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Nature Communications Jul 2023Rapid-eye-movement (REM) sleep is a distinct behavioral state associated with vivid dreaming and memory processing. Phasic bursts of electrical activity, measurable as...
Rapid-eye-movement (REM) sleep is a distinct behavioral state associated with vivid dreaming and memory processing. Phasic bursts of electrical activity, measurable as spike-like pontine (P)-waves, are a hallmark of REM sleep implicated in memory consolidation. However, the brainstem circuits regulating P-waves, and their interactions with circuits generating REM sleep, remain largely unknown. Here, we show that an excitatory population of dorsomedial medulla (dmM) neurons expressing corticotropin-releasing-hormone (CRH) regulates both REM sleep and P-waves in mice. Calcium imaging showed that dmM CRH neurons are selectively activated during REM sleep and recruited during P-waves, and opto- and chemogenetic experiments revealed that this population promotes REM sleep. Chemogenetic manipulation also induced prolonged changes in P-wave frequency, while brief optogenetic activation reliably triggered P-waves along with transiently accelerated theta oscillations in the electroencephalogram (EEG). Together, these findings anatomically and functionally delineate a common medullary hub for the regulation of both REM sleep and P-waves.
Topics: Mice; Animals; Sleep, REM; Electroencephalography; Pons; Medulla Oblongata; Neurons; Corticotropin-Releasing Hormone; Sleep
PubMed: 37400467
DOI: 10.1038/s41467-023-39496-0 -
The Journal of Comparative Neurology Jul 2022Diverse neurons in the parabrachial nucleus (PB) communicate with widespread brain regions. Despite evidence linking them to a variety of homeostatic functions, it...
Diverse neurons in the parabrachial nucleus (PB) communicate with widespread brain regions. Despite evidence linking them to a variety of homeostatic functions, it remains difficult to determine which PB neurons influence which functions because their subpopulations intermingle extensively. An improved framework for identifying these intermingled subpopulations would help advance our understanding of neural circuit functions linked to this region. Here, we present the foundation of a developmental-genetic ontology that classifies PB neurons based on their intrinsic, molecular features. By combining transcription factor labeling with Cre fate-mapping, we find that the PB is a blend of two, developmentally distinct macropopulations of glutamatergic neurons. Neurons in the first macropopulation express Lmx1b (and, to a lesser extent, Lmx1a) and are mutually exclusive with those in a second macropopulation, which derive from precursors expressing Atoh1. This second, Atoh1-derived macropopulation includes many Foxp2-expressing neurons, but Foxp2 also identifies a subset of Lmx1b-expressing neurons in the Kölliker-Fuse nucleus (KF) and a population of GABAergic neurons ventrolateral to the PB ("caudal KF"). Immediately ventral to the PB, Phox2b-expressing glutamatergic neurons (some coexpressing Lmx1b) occupy the KF, supratrigeminal nucleus, and reticular formation. We show that this molecular framework organizes subsidiary patterns of adult gene expression (including Satb2, Calca, Grp, and Pdyn) and predicts output projections to the amygdala (Lmx1b), hypothalamus (Atoh1), and hindbrain (Phox2b/Lmx1b). Using this molecular ontology to organize, interpret, and communicate PB-related information could accelerate the translation of experimental findings from animal models to human patients.
Topics: Animals; Brain; GABAergic Neurons; Humans; Hypothalamus; Kolliker-Fuse Nucleus; Parabrachial Nucleus; Pons; Transcription Factors
PubMed: 35134251
DOI: 10.1002/cne.25307 -
Multiple Sclerosis and Related Disorders Dec 2022Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare inflammatory disorder of the central nervous system,... (Review)
Review
INTRODUCTION
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare inflammatory disorder of the central nervous system, characterized by symptoms referable to the brainstem and cerebellum such as, diplopia, gait ataxia and cerebellar dysarthria. The features and outcomes of CLIPPERS remains uncertain. we conducted this comprehensive systematic review to summarize all the existing studies that described CLIPPERS in the literature and to provide a quantitative assessment on the clinical characteristics, management, and outcomes of this rare syndrome.
METHODS
A comprehensive search of PubMed and Web of Science databases was conducted from inception until January 15, 2022, was conducted. We only included the cases that clearly reported probable or definite diagnosis of CLIPPERS based on Taieb et al.'s criteria. The quality of the included studies was assessed using the JBI Critical Appraisal Tool. Descriptive statistics were performed to analyze the studies. Data were expressed as mean and standard deviation (SD) for continuous variables and proportions for categorical variables.
RESULTS
We identified 100 case reports and series including a total of 140 patients with CLIPPERS (mean age: 46±18 years and males were 60%). The average follow-up duration was 32.27±57.8 months. Ataxia was the most common presenting symptom. Sixteen percent of the cases were associated with malignancy, mostly hematologic malignancies. The overall relapse rate was 59.2%, and the duration of steroid therapy was considerably shorter in the relapsed cases than in the non-relapsed (mean 6.19±7.9 vs. 10.14±12.1 days, respectively, P = 0.04). The overall mortality rate was 10%, but mortality in patients with malignancy was 30% and it was 12% in patients with relapses. In the case of steroid dosing (less than 20 mg/d versus greater than 20 mg/d) there was no significant modification in the risk of relapse.
CONCLUSION
CLIPPERS is a rare clinical syndrome that affects mainly middle-aged males. Diagnosis of CLIPPERS is often challenging, and delays in diagnosis and treatment can lead to unfavorable outcomes. Therefore, neurologists should maintain a high index of suspicion for CLIPPERS in any patient presenting with symptoms and signs referrable to the brainstem. These patients should be screened for associated malignancies, especially hematological malignancies. The cases associated with malignancy tend to have worse outcomes. The relapse rate is relatively high. The relapse rate may be associated with worse mortality. Based on our findings, we recommend that CLIPPERS be treated with high-dose steroid therapy for at least ten days during the acute phase with a very slow taper. Prospective studies with a larger sample size are needed to validate our findings and guide the clinical care of these patients.
Topics: Middle Aged; Male; Humans; Adult; Magnetic Resonance Imaging; Prospective Studies; Pons; Inflammation; Steroids; Syndrome; Chronic Disease
PubMed: 36029706
DOI: 10.1016/j.msard.2022.104112 -
Nature Oct 2015Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with...
Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams. Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation, and the neural circuits in the pons have since been studied extensively. The medulla also contains neurons that are active during REM sleep, but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REMmax), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions.
Topics: Animals; Eating; Female; GABAergic Neurons; Grooming; Male; Medulla Oblongata; Mice; Neural Pathways; Optogenetics; Periaqueductal Gray; Pons; Sleep, REM; Spinal Cord; Time Factors; Wakefulness; gamma-Aminobutyric Acid
PubMed: 26444238
DOI: 10.1038/nature14979 -
RoFo : Fortschritte Auf Dem Gebiete Der... Jun 2018
Topics: Aged; Azathioprine; Capillary Permeability; Central Nervous System Diseases; Chronic Disease; Diagnosis, Differential; Drug Therapy, Combination; Encephalitis; Humans; Lymphocytosis; Magnetic Resonance Imaging; Male; Neurologic Examination; Pons; Prednisolone; Rare Diseases; Spinal Cord Diseases; T-Lymphocytes
PubMed: 29458222
DOI: 10.1055/s-0044-101264 -
Tidsskrift For Den Norske Laegeforening... Nov 2023
Topics: Humans; Pons; Demyelinating Diseases
PubMed: 37987074
DOI: 10.4045/tidsskr.23.0479 -
Current Neuropharmacology 2017Diffuse intrinsic pontine gliomas represent a unique subtype of primary brain tumors occuring in a specific location and age. Their growth demonstrates early invasion... (Review)
Review
BACKGROUND
Diffuse intrinsic pontine gliomas represent a unique subtype of primary brain tumors occuring in a specific location and age. Their growth demonstrates early invasion and, following diagnosis, rapid growth not responsive to common therapies. Until recently, the genetic and cellular basis of these tumors was unknown. Genetic evidence implicates mutations in the histone genes in the origin of these tumors.
METHODS
Surgical biopsies performed on selected patients have resulted in the establishment of anatomically accurate mouse models that have been used to examine patterns of growth and response to new therapeutic agents.
RESULTS
Human derived pontine glioma models recapitulate the invasive patterns of growth. The grade of the original tumor affects the latency of tumor growth after implantation.
CONCLUSION
The use of human-derived xenograft models allows for improved pre-clinical testing of new therapeutic targets in a tumor- and organ-specific manner.
Topics: Animals; Brain Stem Neoplasms; Glioma; Humans; Pons; Transplantation, Heterologous
PubMed: 27212051
DOI: 10.2174/1570159x14666160523144117 -
Journal of the Neurological Sciences Aug 2023
Topics: Humans; Child; Inflammation; Encephalitis; Magnetic Resonance Imaging; Pons
PubMed: 37348249
DOI: 10.1016/j.jns.2023.120698 -
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 -
Proceedings of the National Academy of... Dec 2023The rhombicbrain (rhombencephalon or intermediate sector) is the vertebrate central nervous system part between the forebrain-midbrain (rostral sector) and spinal cord...
The rhombicbrain (rhombencephalon or intermediate sector) is the vertebrate central nervous system part between the forebrain-midbrain (rostral sector) and spinal cord (caudal sector), and it has three main divisions: pons, cerebellum, and medulla. Using a data-driven approach, here we examine intrinsic rhombicbrain (intrarhombicbrain) network architecture that in rat consists of 52,670 possible axonal connections between 230 gray matter regions (115 bilaterally symmetrical pairs). Our analysis indicates that only 8,089 (15.4%) of these connections exist. Multiresolution consensus cluster analysis yields a nested hierarchy model of rhombicbrain subsystems that at the top level are associated with 1) the cerebellum and vestibular nuclei, 2) orofacial-pharyngeal-visceral integration, and 3) auditory connections; the bottom level has 68 clusters, ranging in size from 2 to 11 regions. The model provides a basis for functional hypothesis development and interrogation. More granular network analyses performed on the intrinsic connectivity of individual and combined main rhombicbrain divisions (pons, cerebellum, medulla, pons + cerebellum, and pons + medulla) demonstrate the mutability of network architecture in response to the addition or subtraction of connections. Clear differences between the structure-function network architecture of the rhombicbrain and forebrain-midbrain are discussed, with a stark comparison provided by the subsystem and small-world organization of the cerebellar cortex and cerebral cortex. Future analysis of the connections within and between the forebrain-midbrain and rhombicbrain will provide a model of brain neural network architecture in a mammal.
Topics: Rats; Animals; Cerebellum; Pons; Prosencephalon; Central Nervous System; Mammals
PubMed: 38109532
DOI: 10.1073/pnas.2313997120