Immune vigilant state in deep cerebellar nuclei is contributed by multiple glial populations and linked to reduced amyloid plaque pathology.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE223076 | GEO | 2023/08/31
REPOSITORIES: GEO
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Project description:BackgroundIn Friedreich's ataxia (FA) the genetically decreased expression of the mitochondrial protein frataxin leads to disturbance of the mitochondrial iron metabolism. Within the cerebellum the dentate nuclei (DN) are primarily affected. Histopathological studies show atrophy and accumulation of mitochondrial iron in DN. Dentate iron content has been suggested as a biomarker to measure the effects of siderophores/antioxidant treatment of FA. We assessed the iron content and the volume of DN in FA patients and controls based on ultra-high-field MRI (7 Tesla) images.MethodsFourteen FA patients (mean age 38.1 yrs) and 14 age- and gender-matched controls participated. Multi-echo gradient echo and susceptibility weighted imaging (SWI) sequences were acquired on a 7 T whole-body scanner. For comparison SWI images were acquired on a 1.5 T MR scanner. Volumes of the DN and cerebellum were assessed at 7 and 1.5 T, respectively. Parametric maps of T2 and T2* sequences were created and proton transverse relaxation rates were estimated as a measure of iron content.ResultsIn FA, the DN and the cerebellum were significantly smaller compared to controls. However, proton transverse relaxation rates of the DN were not significantly different between both groups.ConclusionsApplying in vivo MRI methods we could demonstrate significant atrophy of the DN in the presence of normal iron content. The findings suggest that relaxation rates are not reliable biomarkers in clinical trials evaluating the potential effect of FA therapy.
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Project description:Deep cerebellar nuclei are a key structure of the cerebellum that are involved in processing motor and sensory information. It is thus a crucial step to accurately segment deep cerebellar nuclei for the understanding of the cerebellum system and its utility in deep brain stimulation treatment. However, it is challenging to clearly visualize such small nuclei under standard clinical magnetic resonance imaging (MRI) protocols and therefore precise segmentation is not feasible. Recent advances in 7 Tesla (T) MRI technology and great potential of deep neural networks facilitate automatic patient-specific segmentation. In this paper, we propose a novel deep learning framework (referred to as DCN-Net) for fast, accurate, and robust patient-specific segmentation of deep cerebellar dentate and interposed nuclei on 7T diffusion MRI. DCN-Net effectively encodes contextual information on the patch images without consecutive pooling operations and adding complexity via proposed dilated dense blocks. During the end-to-end training, label probabilities of dentate and interposed nuclei are independently learned with a hybrid loss, handling highly imbalanced data. Finally, we utilize self-training strategies to cope with the problem of limited labeled data. To this end, auxiliary dentate and interposed nuclei labels are created on unlabeled data by using DCN-Net trained on manual labels. We validate the proposed framework using 7T B0 MRIs from 60 subjects. Experimental results demonstrate that DCN-Net provides better segmentation than atlas-based deep cerebellar nuclei segmentation tools and other state-of-the-art deep neural networks in terms of accuracy and consistency. We further prove the effectiveness of the proposed components within DCN-Net in dentate and interposed nuclei segmentation.
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Project description:Lysosomes robustly accumulate within axonal swellings at Alzheimer's disease (AD) amyloid plaques. However, the underlying mechanisms and disease relevance of such lysosome accumulations are not well understood. Motivated by these problems, we identified JNK-interacting protein 3 (JIP3) as an important regulator of axonal lysosome transport and maturation. JIP3 knockout mouse neuron primary cultures accumulate lysosomes within focal axonal swellings that resemble the dystrophic axons at amyloid plaques. These swellings contain high levels of amyloid precursor protein processing enzymes (BACE1 and presenilin 2) and are accompanied by elevated Aβ peptide levels. The in vivo importance of the JIP3-dependent regulation of axonal lysosomes was revealed by the worsening of the amyloid plaque pathology arising from JIP3 haploinsufficiency in a mouse model of AD. These results establish the critical role of JIP3-dependent axonal lysosome transport in regulating amyloidogenic amyloid precursor protein processing and support a model wherein Aβ production is amplified by plaque-induced axonal lysosome transport defects.
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Project description:We profiled micro-dissected deep cerebellar nuclei (DCN) from 2-3 month old mice for single-nucleus RNAseq to study the cellular populations present in the region and in particular, to define the molecular subtype identity of glutamatergic neurons. From our data, we isolated vGluT2-expressing transcriptomes and identified a graded and anti-correlated expression of two sets of genes associated with the first principal component (PC1) in our dataset, defining separate cell populations. Multiplexed in situ hybridization analysis confirmed the nonoverlapping expression patterns and revealed their topography within the DCN. We then probed the function of these neurons in further experiments and found that one of the two populations was associated with food intake. Our broader study defines a conserved satiation centre and neural mechanism that may represent a novel therapeutic target for the management of excessive eating.
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Project description:Purkinje cells (PC) control deep cerebellar nuclei (DCN), which in turn inhibit inferior olive nucleus, closing a positive feedback loop via climbing fibers. PC highly express potassium BK channels but their contribution to the olivo-cerebellar loop is not clear. Using multiple-unit recordings in alert mice we found in that selective deletion of BK channels in PC induces a decrease in their simple spike firing with a beta-range bursting pattern and fast intraburst frequency (~200?Hz). To determine the impact of this abnormal rhythm on the olivo-cerebellar loop we analyzed simultaneous rhythmicity in different cerebellar structures. We found that this abnormal PC rhythmicity is transmitted to DCN neurons with no effect on their mean firing frequency. Long term depression at the parallel-PC synapses was altered and the intra-burst complex spike spikelets frequency was increased without modification of the mean complex spike frequency in BK-PC-/- mice. We argue that the ataxia present in these conditional knockout mice could be explained by rhythmic disruptions transmitted from mutant PC to DCN but not by rate code modification only. This suggests a neuronal mechanism for ataxia with possible implications for human disease.
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Project description:Background: Essential tremor is among the commonly observed movement disorders in clinical practice, however the exact pathophysiological mechanisms underlying tremor are unknown. It has been suggested that Purkinje cell alterations play a causal factor in tremorgenesis. Altered levels of inhibitory (GABA) and excitatory (glutamate+glutamine, Glx) neurotransmitters could be markers for Purkinje cell alterations. We hypothesize that GABA and Glx levels in the dentate nuclei could be differentially altered in patients responsive to either anticonvulsants or β-adrenergic blockers. Methods: In this explorative study in patients with essential tremor, we measured gamma-aminobutyric acid (GABA) and glutamate+glutamine (Glx) levels in the dentate nucleus region using 1H-magnetic resonance spectroscopy (MRS) in seven patients using propranolol, five patients using anticonvulsants, and eight healthy controls. Results: There were no group differences with respect to GABA+/Cr, Glx/Cr, NAA/Cr, and GABA+/Glx ratios. There was no correlation with tremor severity. Discussion: Our results are in line with previously published studies; however, additional studies on a larger number of patients are warranted to confirm these findings. Furthermore medication-subgroups did not exhibit differences with respect to GABA+/Cr, Glx/Cr, NAA/Cr, and GABA+/Glx ratios. A recent study, of similar size, found an inverse association between tremor severity and the GABA+/Glx ratio in the cerebellum of essential tremor patients. We were unable to replicate these findings. The field of tremor research is plagued by heterogeneous results, and we would caution against drawing firm conclusions based on pilot studies.
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Project description:The deep cerebellar nuclei (DCN) have been suggested to play a critical role in sensorimotor learning and some forms of long-term synaptic plasticity observed in vitro have been proposed as a possible substrate. However, till now it was not clear whether and how DCN neuron responses manifest long-lasting changes in vivo. Here, we have characterized DCN unit responses to tactile stimulation of the facial area in anesthetized mice and evaluated the changes induced by theta-sensory stimulation (TSS), a 4 Hz stimulation pattern that is known to induce plasticity in the cerebellar cortex in vivo. DCN units responded to tactile stimulation generating bursts and pauses, which reflected combinations of excitatory inputs most likely relayed by mossy fiber collaterals, inhibitory inputs relayed by Purkinje cells, and intrinsic rebound firing. Interestingly, initial bursts and pauses were often followed by stimulus-induced oscillations in the peri-stimulus time histograms (PSTH). TSS induced long-lasting changes in DCN unit responses. Spike-related potentiation and suppression (SR-P and SR-S), either in units initiating the response with bursts or pauses, were correlated with stimulus-induced oscillations. Fitting with resonant functions suggested the existence of peaks in the theta-band (burst SR-P at 9 Hz, pause SR-S at 5 Hz). Optogenetic stimulation of the cerebellar cortex altered stimulus-induced oscillations suggesting that Purkinje cells play a critical role in the circuits controlling DCN oscillations and plasticity. This observation complements those reported before on the granular and molecular layers supporting the generation of multiple distributed plasticities in the cerebellum following naturally patterned sensory entrainment. The unique dependency of DCN plasticity on circuit oscillations discloses a potential relationship between cerebellar learning and activity patterns generated in the cerebellar network.
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