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Neuron Mar 2024The properties of the cell types that are selectively vulnerable in Huntington's disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and...
The properties of the cell types that are selectively vulnerable in Huntington's disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and their importance in CNS circuitry have not been delineated. Here, we employed serial fluorescence-activated nuclear sorting (sFANS), deep molecular profiling, and single-nucleus RNA sequencing (snRNA-seq) of motor-cortex samples from thirteen predominantly early stage, clinically diagnosed HD donors and selected samples from cingulate, visual, insular, and prefrontal cortices to demonstrate loss of layer 5a pyramidal neurons in HD. Extensive mHTT CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layers 6a and 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somatic mHTT CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex.
Topics: Animals; Huntington Disease; Neurons; Pyramidal Cells; Cerebral Cortex; Solitary Nucleus; Disease Models, Animal; Huntingtin Protein
PubMed: 38237588
DOI: 10.1016/j.neuron.2023.12.009 -
TheScientificWorldJournal 2023Rheumatoid arthritis (RA), a chronic inflammatory disease primarily affecting synovial joints and tendons, can potentially impact various organs within the body. One... (Review)
Review
Rheumatoid arthritis (RA), a chronic inflammatory disease primarily affecting synovial joints and tendons, can potentially impact various organs within the body. One notable complication associated with RA is upper cervical spine instability, medically termed atlantoaxial subluxation (AAS). This condition can lead to adverse consequences, including chronic myelopathy and acute mechanical compression of the medulla oblongata, with the potential for sudden death. While AAS may often remain asymptomatic, some nonspecific symptoms, such as neck pain, have been documented. Severe atlantoaxial subluxation can trigger more distinct symptoms, including delayed occipital pain attributed to the compression of the exiting C2 nerve root. Recent studies have elucidated a spectrum of symptoms preceding sudden death, encompassing vertigo, dizziness, convulsions, dysphagia, disorientation, and seizures. Remarkably, some cases have reported sudden death occurring during sleep. Historical data reveal a fluctuating incidence of this phenomenon, with eleven cases reported between 1969 and 1975 and six cases documented between 1990 and 2010. Notably, one of the most prevalent causes of sudden mortality in individuals with RA is the acute mechanical damage inflicted upon the medulla oblongata due to atlantoaxial subluxation.
Topics: Humans; Cervical Vertebrae; Prevalence; Atlanto-Axial Joint; Joint Dislocations; Chronic Disease; Arthritis, Rheumatoid
PubMed: 37841539
DOI: 10.1155/2023/6675489 -
ELife Dec 2023Several discrete groups of feeding-regulated neurons in the nucleus of the solitary tract (; NTS) suppress food intake, including avoidance-promoting neurons that...
Several discrete groups of feeding-regulated neurons in the nucleus of the solitary tract (; NTS) suppress food intake, including avoidance-promoting neurons that express (NTS cells) and distinct - and -expressing neurons (NTS and NTS cells, respectively) that suppress food intake without promoting avoidance. To test potential synergies among these cell groups, we manipulated multiple NTS cell populations simultaneously. We found that activating multiple sets of NTS neurons (e.g. NTS plus NTS [NTS], or NTS plus NTS [NTS]) suppressed feeding more robustly than activating single populations. While activating groups of cells that include NTS neurons promoted conditioned taste avoidance (CTA), NTS activation produced no CTA despite abrogating feeding. Thus, the ability to promote CTA formation represents a dominant effect but activating multiple non-aversive populations augments the suppression of food intake without provoking avoidance. Furthermore, silencing multiple NTS neuron groups augmented food intake and body weight to a greater extent than silencing single populations, consistent with the notion that each of these NTS neuron populations plays crucial and cumulative roles in the control of energy balance. We found that silencing NTS neurons failed to blunt the weight-loss response to vertical sleeve gastrectomy (VSG) and that feeding activated many non-NTS neurons, however, suggesting that as-yet undefined NTS cell types must make additional contributions to the restraint of feeding.
Topics: Solitary Nucleus; Neurons; Eating
PubMed: 38059498
DOI: 10.7554/eLife.85640 -
Brain Research Bulletin Sep 2023The nucleus tractus solitarii (NTS) is the primary central station that integrates visceral afferent information and regulates respiratory, gastrointestinal,...
The nucleus tractus solitarii (NTS) is the primary central station that integrates visceral afferent information and regulates respiratory, gastrointestinal, cardiovascular, and other physiological functions. Leptin receptor b (LepRb)-expressing neurons of the NTS (NTS neurons) are implicated in central respiration regulation, respiratory facilitation, and respiratory drive enhancement. Furthermore, LepRb dysfunction is involved in obesity, insulin resistance, and sleep-disordered breathing. However, the monosynaptic inputs and outputs of NTS neurons in whole-brain mapping remain to be elucidated. Therefore, the exploration of its whole-brain connection system may provide strong support for comprehensively understanding the physiological and pathological functions of NTS neurons. In the present study, we used a cell type-specific, modified rabies virus and adeno-associated virus with the Cre-loxp system to map monosynaptic inputs and outputs of NTS neurons in LepRb-Cre mice. The results showed that NTS neurons received inputs from 48 nuclei in the whole brain from five brain regions, including especially the medulla. We found that NTS neurons received inputs from nuclei associated with respiration, such as the pre-Bötzinger complex, ambiguus nucleus, and parabrachial nucleus. Interestingly, some brain areas related to cardiovascular regulation-i.e., the ventrolateral periaqueductal gray and locus coeruleus-also sent a small number of inputs to NTS neurons. In addition, anterograde tracing results demonstrated that NTS neurons sent efferent projections to 15 nuclei, including the dorsomedial hypothalamic nucleus and arcuate hypothalamic nucleus, which are involved in regulation of energy metabolism and feeding behaviors. Quantitative statistical analysis revealed that the inputs of the whole brain to NTS neurons were significantly greater than the outputs. Our study comprehensively revealed neuronal connections of NTS neurons in the whole brain and provided a neuroanatomical basis for further research on physiological and pathological functions of NTS neurons.
Topics: Mice; Animals; Solitary Nucleus; Receptors, Leptin; Neurons; Brain Mapping; Obesity
PubMed: 37348822
DOI: 10.1016/j.brainresbull.2023.110693 -
Neuroscience Bulletin Aug 2023The nucleus tractus solitarii (NTS) is one of the morphologically and functionally defined centers that engage in the autonomic regulation of cardiovascular activity....
The nucleus tractus solitarii (NTS) is one of the morphologically and functionally defined centers that engage in the autonomic regulation of cardiovascular activity. Phenotypically-characterized NTS neurons have been implicated in the differential regulation of blood pressure (BP). Here, we investigated whether phenylethanolamine N-methyltransferase (PNMT)-expressing NTS (NTS) neurons contribute to the control of BP. We demonstrate that photostimulation of NTS neurons has variable effects on BP. A depressor response was produced during optogenetic stimulation of NTS neurons projecting to the paraventricular nucleus of the hypothalamus, lateral parabrachial nucleus, and caudal ventrolateral medulla. Conversely, photostimulation of NTS neurons projecting to the rostral ventrolateral medulla produced a robust pressor response and bradycardia. In addition, genetic ablation of both NTS neurons and those projecting to the rostral ventrolateral medulla impaired the arterial baroreflex. Overall, we revealed the neuronal phenotype- and circuit-specific mechanisms underlying the contribution of NTS neurons to the regulation of BP.
Topics: Solitary Nucleus; Blood Pressure; Phenylethanolamine N-Methyltransferase; Neurons; Paraventricular Hypothalamic Nucleus
PubMed: 36588135
DOI: 10.1007/s12264-022-01008-3 -
ELife Sep 2023Infection with Influenza A virus (IAV) causes the well-known symptoms of the flu, including fever, loss of appetite, and excessive sleepiness. These responses, mediated...
Infection with Influenza A virus (IAV) causes the well-known symptoms of the flu, including fever, loss of appetite, and excessive sleepiness. These responses, mediated by the brain, will normally disappear once the virus is cleared from the system, but a severe respiratory virus infection may cause long-lasting neurological disturbances. These include encephalitis lethargica and narcolepsy. The mechanisms behind such long lasting changes are unknown. The hypothalamus is a central regulator of the homeostatic response during a viral challenge. To gain insight into the neuronal and non-neuronal molecular changes during an IAV infection, we intranasally infected mice with an H1N1 virus and extracted the brain at different time points. Using single-nucleus RNA sequencing (snRNA-seq) of the hypothalamus, we identify transcriptional effects in all identified cell populations. The snRNA-seq data showed the most pronounced transcriptional response at 3 days past infection, with a strong downregulation of genes across all cell types. General immune processes were mainly impacted in microglia, the brain resident immune cells, where we found increased numbers of cells expressing pro-inflammatory gene networks. In addition, we found that most neuronal cell populations downregulated genes contributing to the energy homeostasis in mitochondria and protein translation in the cytosol, indicating potential reduced cellular and neuronal activity. This might be a preventive mechanism in neuronal cells to avoid intracellular viral replication and attack by phagocytosing cells. The change of microglia gene activity suggest that this is complemented by a shift in microglia activity to provide increased surveillance of their surroundings.
Topics: Animals; Mice; Humans; Influenza, Human; Influenza A Virus, H1N1 Subtype; Hypothalamus; Solitary Nucleus; Appetite
PubMed: 37698546
DOI: 10.7554/eLife.87515 -
Frontiers in Public Health 2023Brain hemorrhage was found between 13 and 16 days after acute whole-body 9.5 Gy Co-γ irradiation (IR). This study tested countermeasures mitigating brain hemorrhage and...
INTRODUCTION
Brain hemorrhage was found between 13 and 16 days after acute whole-body 9.5 Gy Co-γ irradiation (IR). This study tested countermeasures mitigating brain hemorrhage and increasing survival from IR. Previously, we found that pegylated G-CSF therapy (PEG) (i.e., Neulasta, an FDA-approved drug) improved survival post-IR by 20-40%. This study investigated whether Ciprofloxacin (CIP) could enhance PEG-induced survival and whether IR-induced brain hemorrhage could be mitigated by PEG alone or combined with CIP.
METHODS
B6D2F1 female mice were exposed to Co-γ-radiation. CIP was fed to mice for 21 days. PEG was injected on days 1, 8, and 15. 30-day survival and weight loss were studied in mice treated with vehicles, CIP, PEG, or PEG + CIP. For the early time point study, blood and sternums on days 2, 4, 9, and 15 and brains on day 15 post-IR were collected. Platelet numbers, brain hemorrhage, and histopathology were analyzed. The cerebellum/pons/medulla oblongata were detected with glial fibrillary acidic protein (GFAP), p53, p16, interleukin-18 (IL-18), ICAM1, Claudin 2, ZO-1, and complement protein 3 (C3).
RESULTS
CIP + PEG enhanced survival after IR by 85% vs. the 30% improvement by PEG alone. IR depleted platelets, which was mitigated by PEG or CIP + PEG. Brain hemorrhage, both surface and intracranial, was observed, whereas the sham mice displayed no hemorrhage. CIP or CIP + PEG significantly mitigated brain hemorrhage. IR reduced GFAP levels that were recovered by CIP or CIP + PEG, but not by PEG alone. IR increased IL-18 levels on day 4 only, which was inhibited by CIP alone, PEG alone, or PEG + CIP. IR increased C3 on day 4 and day 15 and that coincided with the occurrence of brain hemorrhage on day 15. IR increased phosphorylated p53 and p53 levels, which was mitigated by CIP, PEG or PEG + CIP. P16, Claudin 2, and ZO-1 were not altered; ICAM1 was increased.
DISCUSSION
CIP + PEG enhanced survival post-IR more than PEG alone. The Concurrence of brain hemorrhage, C3 increases and p53 activation post-IR suggests their involvement in the IR-induced brain impairment. CIP + PEG effectively mitigated the brain lesions, suggesting effectiveness of CIP + PEG therapy for treating the IR-induced brain hemorrhage by recovering GFAP and platelets and reducing C3 and p53.
Topics: Female; Animals; Mice; Mice, Inbred Strains; Ciprofloxacin; Granulocyte Colony-Stimulating Factor; Recombinant Proteins; Polyethylene Glycols; Intracranial Hemorrhages; Gamma Rays; Body Weight; Brain; Intercellular Adhesion Molecule-1; Claudin-2; Zonula Occludens-1 Protein; Interleukin-18; Complement C3; Radiation Dosage
PubMed: 38162617
DOI: 10.3389/fpubh.2023.1268325 -
Experimental Neurobiology Feb 2024Panic disorder (PD), characterized by recurrent and intense panic attacks, presents a complex interplay between psychological and neurobiological factors. Although the...
Panic disorder (PD), characterized by recurrent and intense panic attacks, presents a complex interplay between psychological and neurobiological factors. Although the amygdala and hippocampus have been studied extensively in the context of PD, the brainstem's involvement remains relatively underexplored. This study aims to address this gap by examining structural abnormalities within specific brainstem regions, including the medulla, pons, and midbrain. The study sample population comprised twenty-one adult patients diagnosed with PD and an age-gender-education-matched control group. Utilizing rigorous inclusion and exclusion criteria, confounding factors related to comorbid psychiatric conditions and brain structure abnormalities were minimized. Our findings revealed a significant reduction in medulla volume among PD patients, a finding that persisted even after correcting for individual differences in total intracranial volume. The medulla's role in cardiovascular regulation and autonomic function, coupled with its involvement in fear responses, underscores its potential significance in the pathophysiology of PD. This study elucidates the medulla's structural abnormalities as a potential biomarker for PD. Understanding the role of the brainstem in PD could pave the way for more targeted and effective interventions for this condition.
PubMed: 38471801
DOI: 10.5607/en23034 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To assess the effects of repeated mild traumatic brain injury (rmTBI) in the parietal cortex on neuronal morphology and synaptic plasticity in the medulla oblongata of...
OBJECTIVE
To assess the effects of repeated mild traumatic brain injury (rmTBI) in the parietal cortex on neuronal morphology and synaptic plasticity in the medulla oblongata of mice.
METHODS
Thirty-two male ICR mice were randomly divided into sham operation group (=8) and rmTBI group (=24). The mice in the latter group were subjected to repeated mild impact injury of the parietal cortex by a free-falling object. The mice surviving the injuries were evaluated for neurological deficits using neurological severity scores (NSS), righting reflex test and forced swimming test, and pathological changes of the neuronal cells in the medulla oblongata were observed with HE and Nissl staining. Western blotting and immunofluorescence staining were used to detect the expressions of neuroligin 1(NLG-1) and postsynaptic density protein 95(PSD-95) in the medulla oblongata of the mice that either survived rmTBI or not.
RESULTS
None of the mice in the sham-operated group died, while the mortality rate was 41.67% in rmTBI group. The mice surviving rmTBI showed significantly reduced NSS, delayed recovery of righting reflex, increased immobility time in forced swimming test ( < 0.05), and loss of Nissl bodies; swelling and necrosis were observed in a large number of neurons in the medulla oblongata, where the expression levels of NLG-1 and PSD-95 were significantly downregulated ( < 0.05). The mice that did not survive rmTBI showed distorted and swelling nerve fibers and decreased density of neurons in the medulla oblongina with lowered expression levels of NLG-1 and PSD-95 compared with the mice surviving the injuries ( < 0.01).
CONCLUSION
The structural and functional anomalies of the synapses in the medulla oblongata may contribute to death and neurological impairment following rmTBI in mice.
Topics: Animals; Mice; Medulla Oblongata; Disks Large Homolog 4 Protein; Male; Mice, Inbred ICR; Parietal Lobe; Cell Adhesion Molecules, Neuronal; Neurons; Brain Injuries, Traumatic; Neuronal Plasticity
PubMed: 38862454
DOI: 10.12122/j.issn.1673-4254.2024.05.18 -
The Journal of Poultry Science 2024Food intake affects poultry productivity. A complete understanding of these regulatory mechanisms provides new strategies to improve productivity. Food intake is... (Review)
Review
Food intake affects poultry productivity. A complete understanding of these regulatory mechanisms provides new strategies to improve productivity. Food intake is regulated by complex mechanisms involving many factors, including the central nervous system, gastrointestinal tract, hormones, and nutrients. Although several studies have been conducted to elucidate regulatory mechanisms in chickens, the mechanisms remain unclear. To update the current knowledge on feeding regulation in chickens, this review focuses on recent findings that have not been summarized in previous reviews, including spexins, adipokines, neurosecretory proteins GL and GM, and central intracellular signaling factors.
PubMed: 38681189
DOI: 10.2141/jpsa.2024012