المؤلفون: Wu, Ming-Fung, Li, Songlin, Lai, Yuan-Yang, Siegel, Jerome, Thannickal, Thomas, Mcgregor, Ronald

المصدر: Sleep. 46(9)

مصطلحات موضوعية: Xyrem, hypocretin, locus coeruleus, narcolepsy, orexin, sodium oxybate, tyrosine hydroxylase, Humans, Mice, Animals, Dogs, Orexins, Sodium Oxybate, Cataplexy, Locus Coeruleus, Narcolepsy, Neurons, Opiate Alkaloids

الوصف: Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found that chronic opiate usage in humans and long-term opiate administration to mice significantly increased the number of detected hypocretin/orexin (Hcrt) neurons, decreased their size, and increased Hcrt level in the hypothalamus. We also found that opiates significantly decreased cataplexy in human narcoleptics as well as in narcoleptic mice and that cessation of locus coeruleus neuronal activity preceded and was tightly linked to cataplectic attacks in narcoleptic dogs. We tested the hypothesis that SXB produces changes similar to opiates and now report that chronic SXB administration significantly increased the size of Hcrt neurons, the reverse of what we had seen with opiates in humans and mice. Levels of Hcrt in the hypothalamus were nonsignificantly lower, in contrast to the significant increase in hypothalamic Hcrt level after opiates. SXB decreased tyrosine hydroxylase levels in the locus coeruleus, the major descending projection of the hypocretin system, also the reverse of what we saw with opioids. Therefore despite some similar effects on narcoleptic symptomatology, SXB does not produce anatomical changes similar to those elicited by opiates. Analysis of changes in other links in the cataplexy pathway might further illuminate SXBs mechanism of action on narcolepsy.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1685v0b7Test

المؤلفون: McGregor, Ronald, Matzeu, Alessandra, Thannickal, Thomas C, Wu, Frank, Cornford, Marcia, Martin-Fardon, Rémi, Siegel, Jerome M

مصطلحات موضوعية: Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Substance Misuse, Neurosciences, Brain Disorders, Behavioral and Social Science, Alcoholism, Alcohol Use and Health, Mental health, Good Health and Well Being, Humans, Male, Rats, Mice, Animals, Orexins, Neuropeptides, Histamine, Hypothalamic Hormones, Hypothalamus, Melanins, Neurons, Ethanol, hypocretin, melanin concentrating hormone, histamine human, alcohol, microglia, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology

الوصف: Human heroin addicts and mice administered morphine for a 2 week period show a greatly increased number of hypothalamic hypocretin (Hcrt or orexin) producing neurons with a concomitant reduction in Hcrt cell size. Male rats addicted to cocaine similarly show an increased number of detectable Hcrt neurons. These findings led us to hypothesize that humans with alcohol use disorder (AUD) would show similar changes. We now report that humans with AUD have a decreased number and size of detectable Hcrt neurons. In addition, the intermingled melanin concentrating hormone (MCH) neurons are reduced in size. We saw no change in the size and number of tuberomammillary histamine neurons in AUD. Within the Hcrt/MCH neuronal field we found that microglia cell size was increased in AUD brains. In contrast, male rats with 2 week alcohol exposure, sufficient to elicit withdrawal symptoms, show no change in the number or size of Hcrt, MCH and histamine neurons, and no change in the size of microglia. The present study indicates major differences between the response of Hcrt neurons to opioids and that to alcohol in human subjects with a history of substance abuse.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0mv3313dTest
https://escholarship.org/content/qt0mv3313d/qt0mv3313d.pdfTest

المؤلفون: Williams, Victoria M, Bhagwandin, Adhil, Swiegers, Jordan, Bertelsen, Mads F, Hård, Therese, Thannickal, Thomas C, Siegel, Jerome M, Sherwood, Chet C, Manger, Paul R

المصدر: The Anatomical Record. 305(6)

مصطلحات موضوعية: Neurosciences, Neurological, Animals, Hylobates, Hypothalamus, Mammals, Neurons, Orexins, Pan troglodytes, ape, brain evolution, hypocretin, immunohistochemistry, orexin, primates, Biological Sciences, Medical and Health Sciences, Anatomy & Morphology

الوصف: Employing orexin-A immunohistochemical staining we describe the nuclear parcellation of orexinergic neurons in the hypothalami of a lar gibbon and a chimpanzee. The clustering of orexinergic neurons within the hypothalamus and the terminal networks follow the patterns generally observed in other mammals, including laboratory rodents, strepsirrhine primates and humans. The orexinergic neurons were found within three distinct clusters in the ape hypothalamus, which include the main cluster, zona incerta cluster and optic tract cluster. In addition, the orexinergic neurons of the optic tract cluster appear to extend to a more rostral and medial location than observed in other species, being observed in the tuberal region in the anterior ventromedial aspect of the hypothalamus. While orexinergic terminal networks were observed throughout the brain, high density terminal networks were observed within the hypothalamus, medial and intralaminar nuclei of the dorsal thalamus, and within the serotonergic and noradrenergic regions of the midbrain and pons, which is typical for mammals. The expanded distribution of orexinergic neurons into the tuberal region of the ape hypothalamus, is a feature that needs to be investigated in other primate species, but appears to correlate with orexin gene expression in the same region of the human hypothalamus, but these neurons are not revealed with immunohistochemical staining in humans. Thus, it appears that apes have a broader distribution of orexinergic neurons compared to other primate species, but that the neurons within this extension of the optic tract cluster in humans, while expressing the orexin gene, do not produce the neuropeptide.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/7j62r3qcTest

المؤلفون: McGregor, Ronald, Thannickal, Thomas C, Siegel, Jerome M

مصطلحات موضوعية: Neurosciences, Drug Abuse (NIDA only), Pain Research, Chronic Pain, Substance Misuse, Sleep Research, Brain Disorders, Neurological, Good Health and Well Being, Animals, Cats, Dogs, Humans, Hypothalamus, Mice, Narcolepsy, Neurons, Orexins, Pleasure, Rats, Affect, Cataplexy, Dopamine, Human leukocyte antigen, Inflammation, Melanin-concentrating hormone, Reward, Neurology & Neurosurgery

الوصف: The hypocretins/orexins were discovered in 1998. Within 2 years, this led to the discovery of the cause of human narcolepsy, a 90% loss of hypothalamic neurons containing these peptides. Further work demonstrated that these neurons were not simply linked to waking. Rather these neurons were active during pleasurable behaviors in waking and were silenced by aversive stimulation. This was seen in wild-type mice, rats, cats, and dogs. It was also evident in humans, with increased Hcrt release during pleasurable activities and decreased release, to the levels seen in sleep, during pain. We found that human heroin addicts have, on average, an increase of 54% in the number of detectable Hcrt neurons compared to "control" human brains and that these Hcrt neurons are substantially smaller than those in control brains. We found that in mice, chronic morphine administration induced the same changes in Hcrt neuron number and size. Our studies in the mouse allowed us to determine the specificity, dose response relations, time course of the change in the number of Hcrt neurons, and that the increased number of Hcrt neurons after opiates was not due to neurogenesis. Furthermore, we found that it took a month or longer for these anatomical changes in the mouse brain to return to baseline. Human narcoleptics, despite their prescribed use of several commonly addictive drugs, do not show significant evidence of dose escalation or substance use disorder. Similarly, mice in which the peptide has been eliminated are resistant to addiction. These findings are consistent with the concept that an increased number of Hcrt neurons may underlie and maintain opioid or cocaine use disorders.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9dv7m7chTest

المؤلفون: Thannickal, Thomas Chacko, Kadotani, Hiroshi

المصدر: Frontiers in Neurology ; volume 14 ; ISSN 1664-2295

مصطلحات موضوعية: Neurology (clinical), Neurology

الإتاحة: https://doi.org/10.3389/fneur.2023.1259390Test

المؤلفون: John, Joshi, Shan, Ling, Swaab, Dick, Wu, Ming-Fung, Ramanathan, Lalini, Chew, Keng-Tee, Cornford, Marcia, Yamanaka, Akihiro, Inutsuka, Ayumu, Fronczek, Rolf, Lammers, Gert, Worley, Paul, Siegel, Jerome, Thannickal, Thomas, Mcgregor, Ronald

المصدر: Science Translational Medicine. 10(447)

مصطلحات موضوعية: Animals, Brain, Cataplexy, Cell Count, Disease Models, Animal, Dose-Response Relationship, Drug, Heroin, Humans, Male, Mice, Inbred C57BL, Morphine, Narcolepsy, Neurogenesis, Neurons, Opiate Alkaloids, Orexins, Rats, Sprague-Dawley, Substance-Related Disorders

الوصف: The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/47s402vpTest

المؤلفون: Thannickal, Thomas C, John, Joshi, Shan, Ling, Swaab, Dick F, Wu, Ming-Fung, Ramanathan, Lalini, McGregor, Ronald, Chew, Keng-Tee, Cornford, Marcia, Yamanaka, Akihiro, Inutsuka, Ayumu, Fronczek, Rolf, Lammers, Gert Jan, Worley, Paul F, Siegel, Jerome M

المصدر: Science translational medicine. 10(447)

مصطلحات موضوعية: Brain, Neurons, Animals, Mice, Inbred C57BL, Humans, Rats, Sprague-Dawley, Narcolepsy, Cataplexy, Substance-Related Disorders, Disease Models, Animal, Morphine, Heroin, Cell Count, Dose-Response Relationship, Drug, Male, Opiate Alkaloids, Neurogenesis, Orexins, Drug Abuse (NIDA only), Brain Disorders, Neurosciences, Substance Misuse, Aetiology, 2.1 Biological and endogenous factors, Neurological, Good Health and Well Being, Biological Sciences, Medical and Health Sciences

الوصف: The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3387f8vjTest

المؤلفون: Williams, Victoria M., Bhagwandin, Adhil, Swiegers, Jordan, Bertelsen, Mads F., Hård, Therese, Thannickal, Thomas C., Siegel, Jerome M., Sherwood, Chet C., Manger, Paul R.

المصدر: Williams , V M , Bhagwandin , A , Swiegers , J , Bertelsen , M F , Hård , T , Thannickal , T C , Siegel , J M , Sherwood , C C & Manger , P R 2022 , ' Nuclear organization of orexinergic neurons in the hypothalamus of a lar gibbon and a chimpanzee ' , Anatomical Record , vol. 305 , no. 6 , pp. 1459-1475 . https://doi.org/10.1002/ar.24775Test

مصطلحات موضوعية: ape, brain evolution, hypocretin, immunohistochemistry, orexin, primates

الوصف: Employing orexin-A immunohistochemical staining we describe the nuclear parcellation of orexinergic neurons in the hypothalami of a lar gibbon and a chimpanzee. The clustering of orexinergic neurons within the hypothalamus and the terminal networks follow the patterns generally observed in other mammals, including laboratory rodents, strepsirrhine primates and humans. The orexinergic neurons were found within three distinct clusters in the ape hypothalamus, which include the main cluster, zona incerta cluster and optic tract cluster. In addition, the orexinergic neurons of the optic tract cluster appear to extend to a more rostral and medial location than observed in other species, being observed in the tuberal region in the anterior ventromedial aspect of the hypothalamus. While orexinergic terminal networks were observed throughout the brain, high density terminal networks were observed within the hypothalamus, medial and intralaminar nuclei of the dorsal thalamus, and within the serotonergic and noradrenergic regions of the midbrain and pons, which is typical for mammals. The expanded distribution of orexinergic neurons into the tuberal region of the ape hypothalamus, is a feature that needs to be investigated in other primate species, but appears to correlate with orexin gene expression in the same region of the human hypothalamus, but these neurons are not revealed with immunohistochemical staining in humans. Thus, it appears that apes have a broader distribution of orexinergic neurons compared to other primate species, but that the neurons within this extension of the optic tract cluster in humans, while expressing the orexin gene, do not produce the neuropeptide.

وصف الملف: application/pdf

الإتاحة: https://doi.org/10.1002/ar.24775Test
https://curis.ku.dk/portal/da/publications/nuclear-organization-of-orexinergic-neurons-in-the-hypothalamus-of-a-lar-gibbon-and-a-chimpanzeeTest(8f77dd63-9ce1-462e-8d94-8e344aa512ec).html
https://curis.ku.dk/ws/files/308556647/nihms_1759964.pdfTest

المؤلفون: John, Joshi, Thannickal, Thomas C, McGregor, Ronald, Ramanathan, Lalini, Ohtsu, Hiroshi, Nishino, Seiji, Sakai, Noriaki, Yamanaka, Akhiro, Stone, Carly, Cornford, Marcia, Siegel, Jerome M

المصدر: Annals of neurology. 74(6)

مصطلحات موضوعية: Brain, Neurons, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Knockout, Dogs, Humans, Mice, Narcolepsy, Cataplexy, Disease Models, Animal, Histamine, Cell Count, Mutation, Adult, Aged, 80 and over, Middle Aged, Female, Male, Sleep Research, Brain Disorders, Neurosciences, Rare Diseases, 5.1 Pharmaceuticals, Aetiology, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, Clinical Sciences, Neurology & Neurosurgery

الوصف: ObjectiveTo determine whether histamine cells are altered in human narcolepsy with cataplexy and in animal models of this disease.MethodsImmunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy were used to detect histamine cells in human narcoleptics, hypocretin (Hcrt) receptor-2 mutant dogs, and 3 mouse narcolepsy models: Hcrt (orexin) knockouts, ataxin-3-orexin, and doxycycline-controlled-diphtheria-toxin-A-orexin.ResultsWe found an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between narcoleptics and controls. However, we did not see altered numbers of HDC cells in any of the animal models of narcolepsy.InterpretationChanges in histamine cell numbers are not required for the major symptoms of narcolepsy, because all animal models have these symptoms. The histamine cell changes we saw in humans did not occur in the 4 animal models of Hcrt dysfunction we examined. Therefore, the loss of Hcrt receptor-2, of the Hcrt peptide, or of Hcrt cells is not sufficient to produce these changes. We speculate that the increased histamine cell numbers we see in human narcolepsy may instead be related to the process causing the human disorder. Although research has focused on possible antigens within the Hcrt cells that might trigger their autoimmune destruction, the present findings suggest that the triggering events of human narcolepsy may involve a proliferation of histamine-containing cells. We discuss this and other explanations of the difference between human narcoleptics and animal models of narcolepsy, including therapeutic drug use and species differences.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2mg133r6Test

المؤلفون: Thannickal, Thomas C, Lai, Yuan-Yang, Siegel, Jerome M

المصدر: Brain. 130(6)

مصطلحات موضوعية: Aging, Sleep Research, Neurosciences, Brain Disorders, Neurodegenerative, Parkinson's Disease, Neurological, Aged, Aged, 80 and over, Cell Count, Disease Progression, Female, Glial Fibrillary Acidic Protein, Humans, Hypothalamic Hormones, Hypothalamus, Immunoenzyme Techniques, Intracellular Signaling Peptides and Proteins, Male, Melanins, Middle Aged, Neurons, Neuropeptides, Orexins, Parkinson Disease, Pituitary Hormones, Severity of Illness Index, Substantia Nigra, alpha-Synuclein, Parkinson, narcolepsy, sleep, hypocretin, orexin, melanin concentrating hormone, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery

الوصف: It has recently been reported that Parkinson's disease (PD) is preceded and accompanied by daytime sleep attacks, nocturnal insomnia, REM sleep behaviour disorder, hallucinations and depression, symptoms which are frequently as troublesome as the motor symptoms of PD. All these symptoms are present in narcolepsy, which is linked to a selective loss of hypocretin (Hcrt) neurons. In this study, the Hcrt system was examined to determine if Hcrt cells are damaged in PD. The hypothalamus of 11 PD (mean age 79 +/- 4) and 5 normal (mean age 77 +/- 3) brains was examined. Sections were immunostained for Hcrt-1, melanin concentrating hormone (MCH) and alpha synuclein and glial fibrillary acidic protein (GFAP). The substantia nigra of 10 PD brains and 7 normal brains were used for a study of neuromelanin pigmented cell loss. The severity of PD was assessed using the Hoehn and Yahr scale and the level of neuropathology was assessed using the Braak staging criteria. Cell number, distribution and size were determined with stereologic techniques on a one in eight series. We found an increasing loss of hypocretin cells with disease progression. Similarly, there was an increased loss of MCH cells with disease severity. Hcrt and MCH cells were lost throughout the anterior to posterior extent of their hypothalamic distributions. The percentage loss of Hcrt cells was minimal in stage I (23%) and was maximal in stage V (62%). Similarly, the percentage loss of MCH cells was lowest in stage I (12%) and was highest in stage V (74%). There was a significant increase (P = 0.0006, t = 4.25, df = 15) in the size of neuromelanin containing cells in PD patients, but no difference in the size of surviving Hcrt (P = 0.18, t = 1.39, df = 14) and MCH (P = 0.28, t = 1.39, df = 14) cells relative to controls. In summary, we found that PD is characterized by a massive loss of Hcrt neurons. Thus, the loss of Hcrt cells may be a cause of the narcolepsy-like symptoms of PD and may be ameliorated by treatments aimed at reversing the Hcrt deficit. We also saw a substantial loss of hypothalamic MCH neurons. The losses of Hcrt and MCH neurons are significantly correlated with the clinical stage of PD, not disease duration, whereas the loss of neuromelanin cells is significantly correlated only with disease duration. The significant correlations that we found between the loss of Hcrt and MCH neurons and the clinical stage of PD, in contrast to the lack of a relationship of similar strength between loss of neuromelanin containing cells and the clinical symptoms of PD, suggests a previously unappreciated relationship between hypothalamic dysfunction and the time course of the overall clinical picture of PD.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2vg1f3jhTest