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Clinical Neuroradiology Dec 2023Despite its small size the cerebellum is an anatomically complex and functionally important part of the brain. Traditionally the cerebellum is viewed as a motor control... (Review)
Review
Despite its small size the cerebellum is an anatomically complex and functionally important part of the brain. Traditionally the cerebellum is viewed as a motor control structure entirely devoted to motor control and learning, but recent functional magnetic resonance imaging (fMRI) studies demonstrated significant involvement of the cerebellum in higher order cognitive functions. The anatomical complexity of the cerebellum is reflected by the several nomenclature systems that exist for the description of cerebellar anatomy. The cerebellum can be affected by a variety of pathological processes, including congenital, infectious and inflammatory, neoplastic, vascular, degenerative and toxic metabolic diseases. The purpose of this pictorial review is to (1) provide a general overview of cerebellar anatomy and function, (2) demonstrate normal cerebellar anatomy on imaging studies, and (3) illustrate both common as well as rare pathological conditions affecting the cerebellum.
Topics: Humans; Cerebellum; Brain; Magnetic Resonance Imaging; Vascular Diseases
PubMed: 37410171
DOI: 10.1007/s00062-023-01326-7 -
Journal of Neuroinflammation Sep 2023Most current disease-modifying therapies approved for multiple sclerosis (MS) are immunomodulatory drugs that counteract the aberrant activity of the immune system....
BACKGROUND
Most current disease-modifying therapies approved for multiple sclerosis (MS) are immunomodulatory drugs that counteract the aberrant activity of the immune system. Hence, new pharmacological interventions that drive anti-inflammatory activity and neuroprotection would represent interesting alternative therapeutic approaches or complementary strategies to treat progressive forms of MS. There is evidence of reduced noradrenaline levels and alterations to locus coeruleus (LC) noradrenergic neurons in MS patients, as well as in animal models of this disease, potentially factors contributing to the pathophysiology. Drugs that enhance noradrenaline appear to have some beneficial effects in MS, suggesting their potential to dampen the underlying pathology and disease progression.
METHODS
Therefore, we explored the consequences of chronic LC noradrenergic neurons activation by chemogenetics in experimental autoimmune encephalomyelitis (EAE) mice, the most widely used experimental model of MS. LC activation from the onset or the peak of motor symptoms was explored as two different therapeutic approaches, assessing the motor and non-motor behavioral changes as EAE progresses, and studying demyelination, inflammation and glial activation in the spinal cord and cerebral cortex during the chronic phase of EAE.
RESULTS
LC activation from the onset of motor symptoms markedly alleviated the motor deficits in EAE mice, as well as their anxiety-like behavior and sickness, in conjunction with reduced demyelination and perivascular infiltration in the spinal cord and glial activation in the spinal cord and prefrontal cortex (PFC). When animals exhibited severe paralysis, LC activation produced a modest alleviation of EAE motor symptoms and it enhanced animal well-being, in association with an improvement of the EAE pathology at the spinal cord and PFC level. Interestingly, the reduced dopamine beta-hydroxylase expression associated with EAE in the spinal cord and PFC was reversed through chemogenetic LC activation.
CONCLUSION
Therefore, clear anti-inflammatory and neuroprotective effects were produced by the selective activation of LC noradrenergic neurons in EAE mice, having greater benefits when LC activation commenced earlier. Overall, these data suggest noradrenergic LC neurons may be targets to potentially alleviate some of the motor and non-motor symptoms in MS.
Topics: Animals; Mice; Multiple Sclerosis; Locus Coeruleus; Encephalomyelitis, Autoimmune, Experimental; Adrenergic Neurons; Norepinephrine
PubMed: 37658434
DOI: 10.1186/s12974-023-02865-z -
Cell Stem Cell Jan 2024The developing human cerebellum has a greater diversity of progenitor types than that of the mouse, necessitating a human-based model for studying cerebellar development...
The developing human cerebellum has a greater diversity of progenitor types than that of the mouse, necessitating a human-based model for studying cerebellar development and disease. Atamian et al. developed a 3D organoid model of cerebellar development, which recapitulates many cell types found in the developing human cerebellum, including Purkinje-neuron-like cells.
Topics: Humans; Animals; Mice; Organoids; Cerebellum
PubMed: 38181748
DOI: 10.1016/j.stem.2023.12.007 -
Translational Psychiatry Sep 2023Autism spectrum disorder (ASD) is a highly heritable condition with a large variation in cognitive function. Here we investigated the shared genetic architecture between...
Autism spectrum disorder (ASD) is a highly heritable condition with a large variation in cognitive function. Here we investigated the shared genetic architecture between cognitive traits (intelligence (INT) and educational attainment (EDU)), and risk loci jointly associated with ASD and the cognitive traits. We analyzed data from genome-wide association studies (GWAS) of INT (n = 269,867), EDU (n = 766,345) and ASD (cases n = 18,381, controls n = 27,969). We used the bivariate causal mixture model (MiXeR) to estimate the total number of shared genetic variants, local analysis of co-variant annotation (LAVA) to estimate local genetic correlations, conditional false discovery rate (cond/conjFDR) to identify specific overlapping loci. The MiXeR analyses showed that 12.7k genetic variants are associated with ASD, of which 12.0k variants are shared with EDU, and 11.1k are shared with INT with both positive and negative relationships within overlapping variants. The majority (59-68%) of estimated shared loci have concordant effect directions, with a positive, albeit modest, genetic correlation between ASD and EDU (r = 0.21, p = 2e-13) and INT (r = 0.22, p = 4e-12). We discovered 43 loci jointly associated with ASD and cognitive traits (conjFDR<0.05), of which 27 were novel for ASD. Functional analysis revealed significant differential expression of candidate genes in the cerebellum and frontal cortex. To conclude, we quantified the genetic architecture shared between ASD and cognitive traits, demonstrated mixed effect directions, and identified the associated genetic loci and molecular pathways. The findings suggest that common genetic risk factors for ASD can underlie both better and worse cognitive functioning across the ASD spectrum, with different underlying biology.
Topics: Humans; Autism Spectrum Disorder; Genome-Wide Association Study; Academic Success; Cerebellum; Cognition
PubMed: 37709755
DOI: 10.1038/s41398-023-02563-7 -
Stem Cell Reports Jul 2023Retrotrapezoid nucleus (RTN) neurons in the brainstem regulate the ventilatory response to hypercarbia. It is unclear how PHOX2B-polyalanine repeat mutations...
Retrotrapezoid nucleus (RTN) neurons in the brainstem regulate the ventilatory response to hypercarbia. It is unclear how PHOX2B-polyalanine repeat mutations (PHOX2B-PARMs) alter the function of PHOX2B and perturb the formation of RTN neurons. Here, we generated human brainstem organoids (HBSOs) with RTN-like neurons from human pluripotent stem cells. Single-cell transcriptomics revealed that expression of PHOX2B+7Ala PARM alters the differentiation trajectories of the hindbrain neurons and hampers the formation of the RTN-like neurons in HBSOs. With the unguided cerebral organoids (HCOs), PHOX2B+7Ala PARM interrupted the patterning of PHOX2B+ neurons with dysregulation of Hedgehog pathway and HOX genes. With complementary use of HBSOs and HCOs with a patient and two mutant induced pluripotent stem cell lines carrying different polyalanine repetition in PHOX2B, we further defined the association between the length of polyalanine repetition and malformation of RTN-respiratory center and demonstrated the potential toxic gain of function of PHOX2B-PARMs, highlighting the uniqueness of these organoid models for disease modeling.
Topics: Humans; Homeodomain Proteins; Hedgehog Proteins; Transcription Factors; Rhombencephalon; Neurons; Mutation
PubMed: 37352849
DOI: 10.1016/j.stemcr.2023.05.020 -
ENeuro Sep 2023The cerebellum communicates with brain areas critically involved in control of goal-directed behaviors including the prefrontal and orbitofrontal cortices and midbrain...
The cerebellum communicates with brain areas critically involved in control of goal-directed behaviors including the prefrontal and orbitofrontal cortices and midbrain and basal ganglia structures. In particular, the posterior cerebellum is important for cognitive flexibility and has been implicated in alcohol and drug-related memory. We hypothesized that the cerebellum, through its multiple connections to reward-related brain circuitry, regulates alcohol consumption. To test this, we expressed inhibitory designer receptors exclusively activated by designer drugs (DREADDs) in molecular layer interneurons (MLIs) in anterior (IV-V) or posterior (VI-VIII) cerebellar lobules of male and female mice and activated them during alcohol drinking sessions. In a home-cage drinking paradigm, alcohol consumption was significantly decreased by clozapine-N-oxide (CNO) or deschloroclozapine (DCZ) administration in male mice expressing DREADDs in posterior but not anterior lobules. CNO/DCZ injections did not affect drinking in DREADD expressing female mice or in male mice expressing the control vector. Activation of DREADDs expressed in anterior or posterior lobules had no effect on sucrose or quinine consumption in male or female mice. During operant self-administration sessions, DCZ decreased the number of licks and bouts in male but not female mice expressing DREADDs in posterior lobules with no effect in control vector mice. Performance on an accelerated rotarod was unaffected by chemogenetic manipulation while distance traveled in the open field was decreased by DREADD activation in anterior but not posterior lobules. These results indicate that neuronal activity within the posterior cerebellar cortex plays an important role in the control of alcohol consumption in male mice.
Topics: Male; Animals; Mice; Cerebellum; Brain; Basal Ganglia; Ethanol; Interneurons
PubMed: 37679043
DOI: 10.1523/ENEURO.0037-23.2023 -
Child's Nervous System : ChNS :... Aug 2023Benedict Stilling (1810-1879), was a prolific, prominent, and ambitious anatomist, who performed works on the organization of the nervous system for many years. He made...
Benedict Stilling (1810-1879), was a prolific, prominent, and ambitious anatomist, who performed works on the organization of the nervous system for many years. He made numerous observations on the anatomy of the nervous system in various animal species. Stilling contributed to the establishment of significant foundations in the anatomy of the spinal cord, brainstem, and cerebellum. Stilling paved the way for future researchers by describing the techniques he used in his diligent studies published in his published books. In his books, which include many drawings and cadaveric images, he revealed the relationships between the structures in the nervous system. He also made significant contributions to neuroanatomy terminology by coining terms in these books. At the same time, some nuclei in the anatomy of the nervous system were later named after him as an eponym by many researchers. Therefore, Stilling's neuroanatomical works, which are still important today, should be appreciated. This article aims to emphasize his pioneering work in neuroanatomy.
Topics: Humans; Animals; Male; Neuroanatomy; Spinal Cord; Brain Stem; Cerebellum; Eponyms
PubMed: 35357551
DOI: 10.1007/s00381-022-05512-9 -
Cell Reports Sep 2023While synaptic plasticity is considered the basis of learning and memory, modifications of the intrinsic excitability of neurons can amplify the output of neuronal...
While synaptic plasticity is considered the basis of learning and memory, modifications of the intrinsic excitability of neurons can amplify the output of neuronal circuits and consequently change behavior. However, the mechanisms that underlie learning-induced changes in intrinsic excitability during memory formation are poorly understood. In the cerebellum, we find that silencing molecular layer interneurons completely abolishes fear memory, revealing their critical role in memory consolidation. The fear conditioning paradigm produces a lasting reduction in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in these interneurons. This change increases intrinsic membrane excitability and enhances the response to synaptic stimuli. HCN loss is driven by a decrease in endocannabinoid levels via altered cGMP signaling. In contrast, an increase in release of cerebellar endocannabinoids during memory consolidation abolishes HCN plasticity. Thus, activity in cerebellar interneurons drives fear memory formation via a learning-specific increase in intrinsic excitability, and this process requires the loss of endocannabinoid-HCN signaling.
Topics: Memory Consolidation; Endocannabinoids; Interneurons; Cerebellum; Fear; Neuronal Plasticity
PubMed: 37656617
DOI: 10.1016/j.celrep.2023.113057 -
Cerebellum (London, England) Apr 2024The cerebellum is a key player in many brain functions and a major topic of neuroscience research. However, the cerebellar nuclei (CN), the main output structures of the... (Review)
Review
The cerebellum is a key player in many brain functions and a major topic of neuroscience research. However, the cerebellar nuclei (CN), the main output structures of the cerebellum, are often overlooked. This neglect is because research on the cerebellum typically focuses on the cortex and tends to treat the CN as relatively simple output nuclei conveying an inverted signal from the cerebellar cortex to the rest of the brain. In this review, by adopting a nucleocentric perspective we aim to rectify this impression. First, we describe CN anatomy and modularity and comprehensively integrate CN architecture with its highly organized but complex afferent and efferent connectivity. This is followed by a novel classification of the specific neuronal classes the CN comprise and speculate on the implications of CN structure and physiology for our understanding of adult cerebellar function. Based on this thorough review of the adult literature we provide a comprehensive overview of CN embryonic development and, by comparing cerebellar structures in various chordate clades, propose an interpretation of CN evolution. Despite their critical importance in cerebellar function, from a clinical perspective intriguingly few, if any, neurological disorders appear to primarily affect the CN. To highlight this curious anomaly, and encourage future nucleocentric interpretations, we build on our review to provide a brief overview of the various syndromes in which the CN are currently implicated. Finally, we summarize the specific perspectives that a nucleocentric view of the cerebellum brings, move major outstanding issues in CN biology to the limelight, and provide a roadmap to the key questions that need to be answered in order to create a comprehensive integrated model of CN structure, function, development, and evolution.
Topics: Cerebellar Nuclei; Cerebellum; Neurons
PubMed: 36781689
DOI: 10.1007/s12311-022-01506-0 -
ELife Sep 2023The cerebellar granule cell layer has inspired numerous theoretical models of neural representations that support learned behaviors, beginning with the work of Marr and...
The cerebellar granule cell layer has inspired numerous theoretical models of neural representations that support learned behaviors, beginning with the work of Marr and Albus. In these models, granule cells form a sparse, combinatorial encoding of diverse sensorimotor inputs. Such sparse representations are optimal for learning to discriminate random stimuli. However, recent observations of dense, low-dimensional activity across granule cells have called into question the role of sparse coding in these neurons. Here, we generalize theories of cerebellar learning to determine the optimal granule cell representation for tasks beyond random stimulus discrimination, including continuous input-output transformations as required for smooth motor control. We show that for such tasks, the optimal granule cell representation is substantially denser than predicted by classical theories. Our results provide a general theory of learning in cerebellum-like systems and suggest that optimal cerebellar representations are task-dependent.
Topics: Cerebellum; Learning; Neurons; Models, Neurological
PubMed: 37671785
DOI: 10.7554/eLife.82914