Objective: To observe the dynamic changes of brainstem locus coeruleus (LC) damage in Parkinson' s disease (PD) -like mice by paraquat (PQ) . Methods: In October 2019, 36 male C57BL/6 mice were randomly divided into the exposure group and the control group, with 18 mice in each group. The mice in the exposure group were given intraperitoneal injection of 15 mg/kg PQ, and the mice in the control group were given intraperitoneal injection of 0.9% saline, twice a week for 8 weeks. Neurobehavioral changes (pole climbing test, swimming test, open field test, tail hanging test, high plus maze test and water maze test) were observed at 4 weeks, 6 weeks and 8 weeks, respectively, and the changes of motor ability, emotion and cognitive function were evaluated. The brain tissue of mice were taken and stained with Hematoxylin-Eosin (HE) to observe the pathological changes of LC. Nissl staining was used to detect the changes of neuronal Nissl bodies in LC. Immunohistochemistry (IHC) staining was used to detect the expression of neuron nuclear antigen (NeuN) , dopamine (DA) neurons and norepinephrine (NE) neuron markers tyrosine hydroxylase (TH) , α-synuclein (α-syn) in substantia nigra (SN) and LC. The expression levels of NeuN, TH and α-syn in the midbrain and brainstem were detected by Western blotting. TUNEL staining was used to detect neuronal apoptosis in LC. Results: Compared with the 4th week of PQ exposure group, the time of pole climbing and swimming immobility were gradually increased, the ratio of open arm residence time of high plus maze test and the number of times of the platform and the residence time of platform quadrant in water maze test were gradually decreased (P<0.05) in the exposure group with the progress of exposure time. The results of HE and Nissl staining showed that the neurons in LC gradually arranged loosely, the nucleus were deeply stained, the cytoplasm was pyknosis, and the number of Nissl bodies gradually decreased (P<0.05) in the exposure group with the progress of exposure time. IHC results showed that the number of NeuN and TH positive cells in SN and LC of mice were gradually decreased, and the positive expression of α-syn was gradually increased (P<0.05) in the exposure group with the progress of exposure time. Western blotting results showed that the expression levels of NeuN and TH in the midbrain and brainstem were gradually decreased, and the expression level of α-syn was gradually increased (P<0.05) in the exposure group with the progress of exposure time. TUNEL staining showed that the apoptosis rates of neurons in LC were gradually increased (P<0.05) in the exposure group with the progress of exposure time. Conclusion: PQ induces progressive damage in the LC area of PD-like mice, which may be caused by the abnormal accumulation of pathological α-syn in the LC area.
Animals ; Dopaminergic Neurons ; Locus Coeruleus/pathology* ; Male ; Mice ; Mice, Inbred C57BL ; Paraquat/toxicity* ; Parkinson Disease/metabolism* ; Substantia Nigra ; Tyrosine 3-Monooxygenase/metabolism*

Acupuncture has remarkable effects on treating functional gastrointestinal diseases, but its central mechanism is not clear. At present, the research has mainly focused on several central nuclei, such as the dorsal vagus complex (DVC), nucleus raphe magnus (NRM), locus coeruleus (LC), subnucleus reticularis dorsalis (SRD), hypothalamic paraventricular nucleus (PVN), cerebellar fastigial nucleus (FN), central amygdala (CeA), etc. It is not clear whether the nuclei are involved in acupuncture regulation of gastric function through certain interrelation. A further summary of related literature indicates that many brain regions or nuclei in the central nervous system are closely related to gastric function, such as DVC, NRM, parabrachial nuclei (PBN), LC, periaqueductal gray (PAG), cerebellum, PVN, arcuate nucleus (Arc), hippocampus, CeA, etc. Most of these nuclei have certain fiber connections with each other, in which DVC is the basic center, and other nuclei are directly or indirectly involved in the regulation of gastric function through DVC. Is DVC the key target in acupuncture regulation of gastric function? Does other nuclei have direct or indirect neural circuit with DVC to participate in the regulation of gastric function by acupuncture, such as the possibility of CeA-DVC neural loop in acupuncture regulating gastric function. Therefore, more advanced techniques such as photogenetics, chemical genetics should be introduced and the central mechanism of acupuncture on regulating gastric function with DVC as center, from the view of nerve loop, will become the focus of further research, which could explain the central integration mechanism of acupoint compatibility by modern neuroscience technology.
Acupuncture Therapy ; Locus Coeruleus ; Paraventricular Hypothalamic Nucleus ; Vagus Nerve

The locus coeruleus (LC) has been studied in major depressive disorder (MDD) and bipolar disorder (BD). A major problem of immunocytochemical studies in the human LC is interference with the staining of the immunocytochemical end-product by the omnipresent natural brown pigment neuromelanin. Here, we used a multispectral method to untangle the two colors: blue immunocytochemical staining and brown neuromelanin. We found significantly increased tyrosine hydroxylase (TH) in the LC of MDD patients-thus validating the method-but not in BD patients, and we did not find significant changes in the receptor tyrosine-protein kinase ErbB4 in the LC in MDD or BD patients. We observed clear co-localization of ErbB4, TH, and neuromelanin in the LC neurons. The different stress-related molecular changes in the LC may contribute to the different clinical symptoms in MDD and BD.
Aged ; Aged, 80 and over ; Bipolar Disorder ; metabolism ; pathology ; Depressive Disorder, Major ; metabolism ; pathology ; Female ; Humans ; Image Processing, Computer-Assisted ; Immunohistochemistry ; methods ; Locus Coeruleus ; metabolism ; pathology ; Male ; Melanins ; metabolism ; Microscopy ; methods ; Middle Aged ; Neurons ; metabolism ; pathology ; Receptor, ErbB-4 ; metabolism ; Sensitivity and Specificity ; Spectrum Analysis ; methods ; Tyrosine 3-Monooxygenase ; metabolism

The characteristic features of Alzheimer's disease (AD) are the appearance of extracellular amyloid-beta (Aβ) plaques and neurofibrillary tangles in the intracellular environment, neuronal death and the loss of synapses, all of which contribute to cognitive decline in a progressive manner. A number of hypotheses have been advanced to explain AD. Abnormal tau phosphorylation may contribute to the formation of abnormal neurofibrillary structures. Many different structures are susceptible to AD, including the reticular formation, the nuclei in the brain stem (e.g., raphe nucleus), thalamus, hypothalamus, locus ceruleus, amygdala, substantia nigra, striatum, and claustrum. Excitotoxicity results from continuous, low-level activation of N-methyl-D-aspartate (NMDA) receptors. Premature synaptotoxicity, changes in neurotransmitter expression, neurophils loss, accumulation of amyloid β-protein deposits (amyloid/senile plaques), and neuronal loss and brain atrophy are all associated with stages of AD progression. Several recent studies have examined the relationship between Aβ and NMDA receptors. Aβ-induced spine loss is associated with a decrease in glutamate receptors and is dependent upon the calcium-dependent phosphatase calcineurin, which has also been linked to long-term depression.
Alzheimer Disease* ; Amygdala ; Amyloid ; Animals, Genetically Modified ; Atrophy ; Basal Ganglia ; Brain Stem ; Brain* ; Calcineurin ; Depression ; Hypothalamus ; Locus Coeruleus ; N-Methylaspartate* ; Neurofibrillary Tangles ; Neurons ; Neurotransmitter Agents ; Pathology* ; Phosphorylation ; Receptors, Glutamate ; Receptors, N-Methyl-D-Aspartate* ; Reticular Formation ; Risk Factors* ; Spine ; Substantia Nigra ; Synapses ; tau Proteins* ; Thalamus

OBJECTIVETo study possible mechanisms of Shangjuxu (ST37) and the large intestine.

METHODSTotally 40 SD rats were selected. The distension of end colon was used as injured afferent stimulus. Activities of locus coeruleus (LC) neurons were recorded by extracellular microelectrode technique. Shangjuxu (ST37) and Hegu (L14) were needled to observe general features of discharge reactions, distention of colon induced discharge reactions of LC, and its effects on distention of colon induced discharge reactions of LC.

RESULTSDistention of colon could induce incrased discharge of LC neurons by 127.33% ± 45.48%. But needling at Shangjuxu (ST37) and Hegu (L14) could inhibit this injured response by 38.24% ± 7.69% and 21.29% ± 13.16% respectively (all P < 0.01).

CONCLUSIONSNeedling at Shangjuxu (ST37) and afferent signals of colon distension converged and interacted with each other. Needling at Shangjuxu (ST37) could significantly inhibit colon distension induced discharge of LC neurons, which might be one of mechanisms for Shangjuxu (ST37) and the large intestine relationship.

Acupuncture Therapy ; Animals ; Colon ; Intestine, Large ; Locus Coeruleus ; physiology ; Neurons ; Rats ; Rats, Sprague-Dawley

Dexmedetomidine, an imidazoline compound, is a highly selective alpha2-adrenoceptor agonist with sympatholytic, sedative, amnestic, and analgesic properties. In order to minimize the patients' pain and anxiety during minimally invasive spine surgery (MISS) when compared to conventional surgery under general anesthesia, an adequate conscious sedation (CS) or monitored anesthetic care (MAC) should be provided. Commonly used intravenous sedatives and hypnotics, such as midazolam and propofol, are not suitable for operations in a prone position due to undesired respiratory depression. Dexmedetomidine converges on an endogenous non-rapid eye movement (NREM) sleep-promoting pathway to exert its sedative effects. The great merit of dexmedetomidine for CS or MAC is the ability of the operator to recognize nerve damage during percutaneous endoscopic lumbar discectomy, a representative MISS. However, there are 2 shortcomings for dexmedetomidine in MISS: hypotension/bradycardia and delayed emergence. Its hypotension/bradycardiac effects can be prevented by ketamine intraoperatively. Using atipamezole (an alpha2-adrenoceptor antagonist) might allow doctors to control the rate of recovery from procedural sedation in the future. MAC, with other analgesics such as ketorolac and opioids, creates ideal conditions for MISS. In conclusion, dexmedetomidine provides a favorable surgical condition in patients receiving MISS in a prone position due to its unique properties of conscious sedation followed by unconscious hypnosis with analgesia. However, no respiratory depression occurs based on the dexmedetomidine-related endogenous sleep pathways involves the inhibition of the locus coeruleus in the pons, which facilitates VLPO firing in the anterior hypothalamus.
Adrenergic alpha-2 Receptor Agonists ; Analgesia ; Analgesics ; Analgesics, Opioid ; Anesthesia, General ; Anxiety ; Conscious Sedation ; Dexmedetomidine* ; Diskectomy ; Diskectomy, Percutaneous ; Eye Movements ; Fires ; Humans ; Hypnosis* ; Hypnotics and Sedatives ; Hypothalamus, Anterior ; Ketamine ; Ketorolac ; Locus Coeruleus ; Midazolam ; Pons ; Prone Position* ; Propofol ; Respiratory Insufficiency ; Spine* ; Surgical Procedures, Minimally Invasive

OBJECTIVETo observe the changes of mitochondria stress in locus coeruleus and the tyrosine hydroxylasic projection after long-term sleep deprivation.

METHODSSleep deprivation mice model was set up by employing "novel environments" method. The expression of NAD -dependent deacetylase Sirtuin type 3 (SIRT3), which regulates mitochondrial energy production and oxidative stress, and heat shock protein 60 (HSP60), a major biomarker of mitochondrial stress, and the tyrosine hydroxylasic projection from locus coeruleus were analyzed after a 5-day sleep deprivation.

RESULTSCompared to the control group, the expression of SIRT3 in locus coeruleus was significantly decreased in respouse to long-term sleep deprivation, while the expression of HSP60 was significantly increased. In addition, relative to control group, pereentage area of the tyrosine hydroxylasic projection to anterior cingulate cortex was substantial decreased in long-term sleep deprivation group.

CONCLUSIONLong-term sleep deprivation induced the decreased level of SIRT3 expression and the elevation of mitochondrial stress in locus coenileus, which may further lead to the loss of tyrosine hydroxylasic projection in mice.

Animals ; Chaperonin 60 ; metabolism ; Locus Coeruleus ; metabolism ; physiology ; Mice ; Mitochondria ; metabolism ; Mitochondrial Proteins ; metabolism ; Oxidative Stress ; physiology ; Sirtuin 3 ; metabolism ; Sleep Deprivation ; Tyrosine ; metabolism

We investigated the anxiolytic-like activity of alpha-asarone (AAS) from Acorus gramineus in an experimental rat model of anxiety induced by repeated administration of the exogenous stress hormone corticosterone (CORT). The putative anxiolytic effect of AAS was studied in behavioral tests of anxiety, such as the elevated plus maze (EPM) test and the hole-board test (HBT) in rats. For 21 consecutive days, male rats received 50, 100, or 200 mg/kg AAS (i.p.) 30 min prior to a daily injection of CORT. Dysregulation of the HPA axis in response to the repeated CORT injections was confirmed by measuring serum levels of CORT and the expression of corticotrophin-releasing factor (CRF) in the hypothalamus. Daily AAS (200 mg/kg) administration increased open-arm exploration significantly in the EPM test, and it increased the duration of head dipping activity in the HBT. It also blocked the increase in tyrosine hydroxylase (TH) expression in the locus coeruleus (LC) and decreased mRNA expression of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, in the hippocampus. These results indicated that the administration of AAS prior to high-dose exogenous CORT significantly improved anxiety-like behaviors, which are associated with modification of the central noradrenergic system and with BDNF function in rats. The current finding may improve understanding of the neurobiological mechanisms responsible for changes in emotions induced by repeated administration of high doses of CORT or by elevated levels of hormones associated with chronic stress. Thus, AAS did exhibit an anxiolytic-like effects in animal models of anxiety.
Acorus* ; Animals ; Anti-Anxiety Agents ; Anxiety ; Axis, Cervical Vertebra ; Brain-Derived Neurotrophic Factor ; Corticosterone ; Head ; Hippocampus ; Humans ; Hypothalamus ; Locus Coeruleus ; Male ; Models, Animal ; Rats ; Receptor, trkB ; RNA, Messenger ; Tyrosine 3-Monooxygenase

Dexmedetomidine, an imidazoline compound, is a highly selective alpha2-adrenoceptor agonist with sympatholytic, sedative, amnestic, and analgesic properties. In order to minimize the patients' pain and anxiety during minimally invasive spine surgery (MISS) when compared to conventional surgery under general anesthesia, an adequate conscious sedation (CS) or monitored anesthetic care (MAC) should be provided. Commonly used intravenous sedatives and hypnotics, such as midazolam and propofol, are not suitable for operations in a prone position due to undesired respiratory depression. Dexmedetomidine converges on an endogenous non-rapid eye movement (NREM) sleep-promoting pathway to exert its sedative effects. The great merit of dexmedetomidine for CS or MAC is the ability of the operator to recognize nerve damage during percutaneous endoscopic lumbar discectomy, a representative MISS. However, there are 2 shortcomings for dexmedetomidine in MISS: hypotension/bradycardia and delayed emergence. Its hypotension/bradycardiac effects can be prevented by ketamine intraoperatively. Using atipamezole (an alpha2-adrenoceptor antagonist) might allow doctors to control the rate of recovery from procedural sedation in the future. MAC, with other analgesics such as ketorolac and opioids, creates ideal conditions for MISS. In conclusion, dexmedetomidine provides a favorable surgical condition in patients receiving MISS in a prone position due to its unique properties of conscious sedation followed by unconscious hypnosis with analgesia. However, no respiratory depression occurs based on the dexmedetomidine-related endogenous sleep pathways involves the inhibition of the locus coeruleus in the pons, which facilitates VLPO firing in the anterior hypothalamus.
Adrenergic alpha-2 Receptor Agonists ; Analgesia ; Analgesics ; Analgesics, Opioid ; Anesthesia, General ; Anxiety ; Conscious Sedation ; Dexmedetomidine ; Diskectomy ; Diskectomy, Percutaneous ; Eye Movements ; Fires ; Humans ; Hypnosis ; Hypnotics and Sedatives ; Hypothalamus, Anterior ; Ketamine ; Ketorolac ; Locus Coeruleus ; Midazolam ; Pons ; Prone Position ; Propofol ; Respiratory Insufficiency ; Spine ; Surgical Procedures, Minimally Invasive

Although physiological function of alpha-synuclein is not yet clearly understood, accumulating evidence strongly suggests it plays a crucial role in the pathogenesis of Parkinson disease. Pathologically, alpha-synuclein is a major component of Lewy bodies, which is the pathological hallmark of Parkinson disease. Alpha-synuclein pathology is observed in the brainstem nuclei, including the dorsal motor nucleus of the vagus nerve, the locus ceruleus, and the substantia nigra in the early phase of Parkinson disease and it may 'spread' to cerebral cortical areas in the advanced Parkinson disease and appears to have a role in the cognitive decline in Parkinson disease. Recently, it is suggested that alpha-synuclein pathology in Parkinson disease starts in the olfactory bulb or enteric nervous system and then spreads to the brainstem. In accordance with this hypothesis, alpha-synuclein pathology has been found in gastric mucosa and colonic mucosa of patients with Parkinson disease. Genetically, SNCA mutations including point mutation and copy number variation are known to cause familial Parkinson disease, further supporting the assumption that alpha-synuclein plays a crucial role in Parkinson disease pathogenesis. In addition, recent GWAS studies consistently show that the SNPs in SNCA genes are associated with risk for sporadic Parkinson disease. It is also known that variations in the promoter region or 3'UTR of SNCA, which increases the expression of SNCA, are associated with the risk for Parkinson disease. Collectively, these findings suggest that further studies on alpha-synuclein will lead to the elucidation of the mechanism of and therapy for Parkinson disease.
3' Untranslated Regions ; alpha-Synuclein ; Brain Stem ; Coat Protein Complex I ; Colon ; Enteric Nervous System ; Gastric Mucosa ; Humans ; Lewy Bodies ; Locus Coeruleus ; Mucous Membrane ; Olfactory Bulb ; Parkinson Disease ; Point Mutation ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Substantia Nigra ; Vagus Nerve