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Cell Dec 2020Neurons in the cerebral cortex connect through descending pathways to hindbrain and spinal cord to activate muscle and generate movement. Although components of this...
Neurons in the cerebral cortex connect through descending pathways to hindbrain and spinal cord to activate muscle and generate movement. Although components of this pathway have been previously generated and studied in vitro, the assembly of this multi-synaptic circuit has not yet been achieved with human cells. Here, we derive organoids resembling the cerebral cortex or the hindbrain/spinal cord and assemble them with human skeletal muscle spheroids to generate 3D cortico-motor assembloids. Using rabies tracing, calcium imaging, and patch-clamp recordings, we show that corticofugal neurons project and connect with spinal spheroids, while spinal-derived motor neurons connect with muscle. Glutamate uncaging or optogenetic stimulation of cortical spheroids triggers robust contraction of 3D muscle, and assembloids are morphologically and functionally intact for up to 10 weeks post-fusion. Together, this system highlights the remarkable self-assembly capacity of 3D cultures to form functional circuits that could be used to understand development and disease.
Topics: Animals; Calcium; Cell Differentiation; Cells, Cultured; Cerebral Cortex; Cervical Vertebrae; Gene Expression Regulation; Glutamates; Humans; Induced Pluripotent Stem Cells; Mice; Motor Cortex; Muscles; Myoblasts; Nerve Net; Optogenetics; Organoids; Rhombencephalon; Spheroids, Cellular; Spinal Cord
PubMed: 33333020
DOI: 10.1016/j.cell.2020.11.017 -
Radiographics : a Review Publication of... 2019The anatomy of the brainstem is complex. It contains numerous cranial nerve nuclei and is traversed by multiple tracts between the brain and spinal cord. Improved MRI... (Review)
Review
The anatomy of the brainstem is complex. It contains numerous cranial nerve nuclei and is traversed by multiple tracts between the brain and spinal cord. Improved MRI resolution now allows the radiologist to identify a higher level of anatomic detail, but an understanding of functional anatomy is crucial for correct interpretation of disease. Brainstem syndromes are most commonly due to occlusion of the posterior circulation or mass effect from intrinsic space-occupying lesions. These syndromes can have subtle imaging findings that may be missed by a radiologist unfamiliar with the anatomy or typical manifesting features. This article presents the developmental anatomy of the brainstem and discusses associated pathologic syndromes. Congenital and acquired syndromes are described and correlated with anatomic locations at imaging, with diagrams to provide a reference to aid in radiologic interpretation. RSNA, 2019.
Topics: Brain Diseases; Brain Infarction; Craniofacial Abnormalities; Humans; Magnetic Resonance Imaging; Medulla Oblongata; Mesencephalon; Neuroimaging; Pons; Syndrome
PubMed: 31283463
DOI: 10.1148/rg.2019180126 -
Annual Review of Neuroscience Jul 2022The cerebellar cortex is an important system for relating neural circuits and learning. Its promise reflects the longstanding idea that it contains simple, repeated... (Review)
Review
The cerebellar cortex is an important system for relating neural circuits and learning. Its promise reflects the longstanding idea that it contains simple, repeated circuit modules with only a few cell types and a single plasticity mechanism that mediates learning according to classical Marr-Albus models. However, emerging data have revealed surprising diversity in neuron types, synaptic connections, and plasticity mechanisms, both locally and regionally within the cerebellar cortex. In light of these findings, it is not surprising that attempts to generate a holistic model of cerebellar learning across different behaviors have not been successful. While the cerebellum remains an ideal system for linking neuronal function with behavior, it is necessary to update the cerebellar circuit framework to achieve its great promise. In this review, we highlight recent advances in our understanding of cerebellar-cortical cell types, synaptic connections, signaling mechanisms, and forms of plasticity that enrich cerebellar processing.
Topics: Cerebellar Cortex; Cerebellum; Learning; Neuronal Plasticity; Purkinje Cells
PubMed: 35803588
DOI: 10.1146/annurev-neuro-091421-125115 -
Cell Stem Cell Jan 2024Research on human cerebellar development and disease has been hampered by the need for a human cell-based system that recapitulates the human cerebellum's cellular...
Research on human cerebellar development and disease has been hampered by the need for a human cell-based system that recapitulates the human cerebellum's cellular diversity and functional features. Here, we report a human organoid model (human cerebellar organoids [hCerOs]) capable of developing the complex cellular diversity of the fetal cerebellum, including a human-specific rhombic lip progenitor population that have never been generated in vitro prior to this study. 2-month-old hCerOs form distinct cytoarchitectural features, including laminar organized layering, and create functional connections between inhibitory and excitatory neurons that display coordinated network activity. Long-term culture of hCerOs allows healthy survival and maturation of Purkinje cells that display molecular and electrophysiological hallmarks of their in vivo counterparts, addressing a long-standing challenge in the field. This study therefore provides a physiologically relevant, all-human model system to elucidate the cell-type-specific mechanisms governing cerebellar development and disease.
Topics: Humans; Infant; Purkinje Cells; Cerebellum; Metencephalon; Organoids
PubMed: 38181749
DOI: 10.1016/j.stem.2023.11.013 -
Neuroscience Mar 2021Nociception is the neuronal process of encoding noxious stimuli and could be modulated at peripheral, spinal, brainstem, and cortical levels. At cortical levels, several... (Review)
Review
Nociception is the neuronal process of encoding noxious stimuli and could be modulated at peripheral, spinal, brainstem, and cortical levels. At cortical levels, several areas including the anterior cingulate cortex (ACC), prefrontal cortex (PFC), ventrolateral orbital cortex (VLO), insular cortex (IC), motor cortex (MC), and somatosensory cortices are involved in nociception modulation through two main mechanisms: (i) a descending modulatory effect at spinal level by direct corticospinal projections or mostly by activation of brainstem structures (i.e. periaqueductal grey matter (PAG), locus coeruleus (LC), the nucleus of raphe (RM) and rostroventral medulla (RVM)); and by (ii) cortico-cortical or cortico-subcortical interactions. This review summarizes evidence related to the participation of the aforementioned cortical areas in nociception modulation and different neurotransmitters or neuromodulators that have been studied in each area. Besides, we point out the importance of considering intracortical neuronal populations and receptors expression, as well as, nociception-induced cortical changes, both functional and connectional, to better understand this modulatory effect. Finally, we discuss the possible mechanisms that could potentiate the use of cortical stimulation as a promising procedure in pain alleviation.
Topics: Humans; Locus Coeruleus; Medulla Oblongata; Neural Pathways; Nociception; Pain; Periaqueductal Gray
PubMed: 33465410
DOI: 10.1016/j.neuroscience.2021.01.001 -
World Neurosurgery Mar 2022Rhombencephalosynapsis is a rare congenital anomaly, characterized by partial or total agenesis of the cerebellar vermis with midline fusion of the cerebellar... (Review)
Review
Rhombencephalosynapsis is a rare congenital anomaly, characterized by partial or total agenesis of the cerebellar vermis with midline fusion of the cerebellar hemispheres, dentate nuclei, and the superior cerebellar peduncles, creating the distinctive keyhole appearance of the fourth ventricle. Rhombencephalosynapsis can be isolated or can occur in association with other congenital anomalies and syndromes such as Gómez-López-Hernández syndrome (GLHS) or VACTERL: vertebral anomalies (V), anal atresia (A), cardiovascular defects (C), esophageal atresia and/or tracheoesophageal fistula (TE), and renal (R) and limb/radial (L) anomalies. Recent advances in prenatal imaging have resulted in an increasing rate of prenatal diagnosis of abnormalities of the posterior fossa including rhombencephalosynapsis. Patients with rhombencephalosynapsis may present with motor developmental delay, ataxia, swallowing difficulties, muscular hypotonia, spastic quadriparesis, abnormal eye movements, and a characteristic "figure-of-eight" head shaking. Cognitive outcome varies from severe intellectual disability to normal intellectual function. Rhombencephalosynapsis with VACTERL is often associated with severe cognitive disabilities, whereas patients with GLHS may have better cognitive function. The most common associated findings with rhombencephalosynapsis include hydrocephalus, mesencephalosynapsis, holoprosencephaly, pontocerebellar hypoplasia, corpus callosum dysgenesis, and absence of septum pellucidum. Patients can be categorized into 4 groups: 1) rhombencephalosynapsis associated with GLHS; 2) rhombencephalosynapsis with VACTERL; 3) rhombencephalosynapsis with atypical holoprosencephaly, and 4) isolated rhomboencephalosynapsis. The etiology of rhombencephalosynapsis is unknown. Here, we discuss several hypotheses about its etiology.
Topics: Abnormalities, Multiple; Alopecia; Cerebellum; Craniofacial Abnormalities; Female; Growth Disorders; Holoprosencephaly; Humans; Neurocutaneous Syndromes; Pregnancy; Rhombencephalon
PubMed: 34954057
DOI: 10.1016/j.wneu.2021.12.062 -
Progress in Brain Research 2022This chapter summarizes early electrophysiological and lesion studies to elucidate cortical, subcortical and cerebellar mechanisms for extracting visual target motion...
This chapter summarizes early electrophysiological and lesion studies to elucidate cortical, subcortical and cerebellar mechanisms for extracting visual target motion and programming a smooth-pursuit response. The importance of a descending pursuit pathway from the middle temporal (MT) cortical visual area, which extracts the speed and direction of a moving target, the projections to dorsolateral pontine nuclei, and onto the cerebellum are outlined. Contributions of the cerebellum to pursuit are discussed and models are presented to account for the ways in which floccular gaze Purkinje cells behave during smooth pursuit, combined eye-head tracking, and during head rotation while viewing a stationary target.
Topics: Cerebellum; Humans; Neurophysiology; Purkinje Cells; Pursuit, Smooth; Reflex, Vestibulo-Ocular
PubMed: 35074066
DOI: 10.1016/bs.pbr.2021.10.021 -
Nature Neuroscience Jun 2023The cerebellum is hypothesized to refine movement through online adjustments. We examined how such predictive control may be generated using a mouse reach paradigm,...
The cerebellum is hypothesized to refine movement through online adjustments. We examined how such predictive control may be generated using a mouse reach paradigm, testing whether the cerebellum uses within-reach information as a predictor to adjust reach kinematics. We first identified a population-level response in Purkinje cells that scales inversely with reach velocity, pointing to the cerebellar cortex as a potential site linking kinematic predictors and anticipatory control. Next, we showed that mice can learn to compensate for a predictable reach perturbation caused by repeated, closed-loop optogenetic stimulation of pontocerebellar mossy fiber inputs. Both neural and behavioral readouts showed adaptation to position-locked mossy fiber perturbations and exhibited aftereffects when stimulation was removed. Surprisingly, position-randomized stimulation schedules drove partial adaptation but no opposing aftereffects. A model that recapitulated these findings suggests that the cerebellum may decipher cause-and-effect relationships through time-dependent generalization mechanisms.
Topics: Cerebellum; Purkinje Cells; Movement; Learning; Conditioning, Classical
PubMed: 37248339
DOI: 10.1038/s41593-023-01347-y -
Cerebellum (London, England) Aug 2022The first attempts at using electric stimulation to study human brain functions followed the experiments of Luigi Galvani and Giovanni Aldini on animal electricity... (Review)
Review
The first attempts at using electric stimulation to study human brain functions followed the experiments of Luigi Galvani and Giovanni Aldini on animal electricity during the eighteenth century. Since then, the cerebellum has been among the areas that have been studied by invasive and non-invasive forms of electrical and magnetic stimulation. During the nineteenth century, animal experiments were conducted to map the motor-related regions of cerebellar cortex by means of direct electric stimulation. As electric stimulation research on the cerebellum moved into the twentieth century, systematic research of electric cerebellar stimulation led to a better understanding of its effects and mechanism of action. In addition, the clinical potential of cerebellar stimulation in the treatment of motor diseases started to be explored. With the introduction of transcranial electric and magnetic stimulation, cerebellar research moved to non-invasive techniques. During the twenty-first century, following on groundbreaking research that linked the cerebellum to non-motor functions, non-invasive techniques have facilitated research into different aspects of cerebellar functioning. The present review provides a brief historical account of cerebellar neurostimulation and discusses current challenges and future direction in this field of research.
Topics: Animals; Cerebellar Cortex; Cerebellum; Electric Stimulation; Humans; Transcranial Direct Current Stimulation; Transcranial Magnetic Stimulation
PubMed: 34403075
DOI: 10.1007/s12311-021-01310-2 -
Development (Cambridge, England) Aug 2021During early development, the hindbrain is sub-divided into rhombomeres that underlie the organisation of neurons and adjacent craniofacial tissues. A gene regulatory... (Review)
Review
During early development, the hindbrain is sub-divided into rhombomeres that underlie the organisation of neurons and adjacent craniofacial tissues. A gene regulatory network of signals and transcription factors establish and pattern segments with a distinct anteroposterior identity. Initially, the borders of segmental gene expression are imprecise, but then become sharply defined, and specialised boundary cells form. In this Review, we summarise key aspects of the conserved regulatory cascade that underlies the formation of hindbrain segments. We describe how the pattern is sharpened and stabilised through the dynamic regulation of cell identity, acting in parallel with cell segregation. Finally, we discuss evidence that boundary cells have roles in local patterning, and act as a site of neurogenesis within the hindbrain.
Topics: Animals; Body Patterning; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Humans; Rhombencephalon; Vertebrates
PubMed: 34323269
DOI: 10.1242/dev.186460