how cerebellar Purkinje cells predict sensory outcomes of self-movements, resolving a long-standing issue of sensory signal suppression during self-motion.
Topics: Animals; Purkinje Cells; Male; Macaca mulatta; Head Movements; Cerebellum; Vestibule, Labyrinth; Motion Perception
PubMed: 38734715
DOI: 10.1038/s41467-024-48376-0 -
Journal of Oral Biosciences Jun 2024The trigeminal spinal subnucleus caudalis (Sp5C), also known as the medullary dorsal horn, receives orofacial somatosensory inputs, particularly nociceptive inputs, from... (Review)
Review
BACKGROUND
The trigeminal spinal subnucleus caudalis (Sp5C), also known as the medullary dorsal horn, receives orofacial somatosensory inputs, particularly nociceptive inputs, from the trigeminal nerve. In the Sp5C, excitatory and inhibitory neurons, glutamatergic and GABAergic/glycinergic neurons, respectively, form the local circuits. The axons of the glutamatergic neurons in lamina I ascend toward the thalamic and parabrachial nuclei, and this projection is the main pathway of orofacial nociception. Additionally, the axons of the higher brain regions, including the locus coeruleus, dorsal raphe, and cerebral cortex, are sent to the Sp5C.
HIGHLIGHT
Among these descending projections, this review focuses on the functional profiles of the corticotrigeminal projections to the Sp5C, along with their anatomical aspects. The primary and secondary somatosensory and insular cortices are of particular interest.
CONCLUSION
Corticotrigeminal projections from the somatosensory cortex to the Sp5C play a suppressive role in nociceptive information processing, whereas recent studies have demonstrated a facilitative role of the insular cortex in nociceptive information processing at the Sp5C level.
Topics: Nociception; Cerebral Cortex; Humans; Animals; Trigeminal Caudal Nucleus; Somatosensory Cortex; Neural Pathways; Trigeminal Nucleus, Spinal; Facial Pain
PubMed: 38734177
DOI: 10.1016/j.job.2024.05.004 -
Cell May 2024The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D...
The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain.
Topics: Animals; Female; Male; Mice; Cerebellum; Ion Channels; Mice, Inbred C57BL; Neurons; Retina; Retinal Ganglion Cells; Retinal Vessels
PubMed: 38733989
DOI: 10.1016/j.cell.2024.04.010