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Nature Dec 2023The function of the mammalian brain relies upon the specification and spatial positioning of diversely specialized cell types. Yet, the molecular identities of the cell...
The function of the mammalian brain relies upon the specification and spatial positioning of diversely specialized cell types. Yet, the molecular identities of the cell types and their positions within individual anatomical structures remain incompletely known. To construct a comprehensive atlas of cell types in each brain structure, we paired high-throughput single-nucleus RNA sequencing with Slide-seq-a recently developed spatial transcriptomics method with near-cellular resolution-across the entire mouse brain. Integration of these datasets revealed the cell type composition of each neuroanatomical structure. Cell type diversity was found to be remarkably high in the midbrain, hindbrain and hypothalamus, with most clusters requiring a combination of at least three discrete gene expression markers to uniquely define them. Using these data, we developed a framework for genetically accessing each cell type, comprehensively characterized neuropeptide and neurotransmitter signalling, elucidated region-specific specializations in activity-regulated gene expression and ascertained the heritability enrichment of neurological and psychiatric phenotypes. These data, available as an online resource ( www.BrainCellData.org ), should find diverse applications across neuroscience, including the construction of new genetic tools and the prioritization of specific cell types and circuits in the study of brain diseases.
Topics: Animals; Mice; Brain; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Hypothalamus; Mesencephalon; Neuropeptides; Neurotransmitter Agents; Phenotype; Rhombencephalon; Single-Cell Gene Expression Analysis; Transcriptome
PubMed: 38092915
DOI: 10.1038/s41586-023-06818-7 -
Journal of Neurophysiology Dec 2022A hedge fund billionaire's children are suffering from cerebellar disease. He invited a group of neuroscientists to plan a search for therapies. What resulted is the... (Review)
Review
A hedge fund billionaire's children are suffering from cerebellar disease. He invited a group of neuroscientists to plan a search for therapies. What resulted is the outline of an implantable neural emulator that might electronically replace the damaged part of the brain.
Topics: Male; Child; Humans; Purkinje Cells; Cerebellum; Cerebellar Diseases
PubMed: 36350062
DOI: 10.1152/jn.00437.2022 -
Journal of Integrative Neuroscience Jan 2022Apoptosis, autophagy and necrosis are the three main types of programmed cell death. One or more of these types of programmed cell death may take place in neurons... (Review)
Review
Apoptosis, autophagy and necrosis are the three main types of programmed cell death. One or more of these types of programmed cell death may take place in neurons leading to their death in various neurodegenerative disorders in humans. Purkinje neurons (PNs) are among the most highly vulnerable population of neurons to cell death in response to intrinsic hereditary diseases or extrinsic toxic, hypoxic, ischemic, and traumatic injury. In this review, we will describe the three main types of programmed cell death, including the molecular mechanisms and the sequence of events in each of them, and thus illustrating the intracellular proteins that mediate and regulate each of these types. Then, we will discuss the role of Ca2+ in PN function and increased vulnerability to cell death. Additionally, PN death will be described in animal models, namely lurcher mutant mouse and shaker mutant rat, in order to illustrate the potential therapeutic implications of programmed cell death in PNs by reviewing the previous studies that were carried out to interfere with the programmed cell death in an attempt to rescue PNs from death.
Topics: Animals; Apoptosis; Autophagy; Cerebellum; Humans; Mice; Necrosis; Neurodegenerative Diseases; Purkinje Cells; Rats
PubMed: 35164466
DOI: 10.31083/j.jin2101030 -
Neuroscience Dec 2020Dexterous forelimb movements like reaching, grasping, and manipulating objects are fundamental building blocks of the mammalian motor repertoire. These behaviors are... (Review)
Review
Dexterous forelimb movements like reaching, grasping, and manipulating objects are fundamental building blocks of the mammalian motor repertoire. These behaviors are essential to everyday activities, and their elaboration underlies incredible accomplishments by human beings in art and sport. Moreover, the susceptibility of these behaviors to damage and disease of the nervous system can lead to debilitating deficits, highlighting a need for a better understanding of function and dysfunction in sensorimotor control. The cerebellum is central to coordinating limb movements, as defined in large part by Joseph Babinski and Gordon Holmes describing motor impairment in patients with cerebellar lesions over 100 years ago (Babinski, 1902; Holmes, 1917), and supported by many important human and animal studies that have been conducted since. Here, with a focus on output pathways of the cerebellar nuclei across mammalian species, we describe forelimb movement deficits observed when cerebellar circuits are perturbed, the mechanisms through which these circuits influence motor output, and key challenges in defining how the cerebellum refines limb movement.
Topics: Animals; Cerebellar Nuclei; Cerebellum; Forelimb; Hand Strength; Humans; Movement
PubMed: 32652173
DOI: 10.1016/j.neuroscience.2020.06.046 -
Cell Dec 2022To track and control self-location, animals integrate their movements through space. Representations of self-location are observed in the mammalian hippocampal...
To track and control self-location, animals integrate their movements through space. Representations of self-location are observed in the mammalian hippocampal formation, but it is unknown if positional representations exist in more ancient brain regions, how they arise from integrated self-motion, and by what pathways they control locomotion. Here, in a head-fixed, fictive-swimming, virtual-reality preparation, we exposed larval zebrafish to a variety of involuntary displacements. They tracked these displacements and, many seconds later, moved toward their earlier location through corrective swimming ("positional homeostasis"). Whole-brain functional imaging revealed a network in the medulla that stores a memory of location and induces an error signal in the inferior olive to drive future corrective swimming. Optogenetically manipulating medullary integrator cells evoked displacement-memory behavior. Ablating them, or downstream olivary neurons, abolished displacement corrections. These results reveal a multiregional hindbrain circuit in vertebrates that integrates self-motion and stores self-location to control locomotor behavior.
Topics: Animals; Zebrafish; Neurons; Rhombencephalon; Brain; Swimming; Homeostasis; Mammals
PubMed: 36563666
DOI: 10.1016/j.cell.2022.11.022 -
Clarification of hypertension mechanisms provided by the research of central circulatory regulation.Hypertension Research : Official... Aug 2023Sympathoexcitation, under the regulatory control of the brain, plays a pivotal role in the etiology of hypertension. Within the brainstem, significant structures... (Review)
Review
Sympathoexcitation, under the regulatory control of the brain, plays a pivotal role in the etiology of hypertension. Within the brainstem, significant structures involved in the modulation of sympathetic nerve activity include the rostral ventrolateral medulla (RVLM), caudal ventrolateral medulla (CVLM), nucleus tractus solitarius (NTS), and paraventricular nucleus (paraventricular). The RVLM, in particular, is recognized as the vasomotor center. Over the past five decades, fundamental investigations on central circulatory regulation have underscored the involvement of nitric oxide (NO), oxidative stress, the renin-angiotensin system, and brain inflammation in regulating the sympathetic nervous system. Notably, numerous significant findings have come to light through chronic experiments conducted in conscious subjects employing radio-telemetry systems, gene transfer techniques, and knockout methodologies. Our research has centered on elucidating the role of NO and angiotensin II type 1 (AT) receptor-induced oxidative stress within the RVLM and NTS in regulating the sympathetic nervous system. Additionally, we have observed that various orally administered AT receptor blockers effectively induce sympathoinhibition by reducing oxidative stress via blockade of the AT receptor in the RVLM of hypertensive rats. Recent advances have witnessed the development of several clinical interventions targeting brain mechanisms. Nonetheless, Future and further basic and clinical research are needed.
Topics: Rats; Animals; Hypertension; Solitary Nucleus; Medulla Oblongata; Sympathetic Nervous System; Paraventricular Hypothalamic Nucleus; Cardiovascular System; Blood Pressure
PubMed: 37277436
DOI: 10.1038/s41440-023-01335-6 -
Neuroscience May 2021In the last 50 years, our vision of the cerebellum has vastly evolved starting with Voogd's (1967) description of extracerebellar projections' terminations and how the... (Review)
Review
In the last 50 years, our vision of the cerebellum has vastly evolved starting with Voogd's (1967) description of extracerebellar projections' terminations and how the projection maps transformed the presumptive homogeneity of the cerebellar cortex into a more complex center subdivided into transverse and longitudinal distinct functional zones. The picture became still more complex with Richard Hawkes and colleagues' (Gravel et al., 1987) discovery of the biochemical heterogeneity of Purkinje cells (PCs), by screening their molecular identities with monoclonal antibodies. Antigens were expressed in a parasagittal pattern with subsets of PCs either possessing or lacking the respective antigens, which divided the cerebellar cortex into precise longitudinal compartments that are congruent with the projection maps. The correlation of these two maps in adult cerebellum shows a perfect matching of developmental mechanisms. This review discusses a series of arguments in favor of the essential role played by PCs in organizing the microzonation of the cerebellum during development (the "matching" hypothesis).
Topics: Antibodies, Monoclonal; Antigens; Cerebellar Cortex; Cerebellum; Purkinje Cells
PubMed: 31982466
DOI: 10.1016/j.neuroscience.2020.01.019 -
Nature Neuroscience Sep 2023The vast expansion from mossy fibers to cerebellar granule cells (GrC) produces a neural representation that supports functions including associative and internal model...
The vast expansion from mossy fibers to cerebellar granule cells (GrC) produces a neural representation that supports functions including associative and internal model learning. This motif is shared by other cerebellum-like structures and has inspired numerous theoretical models. Less attention has been paid to structures immediately presynaptic to GrC layers, whose architecture can be described as a 'bottleneck' and whose function is not understood. We therefore develop a theory of cerebellum-like structures in conjunction with their afferent pathways that predicts the role of the pontine relay to cerebellum and the glomerular organization of the insect antennal lobe. We highlight a new computational distinction between clustered and distributed neuronal representations that is reflected in the anatomy of these two brain structures. Our theory also reconciles recent observations of correlated GrC activity with theories of nonlinear mixing. More generally, it shows that structured compression followed by random expansion is an efficient architecture for flexible computation.
Topics: Cerebellum; Brain; Pons; Learning; Neurons
PubMed: 37604889
DOI: 10.1038/s41593-023-01403-7 -
Nature Dec 2023Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures. Many cell types mediate their...
Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use.
Topics: Animals; Mice; Amygdala; Brain; Consensus Sequence; Datasets as Topic; Epigenomics; Gene Expression Profiling; Hypothalamus; Mesencephalon; Neural Pathways; Neurons; Neurotransmitter Agents; Regulatory Sequences, Nucleic Acid; Rhombencephalon; Single-Cell Analysis; Thalamus; Transcription Factors
PubMed: 38092919
DOI: 10.1038/s41586-023-06823-w -
Communications Biology Jun 2023The cerebellum regulates nonmotor behavior, but the routes of influence are not well characterized. Here we report a necessary role for the posterior cerebellum in...
The cerebellum regulates nonmotor behavior, but the routes of influence are not well characterized. Here we report a necessary role for the posterior cerebellum in guiding a reversal learning task through a network of diencephalic and neocortical structures, and in flexibility of free behavior. After chemogenetic inhibition of lobule VI vermis or hemispheric crus I Purkinje cells, mice could learn a water Y-maze but were impaired in ability to reverse their initial choice. To map targets of perturbation, we imaged c-Fos activation in cleared whole brains using light-sheet microscopy. Reversal learning activated diencephalic and associative neocortical regions. Distinctive subsets of structures were altered by perturbation of lobule VI (including thalamus and habenula) and crus I (including hypothalamus and prelimbic/orbital cortex), and both perturbations influenced anterior cingulate and infralimbic cortex. To identify functional networks, we used correlated variation in c-Fos activation within each group. Lobule VI inactivation weakened within-thalamus correlations, while crus I inactivation divided neocortical activity into sensorimotor and associative subnetworks. In both groups, high-throughput automated analysis of whole-body movement revealed deficiencies in across-day behavioral habituation to an open-field environment. Taken together, these experiments reveal brainwide systems for cerebellar influence that affect multiple flexible responses.
Topics: Mice; Animals; Cerebellum; Brain; Cerebellar Cortex; Purkinje Cells; Learning
PubMed: 37277453
DOI: 10.1038/s42003-023-04920-0