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Cellular and Molecular Life Sciences :... May 2024Vanishing white matter (VWM) is a leukodystrophy caused by biallelic pathogenic variants in eukaryotic translation initiation factor 2B. To date, it remains unclear...
Vanishing white matter (VWM) is a leukodystrophy caused by biallelic pathogenic variants in eukaryotic translation initiation factor 2B. To date, it remains unclear which factors contribute to VWM pathogenesis. Here, we investigated the basis of VWM pathogenesis using the 2b5 mouse model. We first mapped the temporal proteome in the cerebellum, corpus callosum, cortex, and brainstem of 2b5 and wild-type (WT) mice. Protein changes observed in 2b5 mice were then cross-referenced with published proteomic datasets from VWM patient brain tissue to define alterations relevant to the human disease. By comparing 2b5 mice with their region- and age-matched WT counterparts, we showed that the proteome in the cerebellum and cortex of 2b5 mice was already dysregulated prior to pathology development, whereas proteome changes in the corpus callosum only occurred after pathology onset. Remarkably, protein changes in the brainstem were transient, indicating that a compensatory mechanism might occur in this region. Importantly, 2b5 mouse brain proteome changes reflect features well-known in VWM. Comparison of the 2b5 mouse and VWM patient brain proteomes revealed shared changes. These could represent changes that contribute to the disease or even drive its progression in patients. Taken together, we show that the 2b5 mouse brain proteome is affected in a region- and time-dependent manner. We found that the 2b5 mouse model partly replicates the human disease at the protein level, providing a resource to study aspects of VWM pathogenesis by highlighting alterations from early to late disease stages, and those that possibly drive disease progression.
Topics: Animals; Proteomics; Mice; Humans; Proteome; Leukoencephalopathies; Disease Models, Animal; White Matter; Corpus Callosum; Eukaryotic Initiation Factor-2B; Brain; Mice, Inbred C57BL; Cerebellum
PubMed: 38789799
DOI: 10.1007/s00018-024-05258-4 -
Medicine May 2024Subacute combined degeneration of the spinal cord is a degenerative disease of the central and peripheral nervous systems caused by vitamin B12 deficiency, mainly...
RATIONALE
Subacute combined degeneration of the spinal cord is a degenerative disease of the central and peripheral nervous systems caused by vitamin B12 deficiency, mainly involving the spinal cord posterior, lateral, and peripheral nerves, but rarely involving the cerebellum.
PATIENT CONCERNS
A 41-year-old woman presented with a 2-year history of walking unsteadily. Her hematologic examination revealed megaloblastic anemia and vitamin B12 deficiency. Electromyography showed multiple peripheral nerve damage (sensory fibers and motor fibers were involved). Imaging examination showed long T2 signal in the cervical, thoracic and lumbar spinal cord and cerebellum. Gastroscopy revealed autoimmune gastritis.
DIAGNOSES
Subacute combined degeneration of the spinal cord.
INTERVENTIONS
By supplementing with vitamin B12.
OUTCOMES
The patient's symptoms of limb weakness, diet, and consciousness were improved, and the muscle strength of both lower limbs recovered to grade IV.
LESSONS
The symptomatic people should seek medical treatment in time to avoid further deterioration of the disease. When esophagogastroduodenoscopy is performed as part of routine physical examination in asymptomatic people, it should be checked for the presence of autoimmune gastritis. Early diagnosis can prevent irreversible neuropathy.
Topics: Humans; Female; Adult; Subacute Combined Degeneration; Vitamin B 12 Deficiency; Gastritis; Vitamin B 12; Cerebellum; Magnetic Resonance Imaging
PubMed: 38788012
DOI: 10.1097/MD.0000000000037605 -
Scientific Reports May 2024Repetitive transcranial magnetic stimulation (rTMS) for alleviating negative symptoms and cognitive dysfunction in schizophrenia commonly targets the left dorsolateral...
Repetitive transcranial magnetic stimulation (rTMS) for alleviating negative symptoms and cognitive dysfunction in schizophrenia commonly targets the left dorsolateral prefrontal cortex (LDLPFC). However, the therapeutic effectiveness of rTMS at this site remains inconclusive and increasingly, studies are focusing on cerebellar rTMS. Recently, prolonged intermittent theta-burst stimulation (iTBS) has emerged as a rapid-acting form of rTMS with promising clinical benefits. This study explored the cognitive and neurophysiological effects of prolonged iTBS administered to the LDLPFC and cerebellum in a healthy cohort. 50 healthy participants took part in a cross-over study and received prolonged (1800 pulses) iTBS targeting the LDLPFC, cerebellar vermis, and sham iTBS. Mixed effects repeated measures models examined cognitive and event-related potentials (ERPs) from 2-back (P300, N200) and Stroop (N200, N450) tasks after stimulation. Exploratory non-parametric cluster-based permutation tests compared ERPs between conditions. There were no significant differences between conditions for behavioural and ERP outcomes on the 2-back and Stroop tasks. Exploratory cluster-based permutation tests of ERPs did not identify any significant differences between conditions. We did not find evidence that a single session of prolonged iTBS administered to either the LDLPFC or cerebellum could cause any cognitive or ERP changes compared to sham in a healthy sample.
Topics: Humans; Male; Transcranial Magnetic Stimulation; Female; Adult; Cerebellum; Executive Function; Prefrontal Cortex; Evoked Potentials; Young Adult; Healthy Volunteers; Cross-Over Studies; Theta Rhythm; Cognition; Dorsolateral Prefrontal Cortex
PubMed: 38782921
DOI: 10.1038/s41598-024-61404-9 -
ENeuro Jun 2024The Cre-lox system is an indispensable tool in neuroscience research for targeting gene deletions to specific cellular populations. Here we assess the utility of several...
The Cre-lox system is an indispensable tool in neuroscience research for targeting gene deletions to specific cellular populations. Here we assess the utility of several transgenic lines, along with a viral approach, for targeting cerebellar Purkinje cells (PCs) in mice. Using a combination of a fluorescent reporter line () to indicate -mediated recombination and a floxed Dystroglycan line ( ), we show that reporter expression does not always align precisely with loss of protein. The commonly used line exhibits a gradual mosaic pattern of recombination in PCs from Postnatal Day 7 (P7) to P14, while loss of Dag1 protein is not complete until P30. drives recombination in precursor cells that give rise to GABAergic neurons in the embryonic cerebellum, including PCs and molecular layer interneurons. However, due to its transient expression in precursors, results in stochastic loss of Dag1 protein in these neurons. , which is often described as a "pan-neuronal" line for the central nervous system, does not drive -mediated recombination in PCs. We identify a line that drives efficient and complete recombination in embryonic PCs, resulting in loss of Dag1 protein before the period of synaptogenesis. -mediated delivery of at P0 results in gradual transduction of PCs during the second postnatal week, with loss of Dag1 protein not reaching appreciable levels until P35. These results characterize several tools for targeting conditional deletions in cerebellar PCs at different developmental stages and illustrate the importance of validating the loss of protein following recombination.
Topics: Animals; Purkinje Cells; Integrases; Mice, Transgenic; Mice; Recombination, Genetic; Alleles; Gene Deletion; Cerebellum; Mice, Inbred C57BL; Transcription Factors
PubMed: 38777609
DOI: 10.1523/ENEURO.0149-24.2024 -
Revista Da Associacao Medica Brasileira... 2024In this study, the effects of leptin, cannabinoid-1 (CB1) receptor agonist ACEA and antagonist AM251, and the interactions between leptin and CB1 receptor...
OBJECTIVE
In this study, the effects of leptin, cannabinoid-1 (CB1) receptor agonist ACEA and antagonist AM251, and the interactions between leptin and CB1 receptor agonist/antagonist on oxidant and antioxidant enzymes in the cerebrum, cerebellum, and pedunculus cerebri tissue samples were investigated in the penicillin-induced epileptic model.
METHODS
Male Wistar albino rats (n=56) were included in this study. In anesthetized animals, 500 IU penicillin-G potassium was injected into the cortex to induce epileptiform activity. Leptin (1 μg), ACEA (7.5 μg), AM251 (0.25 μg), and the combinations of the leptin+ACEA and leptin+AM251 were administered intracerebroventricularly (i.c.v.) after penicillin injections. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels were measured in the cerebral tissue samples and plasma with the ELISA method.
RESULTS
MDA levels increased, while SOD and GPx levels decreased after penicillin injection in the cerebrum and cerebellum. The efficacy of penicillin on SOD, MDA and GPx levels was further enhanced after leptin or AM251 injections. Whereas, ACEA decreased the MDA levels and increased GPx levels compared with the penicillin group. Administration of AM251+leptin did not change any oxidation parameter compared with the AM251. Furthermore, co-administration of ACEA and leptin significantly increased oxidative stress compared with the ACEA-treated group by increasing MDA and decreasing GPx levels.
CONCLUSION
It was concluded that leptin reversed the effect of ACEA on oxidative stress. Co-administration of AM251 and leptin did not change oxidative stress compared with the AM251-treated group suggesting AM251 and leptin affect oxidative stress using the same pathways.
Topics: Animals; Leptin; Male; Rats, Wistar; Receptor, Cannabinoid, CB1; Epilepsy; Malondialdehyde; Superoxide Dismutase; Piperidines; Pyrazoles; Glutathione Peroxidase; Arachidonic Acids; Rats; Oxidative Stress; Disease Models, Animal; Penicillins; Cerebellum; Cerebrum; Enzyme-Linked Immunosorbent Assay; Cannabinoid Receptor Agonists
PubMed: 38775505
DOI: 10.1590/1806-9282.20231333 -
Proceedings of the National Academy of... May 2024Optimal decision-making balances exploration for new information against exploitation of known rewards, a process mediated by the locus coeruleus and its norepinephrine...
Optimal decision-making balances exploration for new information against exploitation of known rewards, a process mediated by the locus coeruleus and its norepinephrine projections. We predicted that an exploitation-bias that emerges in older adulthood would be associated with lower microstructural integrity of the locus coeruleus. Leveraging in vivo histological methods from quantitative MRI-magnetic transfer saturation-we provide evidence that older age is associated with lower locus coeruleus integrity. Critically, we demonstrate that an exploitation bias in older adulthood, assessed with a foraging task, is sensitive and specific to lower locus coeruleus integrity. Because the locus coeruleus is uniquely vulnerable to Alzheimer's disease pathology, our findings suggest that aging, and a presymptomatic trajectory of Alzheimer's related decline, may fundamentally alter decision-making abilities in later life.
Topics: Locus Coeruleus; Humans; Decision Making; Aged; Male; Female; Aging; Magnetic Resonance Imaging; Alzheimer Disease; Middle Aged; Aged, 80 and over; Reward
PubMed: 38771873
DOI: 10.1073/pnas.2322617121 -
Zoological Research May 2024Painful stimuli elicit first-line reflexive defensive reactions and, in many cases, also evoke second-line recuperative behaviors, the latter of which reflects the...
Painful stimuli elicit first-line reflexive defensive reactions and, in many cases, also evoke second-line recuperative behaviors, the latter of which reflects the sensing of tissue damage and the alleviation of suffering. The lateral parabrachial nucleus (lPBN), composed of external- (elPBN), dorsal- (dlPBN), and central/superior-subnuclei (jointly referred to as slPBN), receives sensory inputs from spinal projection neurons and plays important roles in processing affective information from external threats and body integrity disruption. However, the organizational rules of lPBN neurons that provoke diverse behaviors in response to different painful stimuli from cutaneous and deep tissues remain unclear. In this study, we used region-specific neuronal depletion or silencing approaches combined with a battery of behavioral assays to show that slPBN neurons expressing substance P receptor ( ) (lPBN ) are crucial for driving pain-associated self-care behaviors evoked by sustained noxious thermal and mechanical stimuli applied to skin or bone/muscle, while elPBN neurons are dispensable for driving such reactions. Notably, lPBN neurons are specifically required for forming sustained somatic pain-induced negative teaching signals and aversive memory but are not necessary for fear-learning or escape behaviors elicited by external threats. Lastly, both lPBN and elPBN neurons contribute to chemical irritant-induced nocifensive reactions. Our results reveal the functional organization of parabrachial substrates that drive distinct behavioral outcomes in response to sustained pain versus external danger under physiological conditions.
Topics: Animals; Parabrachial Nucleus; Mice; Nociception; Neurons; Pain; Male; Behavior, Animal
PubMed: 38766746
DOI: 10.24272/j.issn.2095-8137.2023.412 -
European Journal of Histochemistry : EJH May 2024Previous studies on the granular layer of the cerebellar cortex have revealed a wide distribution of different subpopulations of less-known large neuron types, called... (Review)
Review
Previous studies on the granular layer of the cerebellar cortex have revealed a wide distribution of different subpopulations of less-known large neuron types, called "non-traditional large neurons", which are distributed in three different zones of the granular layer. These neuron types are mainly involved in the formation of intrinsiccircuits inside the cerebellar cortex. A subpopulation of these neuron types is represented by the synarmotic neuron, which could play a projective role within the cerebellar circuitry. The synarmotic neuron cell body map within the internal zone of the granular layer or in the subjacent white substance. Furthermore, the axon crosses the granular layer and runs in the subcortical white substance, to reenter in an adjacent granular layer, associating two cortico-cerebellar regions of the same folium or of different folia, or could project to the intrinsic cerebellar nuclei. Therefore, along with the Purkinje neuron, the traditional projective neuron type of the cerebellar cortex, the synarmotic neuron is candidate to represent the second projective neuron type of the cerebellar cortex. Studies of chemical neuroanatomy evidenced a predominant inhibitory GABAergic nature of the synarmotic neuron, suggesting that it may mediate an inhibitory GABAergic output of cerebellar cortex within cortico-cortical interconnections or in projections towards intrinsic cerebellar nuclei. On this basis, the present minireview mainly focuses on the morphofunctional and neurochemical data of the synarmotic neuron, and explores its potential involvement in some forms of cerebellar ataxias.
Topics: Cerebellar Cortex; Animals; Humans; Neurons; GABAergic Neurons
PubMed: 38766720
DOI: 10.4081/ejh.2024.3954 -
Brain Stimulation 2024
Topics: Humans; Trigeminal Nerve; Locus Coeruleus; Pupil; Male; Adult; Female; Electric Stimulation; Healthy Volunteers; Young Adult
PubMed: 38763412
DOI: 10.1016/j.brs.2024.05.008 -
NeuroImage Jul 2024Cerebellar intermittent theta burst stimulation (iTBS) modulates the excitability of the cerebral cortex and may enhance attentional performance. To date, few studies... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of one-week bilateral cerebellar iTBS on resting-state functional brain network and multi-task attentional performance in healthy individuals: A randomized, sham-controlled trial.
BACKGROUND
Cerebellar intermittent theta burst stimulation (iTBS) modulates the excitability of the cerebral cortex and may enhance attentional performance. To date, few studies have conducted iTBS on healthy subjects for one week and used electroencephalography (EEG) to investigate the effect of multiple stimulation sessions on resting-state functional brain networks and the daily stimulation effect on attentional performance.
METHODS
16 healthy subjects participated in a one-week experiment, receiving bilateral cerebellar iTBS or sham stimulation and engaging in multi-task attentional training. The primary measures were the one-week attentional performance and pre- and post-experiment resting-state EEG activities. Amplitude Envelope Correlation (AEC) was used to construct the functional connectivity in the eye-open (EO) and eye-closed (EC) phases.
RESULTS
At least three sessions of iTBS were required to enhance multi-task performance significantly, whereas only one or two sessions failed to elicit the improvement. Compared with the control group, iTBS induced significant changes in PSD, AEC functional connectivity, and AEC network properties during the EO phase, while it had little effect during the EC phase. During the EO phase, the network property changes of the iTBS subject were correlated with improved attentional performance.
CONCLUSION
The multi-task performance requires multiple stimulations to enhance. iTBS affects the resting-state alpha band brain activities during the EO rather than the EC phase. The AEC network properties may serve as a biomarker to assess the attentional potential of healthy subjects.
Topics: Humans; Attention; Male; Female; Cerebellum; Adult; Young Adult; Transcranial Magnetic Stimulation; Electroencephalography; Nerve Net; Rest; Healthy Volunteers
PubMed: 38761882
DOI: 10.1016/j.neuroimage.2024.120648