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The Journal of Physiology Jan 2024The whisker system is widely used as a model system for understanding sensorimotor integration. Purkinje cells in the crus regions of the cerebellum have been reported...
The whisker system is widely used as a model system for understanding sensorimotor integration. Purkinje cells in the crus regions of the cerebellum have been reported to linearly encode whisker midpoint, but it is unknown whether the paramedian and simplex lobules as well as their target neurons in the cerebellar nuclei also encode whisker kinematics and if so which ones. Elucidating how these kinematics are represented throughout the cerebellar hemisphere is essential for understanding how the cerebellum coordinates multiple sensorimotor modalities. Exploring the cerebellar hemisphere of mice using optogenetic stimulation, we found that whisker movements can be elicited by stimulation of Purkinje cells in not only crus1 and crus2, but also in the paramedian lobule and lobule simplex; activation of cells in the medial paramedian lobule had on average the shortest latency, whereas that of cells in lobule simplex elicited similar kinematics as those in crus1 and crus2. During spontaneous whisking behaviour, simple spike activity correlated in general better with velocity than position of the whiskers, but it varied between protraction and retraction as well as per lobule. The cerebellar nuclei neurons targeted by the Purkinje cells showed similar activity patterns characterized by a wide variety of kinematic signals, yet with a dominance for velocity. Taken together, our data indicate that whisker movements are much more prominently and diversely represented in the cerebellar cortex and nuclei than assumed, highlighting the rich repertoire of cerebellar control in the kinematics of movements that can be engaged during coordination. KEY POINTS: Excitation of Purkinje cells throughout the cerebellar hemispheres induces whisker movement, with the shortest latency and longest duration within the paramedian lobe. Purkinje cells have differential encoding for the fast and slow components of whisking. Purkinje cells encode not only the position but also the velocity of whiskers. Purkinje cells with high sensitivity for whisker velocity are preferentially located in the medial part of lobule simplex, crus1 and lateral paramedian. In the downstream cerebellar nuclei, neurons with high sensitivity for whisker velocity are located at the intersection between the medial and interposed nucleus.
Topics: Mice; Animals; Vibrissae; Biomechanical Phenomena; Cerebellum; Purkinje Cells; Cerebellar Cortex
PubMed: 37987552
DOI: 10.1113/JP284064 -
Development (Cambridge, England) Jul 2023Cerebellar granule neurons (CGNs) are the most abundant neurons in the human brain. Dysregulation of their development underlies movement disorders and medulloblastomas....
Cerebellar granule neurons (CGNs) are the most abundant neurons in the human brain. Dysregulation of their development underlies movement disorders and medulloblastomas. It is suspected that these disorders arise in progenitor states of the CGN lineage, for which human models are lacking. Here, we have differentiated human hindbrain neuroepithelial stem (hbNES) cells to CGNs in vitro using soluble growth factors, recapitulating key progenitor states in the lineage. We show that hbNES cells are not lineage committed and retain rhombomere 1 regional identity. Upon differentiation, hbNES cells transit through a rhombic lip (RL) progenitor state at day 7, demonstrating human specific sub-ventricular cell identities. This RL state is followed by an ATOH1+ CGN progenitor state at day 14. By the end of a 56-day differentiation procedure, we obtain functional neurons expressing CGN markers GABAARα6 and vGLUT2. We show that sonic hedgehog promotes GABAergic lineage specification and CGN progenitor proliferation. Our work presents a new model with which to study development and diseases of the CGN lineage in a human context.
Topics: Humans; Hedgehog Proteins; Cerebellum; Rhombencephalon; Cell Differentiation; Neurogenesis; Stem Cells
PubMed: 37381820
DOI: 10.1242/dev.201534 -
Interventional Neuroradiology : Journal... Dec 2022The basic pattern of arterial vascularization is highly conserved across vertebrates and develops under neuromeric rules. The hindbrain has an angioarchitecture that is... (Review)
Review
The basic pattern of arterial vascularization is highly conserved across vertebrates and develops under neuromeric rules. The hindbrain has an angioarchitecture that is homologous to that of the spinal cord, and the hindbrain vascular system can be analyzed at the longitudinal and axial structures. During development, there are two main longitudinal arteries: the longitudinal neural artery and primitive lateral basilovertebral anastomosis. This review discusses the basic pattern of the blood supply of the hindbrain, the development of vascularization, and the anatomical variations, with a special reference to the embryological point of view of two main longitudinal anastomoses (longitudinal neural artery and primitive lateral basilovertebral anastomosis). The formation of commonly observed variations, such as fenestration and duplication of the vertebrobasilar artery, or primitive trigeminal artery variant, can be explained by the partial persistence of the primitive lateral basilovertebral anastomosis. Understanding the pattern and the development of the blood supply of the hindbrain provides useful information of the various anomalies of the vertebrobasilar junction and cerebellar arteries.
Topics: Humans; Basilar Artery; Vertebral Artery; Rhombencephalon; Cerebral Arteries; Spinal Cord
PubMed: 34935534
DOI: 10.1177/15910199211063011 -
American Journal of Medical Genetics.... May 2017Joubert syndrome (JS) is a rare, recessively inherited neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. Little is known about...
Joubert syndrome (JS) is a rare, recessively inherited neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. Little is known about mortality in affected individuals. Identifying the timing and causes of death will allow for development of healthcare guidelines for families and providers and, thus, help to prolong and improve the lives of patients with JS. We evaluated information on 40 deceased individuals with JS to characterize age and cause of death. We compared this population with 525 living individuals with JS to estimate associations between risk of death and extra-neurological features. Genetic causes were examined in both groups. Mean age of death in this cohort was 7.2 years, and the most prevalent causes of death were respiratory failure (35%), particularly in individuals younger than 6 years, and kidney failure (37.5%), which was more common in older individuals. We identified possible associations between risk of death and kidney disease, liver fibrosis, polydactyly, occipital encephalocele, and genetic cause. This work highlights factors (genetic cause, extra-neurological organ involvement, and other malformations) likely to be associated with higher risk of mortality in JS, which should prompt increased monitoring for respiratory issues, kidney disease, and liver fibrosis.
Topics: Abnormalities, Multiple; Adolescent; Cerebellum; Child; Child, Preschool; Eye Abnormalities; Female; Humans; Kidney Diseases, Cystic; Male; Renal Insufficiency; Retina; Rhombencephalon
PubMed: 28371402
DOI: 10.1002/ajmg.a.38158 -
Cell and Tissue Research Jul 2015A defining feature of the mammalian auditory system is the extensive processing of sound information in numerous ultrafast and temporally precise circuits in the... (Review)
Review
A defining feature of the mammalian auditory system is the extensive processing of sound information in numerous ultrafast and temporally precise circuits in the hindbrain. By exploiting the experimental advantages of mouse genetics, recent years have witnessed an impressive advance in our understanding of developmental mechanisms involved in the formation and refinement of these circuits. Here, we will summarize the progress made in four major fields: the dissection of the rhombomeric origins of auditory hindbrain nuclei; the molecular repertoire involved in circuit formation such as Hox transcription factors and the Eph-ephrin signaling system; the timeline of functional circuit assembly; and the critical role of spontaneous activity for circuit refinement. In total, this information provides a solid framework for further exploration of the factors shaping auditory hindbrain circuits and their specializations. A comprehensive understanding of the developmental pathways and instructive factors will also offer important clues to the causes and consequences of hearing-loss related disorders, which represent the most common sensory impairment in humans.
Topics: Animals; Auditory Pathways; Humans; Mammals; Nervous System; Rhombencephalon; Transcription Factors
PubMed: 25636588
DOI: 10.1007/s00441-014-2110-7 -
Developmental Biology Dec 2017Neurons of the dorsal hindbrain and spinal cord are central in receiving, processing and relaying sensory perception and participate in the coordination of sensory-motor... (Review)
Review
Neurons of the dorsal hindbrain and spinal cord are central in receiving, processing and relaying sensory perception and participate in the coordination of sensory-motor output. Numerous cellular and molecular mechanisms that underlie neuronal development in both regions of the nervous system are shared. We discuss here the mechanisms that generate neuronal diversity in the dorsal spinal cord and hindbrain, and emphasize similarities in patterning and neuronal specification. Insight into the developmental mechanisms has provided tools that can help to assign functions to small subpopulations of neurons. Hence, novel information on how mechanosensory or pain sensation is encoded under normal and neuropathic conditions has already emerged. Such studies show that the complex neuronal circuits that control perception of somatosensory and viscerosensory stimuli are becoming amenable to investigations.
Topics: Animals; Body Patterning; Nerve Net; Neural Tube; Neurogenesis; Rhombencephalon; Spinal Cord
PubMed: 27742210
DOI: 10.1016/j.ydbio.2016.10.008 -
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 -
Respiratory Physiology & Neurobiology Nov 2019For many, if not all, air-breathing vertebrates, breathing-like movements begin while the embryo is still ensconced in an aqueous environment. This is because primordial... (Review)
Review
For many, if not all, air-breathing vertebrates, breathing-like movements begin while the embryo is still ensconced in an aqueous environment. This is because primordial regions of the CNS become spontaneously active during early gestation and then must functionally transform and specialize once air breathing commences. The degree to which the embryonic ventilatory control system is established and competent at birth is variable, however, even between different components of the respiratory system. Moreover, the embryological experiences of an individual can also affect the outcomes and responsiveness of ventilation to respiratory stimuli and these details have major clinical implications. The broad field of respiratory neurobiology still has much to learn about the ontogeny of breathing control systems, and the oviparity of birds provides a unique model to examine how early rhythms transform day-to-day as they become functional. This hybrid review and research article will highlight the contributions of birds to the study of breathing control during early development. We will detail what is currently known about the onset and maturation of respiratory rhythm generation and also provide novel data about the development of central chemosensitivity. Finally, we will review data regarding the development of peripheral afferent inputs during early development and discuss whole-animal reflex responsiveness to common respiratory stimuli, both chronic and acute, during the incubation period and following hatching.
Topics: Animals; Animals, Newborn; Birds; Embryo, Nonmammalian; Embryonic Development; Respiration; Rhombencephalon
PubMed: 31283998
DOI: 10.1016/j.resp.2019.06.003 -
The Journal of Neuroscience : the... Jan 2020In many species, vocal communication is essential for coordinating social behaviors including courtship, mating, parenting, rivalry, and alarm signaling. Effective... (Review)
Review
In many species, vocal communication is essential for coordinating social behaviors including courtship, mating, parenting, rivalry, and alarm signaling. Effective communication requires accurate production, detection, and classification of signals, as well as selection of socially appropriate responses. Understanding how signals are generated and how acoustic signals are perceived is key to understanding the neurobiology of social behaviors. Here we review our long-standing research program focused on , a frog genus which has provided valuable insights into the mechanisms and evolution of vertebrate social behaviors. In , vocal signals differ between the sexes, through development, and across the genus, reflecting evolutionary divergence in sensory and motor circuits that can be interrogated mechanistically. Using two preparations, the isolated brain and vocal organ, we have identified essential components of the vocal production system: the sexually differentiated larynx at the periphery, and the hindbrain vocal central pattern generator (CPG) centrally, that produce sex- and species-characteristic sound pulse frequencies and temporal patterns, respectively. Within the hindbrain, we have described how intrinsic membrane properties of neurons in the vocal CPG generate species-specific vocal patterns, how vocal nuclei are connected to generate vocal patterns, as well as the roles of neurotransmitters and neuromodulators in activating the circuit. For sensorimotor integration, we identified a key forebrain node that links auditory and vocal production circuits to match socially appropriate vocal responses to acoustic features of male and female calls. The availability of a well supported phylogeny as well as reference genomes from several species now support analysis of the genetic architecture and the evolutionary divergence of neural circuits for vocal communication. thus provides a vertebrate model in which to study vocal communication at many levels, from physiology, to behavior, and from development to evolution. As one of the most comprehensively studied phylogenetic groups within vertebrate vocal communication systems, provides insights that can inform social communication across phyla.
Topics: Acoustic Stimulation; Animal Communication; Animals; Arytenoid Cartilage; Biological Evolution; Central Pattern Generators; Female; Gonadal Steroid Hormones; In Vitro Techniques; Laryngeal Muscles; Laryngeal Nerves; Male; Medulla Oblongata; Nerve Net; Neurotransmitter Agents; Rhombencephalon; Sex Characteristics; Sexual Behavior, Animal; Social Behavior; Species Specificity; Vocalization, Animal; Xenopus laevis
PubMed: 31896561
DOI: 10.1523/JNEUROSCI.0736-19.2019 -
International Journal of Molecular... Aug 2022The medulla oblongata, located in the hindbrain between the pons and the spinal cord, is an important relay center for critical sensory, proprioceptive, and motoric... (Review)
Review
The medulla oblongata, located in the hindbrain between the pons and the spinal cord, is an important relay center for critical sensory, proprioceptive, and motoric information. It is an evolutionarily highly conserved brain region, both structural and functional, and consists of a multitude of nuclei all involved in different aspects of basic but vital functions. Understanding the functional anatomy and developmental program of this structure can help elucidate potential role(s) of the medulla in neurological disorders. Here, we have described the early molecular patterning of the medulla during murine development, from the fundamental units that structure the very early medullary region into 5 rhombomeres (r7-r11) and 13 different longitudinal progenitor domains, to the neuronal clusters derived from these progenitors that ultimately make-up the different medullary nuclei. By doing so, we developed a schematic overview that can be used to predict the cell-fate of a progenitor group, or pinpoint the progenitor domain of origin of medullary nuclei. This schematic overview can further be used to help in the explanation of medulla-related symptoms of neurodevelopmental disorders, e.g., congenital central hypoventilation syndrome, Wold-Hirschhorn syndrome, Rett syndrome, and Pitt-Hopkins syndrome. Based on the genetic defects seen in these syndromes, we can use our model to predict which medullary nuclei might be affected, which can be used to quickly direct the research into these diseases to the likely affected nuclei.
Topics: Animals; Humans; Medulla Oblongata; Mice; Neurons; Rett Syndrome; Rhombencephalon; Spinal Cord
PubMed: 36012524
DOI: 10.3390/ijms23169260