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ENeuro May 2024Sleep spindles appear to play an important role in learning new motor skills. Motor skill learning engages several brain regions with two important areas being the motor...
Sleep spindles appear to play an important role in learning new motor skills. Motor skill learning engages several brain regions with two important areas being the motor cortex (M1) and the cerebellum (CB). However, the neurophysiological processes in these areas during sleep, especially how spindle oscillations affect local and cross-region spiking, are not fully understood. We recorded an activity from the M1 and cerebellar cortex in eight rats during spontaneous activity to investigate how sleep spindles in these regions are related to local spiking as well as cross-region spiking. We found that M1 firing was significantly changed during both M1 and CB spindles, and this spiking occurred at a preferred phase of the spindle. On average, M1 and CB neurons showed most spiking at the M1 or CB spindle peaks. These neurons also developed a preferential phase locking to local or cross-area spindles with the greatest phase-locking value at spindle peaks; however, this preferential phase locking was not significant for cerebellar neurons when compared with CB spindles. Additionally, we found that the percentage of task-modulated cells in the M1 and CB that fired with nonuniform spike phase distribution during M1/CB spindle peaks were greater in the rats that learned a reach-to-grasp motor task robustly. Finally, we found that spindle band LFP coherence (for M1 and CB LFPs) showed a positive correlation with success rate in the motor task. These findings support the idea that sleep spindles in both the M1 and CB recruit neurons that participate in the awake task to support motor memory consolidation.
Topics: Animals; Motor Cortex; Male; Neurons; Sleep; Rats; Action Potentials; Cerebellum; Learning; Motor Skills; Rats, Sprague-Dawley; Rats, Long-Evans; Cerebellar Cortex
PubMed: 38641414
DOI: 10.1523/ENEURO.0150-23.2024 -
Journal of Molecular Histology Jun 2024Tramadol is a novel centrally acting analgesic. Despite, its implementation during pregnancy may impair neuronal survival and synaptic development in neonatal cerebella....
Evaluation of histological and ultrastructural changes provoked by prenatal tramadol on postnatal cortical cerebellar neuronal development in rats: possible implication of Ki67, GFAP and MicroRNA-7/P53 signalling trajectories.
Tramadol is a novel centrally acting analgesic. Despite, its implementation during pregnancy may impair neuronal survival and synaptic development in neonatal cerebella. The current investigation assessed the histological and ultrastructural alterations in postnatal cortical cerebellar neuronal development induced by prenatal tramadol. 30 offsprings were divided to control group I: fifteen pups born to mothers given saline from D10 till D21 of gestation. Tramadol-treated group II: fifteen pups born to mothers received tramadol HCL (50 mg/kg/day) from D10 till D21 of gestation. Pups were categorized into three subgroups (a, b, and c) and offered for sacrifice on the seventh, fourteenth and twenty-first post-natal days. Light microscopic examination revealed the overcrowding and signs of red degeneration affecting purkinje cell layer. Neurodegenerative signs of both purkinje and granule cell neurons were also confirmed by TEM in form of chromatin condensation, dilated Golgi channels, disrupted endoplasmic reticulum, marked infolding of the nuclear envelope and decrease in granule cell precursors. In addition, the astrocytic processes and terminal nerve axons appeared with different degrees of demyelination and decreased number of oligodendrocytes and degenerated mitochondria. Furthermore, group II exhibited an increase in P53 immune expression. The area percentage of apoptotic cells detected by TUNEL assay was significantly increased. Besides to the significant decrease of Ki67 immunoreactivity in the stem neuronal cell progenitors. Quantitative PCR results showed a significant decline in micro RNA7 gene expression in tramadol treated groups resulting in affection of multiple target genes in P53 signaling pathways, improper cortical size and defect in neuronal development.
Topics: Animals; Tramadol; MicroRNAs; Pregnancy; Signal Transduction; Female; Rats; Tumor Suppressor Protein p53; Prenatal Exposure Delayed Effects; Glial Fibrillary Acidic Protein; Ki-67 Antigen; Cerebellum; Neurons; Apoptosis; Rats, Wistar; Animals, Newborn
PubMed: 38639812
DOI: 10.1007/s10735-024-10189-2 -
Acta Neuropathologica Communications Apr 2024Helsmoortel-Van der Aa syndrome is a neurodevelopmental disorder in which patients present with autism, intellectual disability, and frequent extra-neurological features...
BACKGROUND
Helsmoortel-Van der Aa syndrome is a neurodevelopmental disorder in which patients present with autism, intellectual disability, and frequent extra-neurological features such as feeding and gastrointestinal problems, visual impairments, and cardiac abnormalities. All patients exhibit heterozygous de novo nonsense or frameshift stop mutations in the Activity-Dependent Neuroprotective Protein (ADNP) gene, accounting for a prevalence of 0.2% of all autism cases worldwide. ADNP fulfills an essential chromatin remodeling function during brain development. In this study, we investigated the cerebellum of a died 6-year-old male patient with the c.1676dupA/p.His559Glnfs*3 ADNP mutation.
RESULTS
The clinical presentation of the patient was representative of the Helsmoortel-Van der Aa syndrome. During his lifespan, he underwent two liver transplantations after which the child died because of multiple organ failure. An autopsy was performed, and various tissue samples were taken for further analysis. We performed a molecular characterization of the cerebellum, a brain region involved in motor coordination, known for its highest ADNP expression and compared it to an age-matched control subject. Importantly, epigenome-wide analysis of the ADNP cerebellum identified CpG methylation differences and expression of multiple pathways causing neurodevelopmental delay. Interestingly, transcription factor motif enrichment analysis of differentially methylated genes showed that the ADNP binding motif was the most significantly enriched. RNA sequencing of the autopsy brain further identified downregulation of the WNT signaling pathway and autophagy defects as possible causes of neurodevelopmental delay. Ultimately, label-free quantification mass spectrometry identified differentially expressed proteins involved in mitochondrial stress and sirtuin signaling pathways amongst others. Protein-protein interaction analysis further revealed a network including chromatin remodelers (ADNP, SMARCC2, HDAC2 and YY1), autophagy-related proteins (LAMP1, BECN1 and LC3) as well as a key histone deacetylating enzyme SIRT1, involved in mitochondrial energy metabolism. The protein interaction of ADNP with SIRT1 was further biochemically validated through the microtubule-end binding proteins EB1/EB3 by direct co-immunoprecipitation in mouse cerebellum, suggesting important mito-epigenetic crosstalk between chromatin remodeling and mitochondrial energy metabolism linked to autophagy stress responses. This is further supported by mitochondrial activity assays and stainings in patient-derived fibroblasts which suggest mitochondrial dysfunctions in the ADNP deficient human brain.
CONCLUSION
This study forms the baseline clinical and molecular characterization of an ADNP autopsy cerebellum, providing novel insights in the disease mechanisms of the Helsmoortel-Van der Aa syndrome. By combining multi-omic and biochemical approaches, we identified a novel SIRT1-EB1/EB3-ADNP protein complex which may contribute to autophagic flux alterations and impaired mitochondrial metabolism in the Helsmoortel-Van der Aa syndrome and holds promise as a new therapeutic target.
Topics: Male; Child; Animals; Mice; Humans; Intellectual Disability; Autistic Disorder; Sirtuin 1; Genes, Mitochondrial; Homeodomain Proteins; Cerebellum; Autopsy; Methylation; Nerve Tissue Proteins; DNA-Binding Proteins; Transcription Factors
PubMed: 38637827
DOI: 10.1186/s40478-024-01743-w -
Pediatric Radiology Jun 2024Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a recently described entity that refers to a specific pattern...
Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a recently described entity that refers to a specific pattern of cerebellar edema with restricted diffusion and crowding of the fourth ventricle among other findings. The syndrome is commonly associated with toxic opioid exposure. While most commonly seen in adults, we present a case of a 2-year-old girl who survived characteristic history and imaging findings of CHANTER syndrome.
Topics: Humans; Female; Child, Preschool; Brain Edema; Hippocampus; Syndrome; Diagnosis, Differential; Magnetic Resonance Imaging; Cerebellar Diseases; Diffusion Magnetic Resonance Imaging; Cerebellum
PubMed: 38630282
DOI: 10.1007/s00247-024-05928-2 -
ELife Apr 2024The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and...
The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and the vessel 'shadow' was quantified to evaluate the magnitude of the frequency-locked vasomotion. This method allows vasomotion to be easily quantified in non-transgenic wild-type mice using either the wide-field macro-zoom microscopy or the deep-brain fiber photometry methods. Vertical stripes horizontally oscillating at a low temporal frequency (0.25 Hz) were presented to the awake mouse, and oscillatory vasomotion locked to the temporal frequency of the visual stimulation was induced not only in the primary visual cortex but across a wide surface area of the cortex and the cerebellum. The visually induced vasomotion adapted to a wide range of stimulation parameters. Repeated trials of the visual stimulus presentations resulted in the plastic entrainment of vasomotion. Horizontally oscillating visual stimulus is known to induce horizontal optokinetic response (HOKR). The amplitude of the eye movement is known to increase with repeated training sessions, and the flocculus region of the cerebellum is known to be essential for this learning to occur. Here, we show a strong correlation between the average HOKR performance gain and the vasomotion entrainment magnitude in the cerebellar flocculus. Therefore, the plasticity of vasomotion and neuronal circuits appeared to occur in parallel. Efficient energy delivery by the entrained vasomotion may contribute to meeting the energy demand for increased coordinated neuronal activity and the subsequent neuronal circuit reorganization.
Topics: Mice; Animals; Cerebellum; Brain; Nystagmus, Optokinetic; Neurons; Learning; Photic Stimulation
PubMed: 38629828
DOI: 10.7554/eLife.93721 -
American Journal of Human Genetics May 2024Expanded CAG repeats in coding regions of different genes are the most common cause of dominantly inherited spinocerebellar ataxias (SCAs). These repeats are unstable...
Expanded CAG repeats in coding regions of different genes are the most common cause of dominantly inherited spinocerebellar ataxias (SCAs). These repeats are unstable through the germline, and larger repeats lead to earlier onset. We measured somatic expansion in blood samples collected from 30 SCA1, 50 SCA2, 74 SCA3, and 30 SCA7 individuals over a mean interval of 8.5 years, along with postmortem tissues and fetal tissues from SCA1, SCA3, and SCA7 individuals to examine somatic expansion at different stages of life. We showed that somatic mosaicism in the blood increases over time. Expansion levels are significantly different among SCAs and correlate with CAG repeat lengths. The level of expansion is greater in individuals with SCA7 who manifest disease compared to that of those who do not yet display symptoms. Brain tissues from SCA individuals have larger expansions compared to the blood. The cerebellum has the lowest mosaicism among the studied brain regions, along with a high expression of ATXNs and DNA repair genes. This was the opposite in cortices, with the highest mosaicism and lower expression of ATXNs and DNA repair genes. Fetal cortices did not show repeat instability. This study shows that CAG repeats are increasingly unstable during life in the blood and the brain of SCA individuals, with gene- and tissue-specific patterns.
Topics: Humans; Mosaicism; Spinocerebellar Ataxias; Trinucleotide Repeat Expansion; Female; Male; Adult; Middle Aged; Cerebellum; Aged; Brain; Ataxin-1
PubMed: 38626762
DOI: 10.1016/j.ajhg.2024.03.015 -
PloS One 2024Tinnitus is a common annoying symptom without effective and accepted treatment. In this controlled experimental study, photobiomodulation therapy (PBMT), which uses...
Tinnitus is a common annoying symptom without effective and accepted treatment. In this controlled experimental study, photobiomodulation therapy (PBMT), which uses light to modulate and repair target tissue, was used to treat sodium salicylate (SS)-induced tinnitus in a rat animal model. Here, PBMT was performed simultaneously on the peripheral and central regions involved in tinnitus. The results were evaluated using objective tests including gap pre-pulse inhibition of acoustic startle (GPIAS), auditory brainstem response (ABR) and immunohistochemistry (IHC). Harmful neural plasticity induced by tinnitus was detected by doublecortin (DCX) protein expression, a known marker of neural plasticity. PBMT parameters were 808 nm wavelength, 165 mW/cm2 power density, and 99 J/cm2 energy density. In the tinnitus group, the mean gap in noise (GIN) value of GPIAS test was significantly decreased indicated the occurrence of an additional perceived sound like tinnitus and also the mean ABR threshold and brainstem transmission time (BTT) were significantly increased. In addition, a significant increase in DCX expression in the dorsal cochlear nucleus (DCN), dentate gyrus (DG) and the parafloccular lobe (PFL) of cerebellum was observed in the tinnitus group. In PBMT group, a significant increase in the GIN value, a significant decrease in the ABR threshold and BTT, and also significant reduction of DCX expression in the DG were observed. Based on our findings, PBMT has the potential to be used in the management of SS-induced tinnitus.
Topics: Rats; Animals; Sodium Salicylate; Tinnitus; Low-Level Light Therapy; Cochlear Nucleus; Neuronal Plasticity
PubMed: 38626075
DOI: 10.1371/journal.pone.0296607 -
JCI Insight Apr 2024Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic...
Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic mechanism of neurodegeneration remains limited. Here, we show that cerebellar neurodegeneration caused by Sorting Nexin 14 (SNX14) deficiency is associated with lipid homeostasis defects. Recent studies indicate that SNX14 is an interorganelle lipid transfer protein that regulates lipid transport, lipid droplet (LD) biogenesis, and fatty acid desaturation, suggesting that human SNX14 deficiency belongs to an expanding class of cerebellar neurodegenerative disorders caused by altered cellular lipid homeostasis. To test this hypothesis, we generated a mouse model that recapitulates human SNX14 deficiency at a genetic and phenotypic level. We demonstrate that cerebellar Purkinje cells (PCs) are selectively vulnerable to SNX14 deficiency while forebrain regions preserve their neuronal content. Ultrastructure and lipidomic studies reveal widespread lipid storage and metabolism defects in SNX14-deficient mice. However, predegenerating SNX14-deficient cerebella show a unique accumulation of acylcarnitines and depletion of triglycerides. Furthermore, defects in LD content and telolysosome enlargement in predegenerating PCs suggest lipotoxicity as a pathogenic mechanism of SNX14 deficiency. Our work shows a selective cerebellar vulnerability to altered lipid homeostasis and provides a mouse model for future therapeutic studies.
Topics: Sorting Nexins; Animals; Mice; Homeostasis; Lipid Metabolism; Humans; Purkinje Cells; Disease Models, Animal; Neurodegenerative Diseases; Mice, Knockout; Cerebellum; Male; Lipid Droplets
PubMed: 38625743
DOI: 10.1172/jci.insight.168594 -
Brain Structure & Function Jun 2024The noradrenergic nucleus Locus Coeruleus (LC) is precociously involved in Alzheimer's Disease (AD) pathology, and its degeneration progresses during the course of the...
The noradrenergic nucleus Locus Coeruleus (LC) is precociously involved in Alzheimer's Disease (AD) pathology, and its degeneration progresses during the course of the disease. Using Magnetic Resonance Imaging (MRI), researchers showed also in vivo in patients the disruption of LC, which can be observed both in Mild Cognitively Impaired individuals and AD demented patients. In this study, we report the results of a follow-up neuroradiological assessment, in which we evaluated the LC degeneration overtime in a group of cognitively impaired patients, submitted to MRI both at baseline and at the end of a 2.5-year follow-up. We found that a progressive LC disruption can be observed also in vivo, involving the entire nucleus and associated with clinical diagnosis. Our findings parallel neuropathological ones, which showed a continuous increase of neuronal death and volumetric atrophy within the LC with the progression of Braak's stages for neurofibrillary pathology. This supports the reliability of MRI as a tool for exploring the integrity of the central noradrenergic system in neurodegenerative disorders.
Topics: Humans; Locus Coeruleus; Alzheimer Disease; Disease Progression; Aged; Male; Female; Magnetic Resonance Imaging; Aged, 80 and over; Follow-Up Studies; Neuroimaging; Nerve Degeneration; Atrophy; Middle Aged; Cognitive Dysfunction
PubMed: 38625557
DOI: 10.1007/s00429-024-02797-1 -
PeerJ 2024Driving is a complex skill involving various cognitive activities. Previous research has explored differences in the brain structures related to the navigational...
BACKGROUND
Driving is a complex skill involving various cognitive activities. Previous research has explored differences in the brain structures related to the navigational abilities of drivers compared to non-drivers. However, it remains unclear whether changes occur in the structures associated with low-level sensory and higher-order cognitive abilities in drivers.
METHODS
Gray matter volume, assessed voxel-based morphometry analysis of T1-weighted images, is considered a reliable indicator of structural changes in the brain. This study employs voxel-based morphological analysis to investigate structural differences between drivers ( = 22) and non-drivers ( = 20).
RESULTS
The results indicate that, in comparison to non-drivers, drivers exhibit significantly reduced gray matter volume in the middle occipital gyrus, middle temporal gyrus, supramarginal gyrus, and cerebellum, suggesting a relationship with driving-related experience. Furthermore, the volume of the middle occipital gyrus, and middle temporal gyrus, is found to be marginally negative related to the years of driving experience, suggesting a potential impact of driving experience on gray matter volume. However, no significant correlations were observed between driving experiences and frontal gray matter volume.
CONCLUSION
These findings suggest that driving skills and experience have a pronounced impact on the cortical areas responsible for low-level sensory and motor processing. Meanwhile, the influence on cortical areas associated with higher-order cognitive function appears to be minimal.
Topics: Gray Matter; Brain; Cerebellum; Cognition; Occipital Lobe
PubMed: 38618564
DOI: 10.7717/peerj.17228