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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 -
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 -
Biology of Sex Differences Sep 2023In addition to social and cultural factors, sex differences in the central nervous system have a critical influence on behavior, although the neurobiology underlying...
BACKGROUND
In addition to social and cultural factors, sex differences in the central nervous system have a critical influence on behavior, although the neurobiology underlying these differences remains unclear. Interestingly, the Locus Coeruleus (LC), a noradrenergic nucleus that exhibits sexual dimorphism, integrates signals that are related to diverse activities, including emotions, cognition and pain. Therefore, we set-out to evaluate sex differences in behaviors related to LC nucleus, and subsequently, to assess the sex differences in LC morphology and function.
METHODS
Female and male C57BL/6J mice were studied to explore the role of the LC in anxiety, depressive-like behavior, well-being, pain, and learning and memory. We also explored the number of noradrenergic LC cells, their somatodendritic volume, as well as the electrophysiological properties of LC neurons in each sex.
RESULTS
While both male and female mice displayed similar depressive-like behavior, female mice exhibited more anxiety-related behaviors. Interestingly, females outperformed males in memory tasks that involved distinguishing objects with small differences and they also showed greater thermal pain sensitivity. Immunohistological analysis revealed that females had fewer noradrenergic cells yet they showed a larger dendritic volume than males. Patch clamp electrophysiology studies demonstrated that LC neurons in female mice had a lower capacitance and that they were more excitable than male LC neurons, albeit with similar action potential properties.
CONCLUSIONS
Overall, this study provides new insights into the sex differences related to LC nucleus and associated behaviors, which may explain the heightened emotional arousal response observed in females.
Topics: Female; Male; Mice; Animals; Locus Coeruleus; Mice, Inbred C57BL; Neurons; Norepinephrine; Emotions
PubMed: 37770907
DOI: 10.1186/s13293-023-00550-7 -
Cerebellum (London, England) Dec 2023The present Cerebellar Classic highlights a paper published in 1908 by the American pathologist Simeon Burt Wolbach (1880-1954), in which he reported multiple hernias of...
The present Cerebellar Classic highlights a paper published in 1908 by the American pathologist Simeon Burt Wolbach (1880-1954), in which he reported multiple hernias of the cerebellum for the first time in 9 cases of increased intracranial pressure. The importance of the meninges and the anatomy of involved compartments is emphasized.
Topics: Male; Humans; United States; Cerebellum
PubMed: 36173509
DOI: 10.1007/s12311-022-01478-1 -
Nature Communications Aug 2023The modulation of dopamine release from midbrain projections to the striatum has long been demonstrated in reward-based learning, but the synaptic basis of aversive...
The modulation of dopamine release from midbrain projections to the striatum has long been demonstrated in reward-based learning, but the synaptic basis of aversive learning is far less characterized. The cerebellum receives axonal projections from the locus coeruleus, and norepinephrine release is implicated in states of arousal and stress, but whether aversive learning relies on plastic changes in norepinephrine release in the cerebellum is unknown. Here we report that in mice, norepinephrine is released in the cerebellum following an unpredicted noxious event (a foot-shock) and that this norepinephrine release is potentiated powerfully with fear acquisition as animals learn that a previously neutral stimulus (tone) predicts the aversive event. Importantly, both chemogenetic and optogenetic inhibition of the locus coeruleus-cerebellum pathway block fear memory without impairing motor function. Thus, norepinephrine release in the cerebellum is modulated by experience and underlies aversive learning.
Topics: Mice; Animals; Avoidance Learning; Norepinephrine; Locus Coeruleus; Cerebellum; Mesencephalon
PubMed: 37563141
DOI: 10.1038/s41467-023-40548-8 -
Progress in Neuro-psychopharmacology &... Jul 2023Reward learning is key to survival for individuals. Attention plays an important role in the rapid recognition of reward cues and establishment of reward memories.... (Review)
Review
Reward learning is key to survival for individuals. Attention plays an important role in the rapid recognition of reward cues and establishment of reward memories. Reward history reciprocally guides attention to reward stimuli. However, the neurological processes of the interplay between reward and attention remain largely elusive, due to the diversity of the neural substrates that participate in these two processes. In this review, we delineate the complex and differentiated locus coeruleus norepinephrine (LC-NE) system in relation to different behavioral and cognitive substrates of reward and attention. The LC receives reward related sensory, perceptual, and visceral inputs, releases NE, glutamate, dopamine and various neuropeptides, forms reward memories, drives attentional bias and selects behavioral strategies for reward. Preclinical and clinical studies have found that abnormalities in the LC-NE system are involved in a variety of psychiatric conditions marked by disturbed functions in reward and attention. Therefore, we propose that the LC-NE system is an important hub in the interplay between reward and attention as well as a critical therapeutic target for psychiatric disorders characterized by compromised functions in reward and attention.
Topics: Humans; Norepinephrine; Learning; Cues; Glutamic Acid; Reward; Locus Coeruleus
PubMed: 36933778
DOI: 10.1016/j.pnpbp.2023.110751 -
BioEssays : News and Reviews in... Jun 2024Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and... (Review)
Review
Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In this article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms.
Topics: Purkinje Cells; Animals; Neuronal Plasticity; Humans; Action Potentials; Synapses; Cerebellar Cortex
PubMed: 38697917
DOI: 10.1002/bies.202400008 -
Endocrinology Nov 2023Hindbrain adrenergic/noradrenergic nuclei facilitate endocrine and autonomic responses to physical and psychological challenges. Neurons that synthesize adrenaline and... (Review)
Review
Hindbrain adrenergic/noradrenergic nuclei facilitate endocrine and autonomic responses to physical and psychological challenges. Neurons that synthesize adrenaline and noradrenaline target hypothalamic structures to modulate endocrine responses while descending spinal projections regulate sympathetic function. Furthermore, these neurons respond to diverse stress-related metabolic, autonomic, and psychosocial challenges. Accordingly, adrenergic and noradrenergic nuclei are integrative hubs that promote physiological adaptation to maintain homeostasis. However, the precise mechanisms through which adrenaline- and noradrenaline-synthesizing neurons sense interoceptive and exteroceptive cues to coordinate physiological responses have yet to be fully elucidated. Additionally, the regulatory role of these cells in the context of chronic stress has received limited attention. This mini-review consolidates reports from preclinical rodent studies on the organization and function of brainstem adrenaline and noradrenaline cells to provide a framework for how these nuclei coordinate endocrine and autonomic physiology. This includes identification of hindbrain adrenaline- and noradrenaline-producing cell groups and their role in stress responding through neurosecretory and autonomic engagement. Although temporally and mechanistically distinct, the endocrine and autonomic stress axes are complementary and interconnected. Therefore, the interplay between brainstem adrenergic/noradrenergic nuclei and peripheral physiological systems is necessary for integrated stress responses and organismal survival.
Topics: Adrenergic Agents; Norepinephrine; Epinephrine; Brain Stem; Rhombencephalon
PubMed: 38015813
DOI: 10.1210/endocr/bqad178 -
Nature Communications Mar 2024The "dorsal pons", or "dorsal pontine tegmentum" (dPnTg), is part of the brainstem. It is a complex, densely packed region whose nuclei are involved in regulating many...
The "dorsal pons", or "dorsal pontine tegmentum" (dPnTg), is part of the brainstem. It is a complex, densely packed region whose nuclei are involved in regulating many vital functions. Notable among them are the parabrachial nucleus, the Kölliker Fuse, the Barrington nucleus, the locus coeruleus, and the dorsal, laterodorsal, and ventral tegmental nuclei. In this study, we applied single-nucleus RNA-seq (snRNA-seq) to resolve neuronal subtypes based on their unique transcriptional profiles and then used multiplexed error robust fluorescence in situ hybridization (MERFISH) to map them spatially. We sampled ~1 million cells across the dPnTg and defined the spatial distribution of over 120 neuronal subtypes. Our analysis identified an unpredicted high transcriptional diversity in this region and pinpointed the unique marker genes of many neuronal subtypes. We also demonstrated that many neuronal subtypes are transcriptionally similar between humans and mice, enhancing this study's translational value. Finally, we developed a freely accessible, GPU and CPU-powered dashboard ( http://harvard.heavy.ai:6273/ ) that combines interactive visual analytics and hardware-accelerated SQL into a data science framework to allow the scientific community to query and gain insights into the data.
Topics: Humans; Animals; Mice; In Situ Hybridization, Fluorescence; Pontine Tegmentum; Brain Stem; Locus Coeruleus; Parabrachial Nucleus; Ascomycota
PubMed: 38438345
DOI: 10.1038/s41467-024-45907-7