自律神経機能研究

メンバー

リーダー 研究部長　堀田 晴美
専門副部長 内田 さえ
研究員 渡辺 信博
非常勤研究員 守屋 正道

キーワード

自律神経、アセチルコリン、脳血流、神経栄養因子、ホルモン、痛み、膀胱、皮膚刺激、筋刺激、運動、嗅覚

主な研究

  1. 認知機能に関わる脳内コリン作動系のはたらき
  2. 高齢者の自律神経活動の調整

研究紹介

１．認知機能に関わる脳内コリン作動系のはたらき

認知症患者や高齢者における認知機能低下には、前脳基底部コリン作動性ニューロンの減少や機能障害が関わると考えられています。本研究は、大脳皮質や海馬、嗅球における脳血流調節や神経成長因子（NGF）分泌調節におけるコリン作動性ニューロン及びコリン作動性受容体の役割を明らかにし、加齢に伴うコリン作動性機能の低下を予防･改善する方法をみつけることを目的とします。そのために、成熟および老齢動物を用い、臨床応用に向けて、コリン作動性機能を賦活する方法を開発します。具体的には、皮膚や筋の刺激、脳深部電気刺激、薬理的操作が、大脳皮質や海馬における血流（レーザドップラー法やイメージング技術で測定）・NGF分泌（マイクロダイアリシスとELISA法で測定）・ニューロン活動（電気生理学的手法で測定）に及ぼす効果とそのメカニズムを調べます。我々は、コリン作動性機能の制御メカニズムについての研究を展開し、これまでに患者に容易に用い得るコリン作動性神経活動を高めるいくつかの簡単な方法を明らかにしています。

２．高齢者の自律神経活動の調整

高齢者における安静時高血圧と一過性低血圧は、ふらつきや転倒、それによる骨折、さらには認知症の発生など、重篤な疾患の主要な一因となります。また高齢者では頻尿や失禁など排尿の問題も増えてきます。これらの症状には自律神経系が密接に関わります。本研究は、自律神経機能の加齢変化の特徴を明らかにし、自律神経系の活動を制御する方法を究明することを目的とします。その一例として、皮膚や筋への機械的刺激（鍼や圧刺激など）が自律神経系の活動を変化させ、それによって心血管機能、排尿機能、内分泌機能などを調節することを見出してきました。また、高齢患者の多くは痛みを抱えており、痛みと自律神経系は互いに影響を及ぼすことから、皮膚や筋刺激を利用した鎮痛方法の探索にも取り組みます。我々は、様々な電気生理学的手法やイメージング技術を用い、体性感覚刺激が自律機能に及ぼす効果（体性-自律神経反射）のメカニズムを動物とヒトで研究し、自律神経活動の調整や疼痛緩和に最適な体性感覚刺激方法を明らかにします。

近年では、動物で明らかにした排尿抑制作用のある皮膚刺激ローラーが、高齢者の夜間頻尿を緩和し得ることを明らかにしています。

主要文献

  1. Uchida S, Kagitani F. (2024) Influence of age on nicotinic cholinergic regulation of blood flow in rat's olfactory bulb and neocortex. Journal of Physiological Sciences, 74:18.[Review]
    https://doi.org/10.1186/s12576-024-00913-8
  2. Izuo N, Watanabe N, Noda Y, Saito T, Saido TC, Yokote K, Hotta H, Shimizu T. (2023) Insulin resistance induces earlier initiation of cognitive dysfunction mediated by cholinergic deregulation in a mouse model of Alzheimer's disease. Aging Cell, 22:e13994.
  3. Hotta H, Iimura K, Watanabe N, Suzuki H, Sugie M, Shigemoto K. (2023) Sympathetic modulation of hindlimb muscle contractility is altered in aged rats. Scientific Reports,13(1):7504.
  4. Watanabe N, Nara M, Suzuki S, Sugie M, Yamamoto T, Hotta H. (2023) Effects of gentle mechanical skin stimulation on subjective symptoms and joint range of motions in people with chronic neck and shoulder discomfort. Journal of Physiological Sciences, 73, 4.
    https://doi.org/10.1186/s12576-023-00862-8
  5. Uchida S, Moriya J, Morihara D, Kagitani F. (2023) Nicotinic cholinergic regulation of olfactory bulb blood flow response in aged rats. Journal of Physiological Sciences, 73, 1.
    https://doi.org/10.1186/s12576-022-00859-9
  6. Iimura K, Watanabe N, Hotta H. (2022) Mild thermal stimulation of the buttock skin increases urinary voiding efficiency in anesthetized rats. Autonomic Neuroscience: Basic and Clinical, 242, 103022.
  7. Uchida S, Shimada C, Sakuma N, Kagitani F, Kan A, Awata A. (2022) Olfactory function and discrimination ability in the elderly: a pilot study. Journal of Physiological Sciences, 72, 8.
    https://doi.org/10.1186/s12576-022-00832-6
  8. Hasebe R, Murakami K, Harada M, Halaka N, Nakagawa H, Kawano F, Ohira Y, Kawamoto T, Yull EF, Blackwell ST, Nio-Kobayashi J, Iwanaga T, Watanabe M, Watanabe N, Hotta H, Yamashita T, Kamimura D, Tanaka Y, Murakami M. (2022) ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons. Journal of Experimental Medicine, 219(6), e20212019.
  9. Tokunaga R, Takahashi Y, Touj S, Hotta H, Leblond H, Kato F, Piché M. (2022) Attenuation of widespread hypersensitivity to noxious mechanical stimuli by inhibition of GABAergic neurons of the right amygdala in a rat model of chronic back pain. European Journal of Pain, 26(4), 911-928.
  10. Hotta H, Iimura K, Watanabe N, Shigemoto K. (2021) Maintenance of contractile force of the hind limb muscles by the somato‑lumbar sympathetic reflexes. Journal of Physiological Sciences, 71, 15.
    https://doi.org/10.1186/s12576-021-00799-w
  11. Watanabe N, Iimura K, Hotta H. (2021) Influence of intragastric administration of traditional Japanese medicine, ninjin'yoeito, on cerebral blood flow via muscarinic acetylcholine receptors. Evidence-Based Complementary and Alternative Medicine, 2021, 9930023.
  12. Watanabe, N., Noda, Y., Nemoto, T., Iimura, K., Shimizu, T., Hotta, H. (2020) Cerebral artery dilation during transient ischemia is impaired by amyloid β deposition around the cerebral artery in Alzheimer's disease model mice. Journal of Physiological Sciences, 70, 57
  13. Hotta, H., Suzuki, H., Inoue, T., Stewart, M. (2020) Involvement of the basal nucleus of Meynert on regional cerebral cortical vasodilation associated with masticatory muscle activity in rats. Journal of Cerebral Blood Flow and Metabolism, 40(12), 2416-2428
  14. Uchida, S., Shimada, C., Sakuma, N., Kagitani, F., Kan, A., Awata, S. (2020) The relationship between olfaction and cognitive function in the elderly. Journal of Physiological Sciences, 70, 48
  15. Iimura, K†., Watanabe, N†., Milliken, P., Hsieh, YH., Lewis, SJ., Sridhar, A., Hotta, H. (2020) Chronic electrical stimulation of the superior laryngeal nerve in the rat: A potential therapeutic approach for postmenopausal osteoporosis. Biomedicines, 8(9), E369 († equally contributed)
  16. Uchida, S., Kagitani, F. (2020) Effects of nicotine on regional blood flow in the olfactory bulb in response to olfactory nerve stimulation. Journal of Physiological Sciences, 70(1), 30
  17. Iimura, K., Suzuki, H., Hotta, H. (2019) Thyroxin and calcitonin secretion into thyroid venous blood is regulated by pharyngeal mechanical stimulation in anesthetized rats. Journal of Physiological Sciences, 69(5), 749-756
  18. Hotta, H., Watanabe, N. (2019) Gentle perineal skin stimulation for control of nocturia. Anatomical Record, 302(10),1824-1836[Review]
  19. Uchida, S., Kagitani, F. (2019) Neural mechanisms involved in the noxious physical stress-induced inhibition of ovarian estradiol secretion. Anatomical Record, 302(6),904-911[Review]
  20. Uchida, S., Taniguchi, H., Ito, Y., Kagitani, F. (2019) Blood pressure-independent increase in the cortical cerebral blood flow induced by manual acupuncture of the auricular region in rats. Journal of Physiological Sciences, 69, 165-170
  21. Uchida, S., Ito, Y., Kagitani, F. (2019) Effects of nicotine on odor-induced increases in regional blood flow in the olfactory bulb in rats. Journal of Physiological Sciences, 69, 425-431
  22. Watanabe, N., Sasaki, S., Masamoto, K., Hotta, H. (2018) Vascular gap junctions contribute to forepaw stimulation-Induced vasodilation differentially in the pial and penetrating arteries in isoflurane-anesthetized rats. Frontiers in Molecular Neuroscience, 11: 446
  23. Hotta, H., Suzuki, H., Iimura, K., Watanabe, N. (2018) Age-related changes in neuromodulatory control of bladder micturition contractions originating in the skin. Frontiers in Neuroscience, 12: 117
  24. Kamei, J., Ito, H., Aizawa, N., Hotta, H., Kojima, T., Fujita, Y., Ito, M., Homma, Y., Igawa, Y. (2018) Age-related changes in function and gene expression of the male and female mouse bladder. Scientific Reports, 8(1): 2089
  25. Uchida, S., Kagitani, F. (2018) Effect of basal forebrain stimulation on extracellular acetylcholine release and blood flow in the olfactory bulb. Journal of Physiological Sciences, 68: 415-423
  26. Hotta, H., Onda, A., Suzuki, H., Milliken, P., Sridhar, A. (2017) Modulation of calcitonin, parathyroid hormone, and thyroid hormone secretion by electrical stimulation of sympathetic and parasympathetic nerves in anesthetized rats. Front Neurosci. 11, 375
  27. Touj, S., Houle, S., Ramla, D., Jeffrey-Gauthier, R., Hotta, H., Bronchti, G., Martinoli, M.G., Piché, M. (2017) Sympathetic regulation and anterior cingulate cortex volume are altered in a rat model of chronic back pain. Neuroscience. 352, 9-18
  28. Uchida, S., Bois, S., Guillemot, J.P., Leblond, H., Piché, M. (2017) Systemic blood pressure alters cortical blood flow and neurovascular coupling during nociceptive processing in the primary somatosensory cortex of the rat. Neuroscience, 343, 250-259
  29. Watanabe, N., Hotta, H．(2017) Heart rate changes in response to mechanical pressure stimulation of skeletal muscles are mediated by cardiac sympathetic nerve activity. Front. Neurosci.,10, 614
  30. Uchida, S., Kagitani, F. (2017) Mechanism of physical stress-induced inhibition of ovarian estradiol secretion in anesthetized rats. Auton. Neurosci., 206, 63-66
  31. Uchida, S., Kagitani, F., Hotta, H., Watanabe, S., Misawa, H. (2017) Effect of radial nerve stimulation on regional cerebral blood flow in anesthetized mice. Auton.Nerv.Syst. 54, 26-33, Japanese
  32. Onda, A., Uchida, S., Suzuki, H., Hotta, H. (2016) Stimulus frequency-dependent inhibition of micturition contractions of the urinary bladder by electrical stimulation of afferent Aβ, Aδ, and C fibers in cutaneous branches of the pudendal nerve. J. Physiol. Sci., 66, 491-496
  33. Morisaki, Y., Niikura, M., Watanabe, M., Onishi, K., Tanabe, S., Moriwaki, Y., Okuda, T., Ohara, S., Murayama, S., Takao, M., Uchida, S., Yamanaka, K., Misawa, H. (2016) Selective Expression of Osteopontin in ALS-resistant Motor Neurons is a Critical Determinant of Late Phase Neurodegeneration Mediated by Matrix Metalloproteinase-9. Sci. Rep.,6, 27354
  34. Uchida, S., Kagitani, F. (2016) Sympathetic regulation of ovarian functions under chronic estradiol treatment in rats. Auton. Neurosci., 197, 19-24
  35. Iimura, K., Watanabe, N., Masunaga, K., Miyazaki, S., Hotta, H., Kim, H., Hisajima, H., Takahashi, H., Kasuya, Y. (2016) Effects of a gentle, self-administered stimulation of perineal skin for nocturia in elderly women: a randomized, placebo-controlled, double-blind crossover trial. PLoS One, 11, e0151726
  36. Hotta, H., Watanabe, N. (2015) Gentle mechanical skin stimulation inhibits micturition contractions via the spinal opioidergic system and by decreasing both ascending and descending transmissions of the micturition reflex in the spinal cord. PLoS One, 10, e0135185.
  37. Uchida, S., Kagitani, F., Hotta, H. (2015) Afferent fibers involved in the bradykinin-induced cardiovascular reflexes from the ovary in rats. Auton. Neurosci., 193, 57-62
  38. Watanabe, N., Piché, M., Hotta, H. (2015) Types of skin afferent fibers and spinal opioid receptors that contribute to touch-induced inhibition of heart rate changes evoked by noxious cutaneous heat stimulation. Mol. Pain, 11, 4
  39. Uchida, S., Kagitani, F. (2014) Effect of acupuncture-like stimulation on cortical cerebral blood flow in aged rats. J Physiol Sci, 65, 67-75
  40. Piché, M., Watanabe, N., Sakata, M., Oda, K., Toyohara, J., Ishii, K., Ishiwata, K., Hotta, H. (2014) Basal μ-opioid receptor availability in the amygdala predicts the inhibition of pain-related brain activity during heterotopic noxious counter-stimulation. Neurosci. Res., 81-82, 78-84
  41. Hotta, H., Watanabe, N., Piché, M., Hara, S., Yokawa, T., Uchida, S. (2014) Non-noxious skin stimulation activates the nucleus basalis of Meynert and promotes NGF secretion in the parietal cortex via nicotinic ACh receptors. J. Physiol. Sci., 64, 253-260
  42. Uchida, S., Kagitani, F. (2014) Effects of electrical stimulation of autonomic nerves to the ovary on the ovarian testosterone secretion rate in rats. Auton. Neurosci., 180, 48-52
  43. Piché, M., Watanabe, N., Hotta, H. (2014) Regulation of gastric motility and blood flow during acute nociceptive stimulation of the paraspinal muscles in urethane-anaesthetised rats. J. Physiol. Sci., 64, 37-46
  44. Iimura, K., Miyazaki, S., Watanabe, N., Hotta, H. (2014) The influence of different tactile stimulation for perineal area on micturition contraction in anesthetized rats. Auton. Nerv. Syst. 51,168-173, Japanese
  45. Hotta, H., Masamoto, K., Uchida, S., Sekiguchi, Y., Takuwa, H., Kawaguchi, H., Shigemoto, K., Sudo, R., Tanishita, K., Ito, H., Kanno, I. (2013) Layer-specific dilation of penetrating arteries induced by stimulation of the nucleus basalis of Meynert in the mouse frontal cortex. J Cereb Blood Flow Metab., 33, 1440-1447
  46. Watanabe, N., Ishii, K., Hotta, H., Oda, K., Sakata, M., Toyohara, J., Ishiwata, K. (2013) Differential human brain activity induced by two perceptually indistinguishable gentle cutaneous stimuli. Neuroreport, 24, 425-430
  47. Uchida, S., Hotta, H., Misawa, H., Kawashima, K. (2013) The missing link between long-term stimulation of nicotinic receptors and the increases of acetylcholine release and vasodilation in the cerebral cortex of aged rats. J Physiol Sci., 63, 95-101
  48. Uchida, S., Kagitani, F., Hotta, H. (2012) Reflex modulation of ovarian estradiol secretion by noxious mechanical stimulation of a hindpaw in anesthetized rats. Auton. Neurosci., 171, 14-20
  49. Naggar, I., Uchida, S., Kamran, H., Lazar, J., Stewart, M. (2012) Autonomic boundary conditions for ventricular fibrillation and their implications for a novel defibrillation technique. J Physiol Sci., 62, 479-492
  50. Watanabe, N., Miyazaki, S., Mukaino, Y., Hotta, H. (2012) Effect of gentle cutaneous stimulation on heat-induced autonomic response and subjective pain intensity in healthy humans. J Physiol Sci., 62, 343-350
  51. Hotta, H., Masunaga, K., Miyazaki, S., Watanabe, N., Kasuya, Y. (2012) A gentle mechanical skin stimulation technique for inhibition of micturition contractions of the urinary bladder. Auton. Neurosci., 167, 12-20.
  52. Hanada, T., Uchida, S., Hotta, H., Aikawa, Y. (2011) Number, size, conduction, and vasoconstrictor ability of unmyelinated fibers of the ovarian nerve in adult and aged rats. Auton. Neurosci., 164, 6-12.
  53. Watanabe, N., Uchida, S., Hotta, H. (2011) Age-related change in the effect of gentle mechanical cutaneous stimulation on the somato-cardiac sympathetic C-reflex. J. Physiol. Sci., 61, 287-91.
  54. Hotta, H., Uchida, S., Kagitani, F., Maruyama, N. (2011) Control of cerebral cortical blood flow by stimulation of basal forebrain cholinergic areas in mice. J. Physiol. Sci., 61, 201-209
  55. Kagitani, F., Uchida, S., Hotta, H. (2011) The role of alpha adrenoceptors in the vascular and estradiol secretory responses to stimulation of the superior ovarian nerve. J. Physiol. Sci., 61, 247-251
  56. Uchida, S., Hotta, H., Misawa, H., Kawashima, K. (2011) Sustained subcutaneous infusion of nicotine enhances cholinergic vasodilation in the cerebral cortex induced by stimulation of the nucleus basalis of Meynert in rats. Eur. J. Pharmacol., 654,235-240
  57. Gotoh, M., Hotta, H., Murakami-Murofushi, K. (2010) Effects of cyclic phosphatidic acid on delayed neuronal death following transient ischemia in rat hippocampal CA1. Eur. J. Pharmacol., 649, 206-209
  58. Piché, M., Uchida, S., Hara, S., Aikawa, Y., Hotta, H. (2010) Modulation of somatosensory-evoked cortical blood flow changes by GABAergic inhibition of the nucleus basalis of Meynert in urethane-anesthetized rats. J. Physiol., 588 (Pt 12), 2163-2171.
  59. Hotta, H., Watanabe, N., Orman, R., Stewart, M. (2010) Efferent and afferent vagal actions on cortical blood flood flow and kainic acid-induced seizure activity in urethanized rats. Auton. Neurosci., 156, 144-148.
  60. Fischer, M.J., Uchida, S., Messlinger, K. (2010) Measurement of meningeal blood vessel diameter in vivo with a plug-in for ImageJ. Microvasc. Res., 80,258-266
  61. Hotta, H., Schmidt, R.F., Uchida, S., Watanabe, N. (2010) Gentle mechanical skin stimulation inhibits the somatocardiac sympathetic C-reflex elicited by excitation of unmyelinated C-afferent fibers. Europ. J. Pain, 14, 806-813.
  62. Uchida, S., Kagitani, F., Watanabe, N., Hotta, H. (2010) Sympatho-inhibitory response of the heart as a result of short-term acupuncture-like stimulation of the rat hindlimb is not augmented when sympathetic tone is high due to hypercapnia. J. Physiol. Sci., 60: 221-225.
  63. Hotta, H., Lazar, J., Orman, R., Koizumi, K., Shiba, K., Kamran, H., Stewart, M. (2009) Vagus nerve stimulation-induced bradyarrhythmias in rats. Auton. Neurosci., 151: 98-105.
  64. Uchida, S., Hotta, H., Kawashima, K. (2009) Long-term nicotine treatment reduces cerebral cortical vasodilation mediated by α4β2-like nicotinic acetylcholine receptors in rats. Eur. J. Pharmacol., 609, 100-104.
  65. Shiba, K., Machida, T., Uchida, S., Hotta, H. (2009) Sympathetic neural regulation of olfactory bulb blood flow in adult and aged rats. Auton. Neurosci., 147, 75-79.
  66. Hotta, H., Koizumi, K., Stewart, M. (2009) Cardiac sympathetic nerve activity during kainic acid-induced limbic cortical seizures in rats. Epilepsia, 50, 923-927.
  67. Hotta, H., Kagitani, F., Kondo, M., Uchida, S. (2009) Basal forebrain stimulation induces NGF secretion in ipsilateral parietal cortex via nicotinic receptor activation in adult, but not aged rats. Neurosci. Res., 63, 122-128.
  68. Uchida, S., Kagitani, F., Hotta, H. (2008) Mechanism of the reflex inhibition of heart rate elicited by acupuncture-like stimulation in anesthetized rats. Auton. Neurosci., 143, 12-19.
  69. Kagitani, F., Uchida, S., Hotta, H. (2008) Effects of electrical stimulation of the superior ovarian nerve and the ovarian plexus nerve on the ovarian estradiol secretion rate in rats. J. Physiol. Sci., 58, 133-138.
  70. Uchida, S., Shimura, M., Ohsawa, H., Suzuki, A. (2007) Neural mechanism of bradycardiac responses elicited by acupuncture-like stimulation to a hind limb in anesthetized rats. J. Physiol. Sci., 57, 377-382.
  71. Hotta, H., Uchida, S., Kagitani, F. (2007) Stimulation of the nucleus basalis of Meynert produces an increase in the extracellular release of nerve growth factor in the rat cerebral cortex. J. Physiol. Sci., 57, 383-387.
  72. Uchida, S., Hotta, H., Hanada, T., Okuno, Y., Aikawa, Y. (2007) Effects of thermal stimulation, applied to the hindpaw via a hot water bath, upon ovarian blood flow in anesthetized nonpregnant rats. J. Physiol. Sci., 57, 227-233.
  73. Hotta, H., Uchida, S., Shiba, K. (2007) Cerebral cortical blood flow response during basal forebrain stimulation in cats. NeuroReport, 18, 809-812.