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Human Brain Mapping Jun 2024Twin studies have found gross cerebellar volume to be highly heritable. However, whether fine-grained regional volumes within the cerebellum are similarly heritable is...
Twin studies have found gross cerebellar volume to be highly heritable. However, whether fine-grained regional volumes within the cerebellum are similarly heritable is still being determined. Anatomical MRI scans from two independent datasets (QTIM: Queensland Twin IMaging, N = 798, mean age 22.1 years; QTAB: Queensland Twin Adolescent Brain, N = 396, mean age 11.3 years) were combined with an optimised and automated cerebellum parcellation algorithm to segment and measure 28 cerebellar regions. We show that the heritability of regional volumetric measures varies widely across the cerebellum ( 47%-91%). Additionally, the good to excellent test-retest reliability for a subsample of QTIM participants suggests that non-genetic variance in cerebellar volumes is due primarily to unique environmental influences rather than measurement error. We also show a consistent pattern of strong associations between the volumes of homologous left and right hemisphere regions. Associations were predominantly driven by genetic effects shared between lobules, with only sparse contributions from environmental effects. These findings are consistent with similar studies of the cerebrum and provide a first approximation of the upper bound of heritability detectable by genome-wide association studies.
Topics: Humans; Cerebellum; Male; Adolescent; Female; Magnetic Resonance Imaging; Young Adult; Child; Adult; Organ Size; Twins, Monozygotic
PubMed: 38798116
DOI: 10.1002/hbm.26717 -
Hearing Research Aug 2024Although rats and mice are among the preferred animal models for investigating many characteristics of auditory function, they are rarely used to study an essential...
Although rats and mice are among the preferred animal models for investigating many characteristics of auditory function, they are rarely used to study an essential aspect of binaural hearing: the ability of animals to localize the sources of low-frequency sounds by detecting the interaural time difference (ITD), that is the difference in the time at which the sound arrives at each ear. In mammals, ITDs are mostly encoded in the medial superior olive (MSO), one of the main nuclei of the superior olivary complex (SOC). Because of their small heads and high frequency hearing range, rats and mice are often considered unable to use ITDs for sound localization. Moreover, their MSO is frequently viewed as too small or insignificant compared to that of mammals that use ITDs to localize sounds, including cats and gerbils. However, recent research has demonstrated remarkable similarities between most morphological and physiological features of mouse MSO neurons and those of MSO neurons of mammals that use ITDs. In this context, we have analyzed the structure and neural afferent and efferent connections of the rat MSO, which had never been studied by injecting neuroanatomical tracers into the nucleus. The rat MSO spans the SOC longitudinally. It is relatively small caudally, but grows rostrally into a well-developed column of stacked bipolar neurons. By placing small, precise injections of the bidirectional tracer biotinylated dextran amine (BDA) into the MSO, we show that this nucleus is innervated mainly by the most ventral and rostral spherical bushy cells of the anteroventral cochlear nucleus of both sides, and by the most ventrolateral principal neurons of the ipsilateral medial nucleus of the trapezoid body. The same experiments reveal that the MSO densely innervates the most dorsolateral region of the central nucleus of the inferior colliculus, the central region of the dorsal nucleus of the lateral lemniscus, and the most lateral region of the intermediate nucleus of the lateral lemniscus of its own side. Therefore, the MSO is selectively innervated by, and sends projections to, neurons that process low-frequency sounds. The structural and hodological features of the rat MSO are notably similar to those of the MSO of cats and gerbils. While these similarities raise the question of what functions other than ITD coding the MSO performs, they also suggest that the rat MSO is an appropriate model for future MSO-centered research.
Topics: Animals; Superior Olivary Complex; Auditory Pathways; Sound Localization; Axons; Rats; Male; Dextrans; Biotin; Acoustic Stimulation; Efferent Pathways; Olivary Nucleus; Female; Neuroanatomical Tract-Tracing Techniques; Rats, Wistar
PubMed: 38797037
DOI: 10.1016/j.heares.2024.109036 -
Nature Communications May 2024About half of the neurons in the parabrachial nucleus (PB) that are activated by CO are located in the external lateral (el) subnucleus, express calcitonin gene-related...
About half of the neurons in the parabrachial nucleus (PB) that are activated by CO are located in the external lateral (el) subnucleus, express calcitonin gene-related peptide (CGRP), and cause forebrain arousal. We report here, in male mice, that most of the remaining CO-responsive neurons in the adjacent central lateral (PBcl) and Kölliker-Fuse (KF) PB subnuclei express the transcription factor FoxP2 and many of these neurons project to respiratory sites in the medulla. PBcl neurons show increased intracellular calcium during wakefulness and REM sleep and in response to elevated CO during NREM sleep. Photo-activation of the PBcl neurons increases respiration, whereas either photo-inhibition of PBcl or genetic deletion of PB/KF neurons reduces the respiratory response to CO stimulation without preventing awakening. Thus, augmenting the PBcl/KF response to CO in patients with sleep apnea in combination with inhibition of the PBel neurons may avoid hypoventilation and minimize EEG arousals.
Topics: Animals; Hypercapnia; Neurons; Male; Parabrachial Nucleus; Forkhead Transcription Factors; Mice; Carbon Dioxide; Wakefulness; Respiration; Mice, Inbred C57BL; Calcitonin Gene-Related Peptide; Sleep, REM; Repressor Proteins
PubMed: 38796568
DOI: 10.1038/s41467-024-48773-5 -
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 -
BMC Neurology May 2024Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory autoimmune disease with high risk of recurrence and disability, the treatment goal is a recurrence free...
BACKGROUND
Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory autoimmune disease with high risk of recurrence and disability, the treatment goal is a recurrence free state. Area postrema (AP) is one of the most common involved area of NMOSD, which may have a particular significance in the pathogenesis of NMOSD and clinical heterogeneity. Our study is to investigate the clinical and recurrent characteristics AP onset NMOSD patients.
METHODS
A retrospective study was done in a cohort of 166 AQP4-IgG seropositive NMOSD patients which were identified by the 2015 IPND criteria. The patients were divided into AP onset (APO-NMOSD) group and non-AP onset (NAPO-NMOSD) group based on the initial episode location. Clinical features and recurrence differences of two groups were compared.
RESULTS
The APO-NMOSD group and NAPO-NMOSD group had a population ratio of 24:142. APO-NMOSD patients were younger (34.6y VS 42.3y, P = 0.013), had lower EDSS at first episode (0.7 VS 4.2, p = 0.028) and last follow up (1.9 VS 3.3, p = 0.001), more likely to have multi-core lesions at the first attack (33.3% VS 9.2%, P = 0.001). Also, they had a higher annual recurrence rate (0.4 ± 0.28 VS 0.19 ± 0.25, P = 0.012). In natural course NMOSD patients without immunotherapy, APO-NMSOD had a shorter time of first relapse (P < 0.001) and higher annual recurrence rate (0.31 ± 0.22 VS 0.16 ± 0.26, P = 0.038) than NAPO-NMOSD. APO-NMOSD group also have a higher risk of having the first relapsing compared to optic neuritis onset-NMOSD (HR 2.641, 95% CI 1.427-4.887, p = 0.002) and myelitis onset-NMOSD group (HR 3.593, 95% CI 1.736-7.438, p = 0.001). Compared to NAPO-NMOSD, APO-NMOSD has a higher likelihood of brainstem recurrence (28.6% vs. 4.7%, p<0.001) during the first recurrence, while NAPO-NMOSD is more susceptible to optic nerve involvement (10.7% vs. 41.1%, p = 0.01).
CONCLUSION
AQP4-IgG seropositive NMOSD patients with AP onset are youngers and have higher risk of recurrence. Clinicians should pay attention to AP damage in NMOSD, as it indicates a potential risk of recurrence.
TRIAL REGISTRATION
Retrospectively registered.
Topics: Humans; Neuromyelitis Optica; Female; Retrospective Studies; Adult; Male; Recurrence; Middle Aged; Area Postrema; Young Adult; Cohort Studies; Aquaporin 4
PubMed: 38773402
DOI: 10.1186/s12883-024-03667-3 -
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