Autonomic Neuroscience

Members

Theme Leader :
Sae Uchida, Ph.D.
Researcher :
Nobuhiro Watanabe, Ph.D.

Keywords

autonomic nervous system, hormone, somatosensory stimulation, aging, basal forebrain cholinergic system, acetylcholine, blood flow, nerve growth factor, olfaction

Major Research Titles

  1. Autonomic nervous system function in the elderly
  2. Cholinergic neurons and cognitive function

Profile

We perform research activity using electrophysiological and imaging techniques mainly on anesthetized animals (and humans in some cases).
Our goal is to characterize autonomic function in the elderly, and to identify strategies to regulate autonomic nervous system activity. We have studied neural mechanisms for somatosensory stimulation to influence autonomic functions. Recently we showed: (1) a method of subtle skin stimulation that suppresses micturition reflex via activating the endogenous opioid system, may be applicable to improve incontinence; (2) a novel role of ovarian sympathetic nerve is ovarian estradiol secretion regulation and the nerve activity is facilitated by noxious skin stimulation, causing estradiol secretion decrease.
Cognitive decline in patients with dementia and the elderly is related to the dysfunction of cholinergic basal forebrain neurons. Another goal is to define the roles of cholinergic system in the regulation of cortical arteries and nerve growth factor (NGF) secretion. We showed: (1) tactile stimulation activates the cholinergic system, thereby facilitates cerebral blood flow and NGF secretion; (2) chronic nicotine infusion enhances responses of cortical ACh release and vasodilation during basal forebrain stimulation in adult, but not aged, rats, suggesting that a reduction of nicotinic receptors may relate to dysfunction of the cholinergic system during aging.

References

  1. Watanabe N, Takeno K, Tomioka NH, Moriya M, Nishimune H, Hotta H. Activation of aortic baroreceptors depresses the somato-lumbar sympathetic reflex, reducing hindlimb muscle contractile force. The Journal of Physiological Sciences, doi:10.1016/j.jphyss.2025.100051
  2. Watanabe N, Moriya M, Hotta H. (2026) Intermittent mild skin cooling stimulation inhibits pineal melatonin secretion in urethane-anesthetized rats. Neuroscience Letters, 870: 138444. https://doi.org/10.1016/j.neulet.2025.138444
  3. Polus B, Stylianou S, Harman S, Kumar DK, Watanabe N. (2025) A pilot investigation of muscle conditioning as a tool to study neck proprioception and vestibular reweighting during head to trunk movement. Scientific Reports, 15: 27062. https://doi.org/10.1038/s41598-025-10126-7
  4. Uchida, S., Morihara, D., Sakurai, R., Kagitani, F., Suzuki, H. (2025) Cardiac autonomic function and olfactory discrimination ability in older adults. The Autonomic Nervous System, 62(2): 71-77. https://doi.org/10.32272/ans.62.2_71
  5. Morihara, D., Moriya, J., Kagitani, F., Uchida, S. (2025) Cerebral blood flow responses to trigeminal olfactory stimulation and their nicotinic cholinergic regulation in anesthetized rats. European Journal of Neruroscience, 61(9):e70135. doi: 10.1111/ejn.70135.
  6. Watanabe N, Iimura K, Hotta H. (2024) Ninjin'yoeito modulates baseline and reperfusion-induced changes in the arteriole diameter and blood flow in the cerebral cortex of anesthetized mice. Microcirculation, 31(7): e12880.
  7. Uchida S, Moriya J, Morihara D, Shimura M, Kagitani F. (2024) Cerebral cortical vasodilation via nicotinic receptors by heated tobacco product aerosol extract in rats. Journal of Vascular Research, 61: 318-326.
  8. Takeno K, Watanabe N, Morifuji M, Hotta H, Nishimune H. (2024) Identification of adrenergic presynaptic and postsynaptic protein locations at neuromuscular junctions, their decrease during aging, and recovery by nicotinamide mononucleotide administration. Neuroreport, 35(2): 805-812.
  9. Iketani M, Hatomi M, Fujita Y, Watanabe N, Ito M, Kawaguchi H, Ohsawa I. (2024) Inhalation of hydrogen gas mitigates sevoflurane‐induced neuronal apoptosis in the neonatal cortex and is associated with changes in protein phosphorylation. Journal of Neurochemistry, 168: 2775-2790.
  10. 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
  11. 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.
  12. 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.
  13. 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
  14. 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
  15. 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.
  16. 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
  17. 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.
  18. 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.
  19. 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
  20. 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.
  21. 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
  22. 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
  23. 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
  24. 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)
  25. 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
  26. 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
  27. Hotta, H., Watanabe, N. (2019) Gentle perineal skin stimulation for control of nocturia. Anatomical Record, In press
  28. Uchida, S., Kagitani, F. (2019) Neural mechanisms involved in the noxious physical stress-induced inhibition of ovarian estradiol secretion. Anatomical Record, In press
  29. 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
  30. 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
  31. 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
  32. 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
  33. 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
  34. 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
  35. 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
  36. 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
  37. 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
  38. 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
  39. Uchida, S., Kagitani, F. (2017) Mechanism of physical stress-induced inhibition of ovarian estradiol secretion in anesthetized rats. Auton. Neurosci., 206, 63-66
  40. 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
  41. 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
  42. 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
  43. Uchida, S., Kagitani, F. (2016) Sympathetic regulation of ovarian functions under chronic estradiol treatment in rats. Auton. Neurosci., 197, 19-24
  44. 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
  45. 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.
  46. 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
  47. 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
  48. Uchida, S., Kagitani, F. (2014) Effect of acupuncture-like stimulation on cortical cerebral blood flow in aged rats. J Physiol Sci, 65, 67-75
  49. 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
  50. 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
  51. 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
  52. 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
  53. 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
  54. 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
  55. 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
  56. 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
  57. 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
  58. 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
  59. 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
  60. 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.
  61. 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.
  62. 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.
  63. 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
  64. 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
  65. 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
  66. 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
  67. 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.
  68. 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.
  69. 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
  70. 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.
  71. 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.
  72. 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.
  73. 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.
  74. 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.
  75. Hotta, H., Koizumi, K., Stewart, M. (2009) Cardiac sympathetic nerve activity during kainic acid-induced limbic cortical seizures in rats. Epilepsia, 50, 923-927.
  76. 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.
  77. 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.
  78. 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.
  79. 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.
  80. 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.
  81. 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.
  82. Hotta, H., Uchida, S., Shiba, K. (2007) Cerebral cortical blood flow response during basal forebrain stimulation in cats. NeuroReport, 18, 809-812.