title: Cerebellar fastigial nuclear glutamatergic neurons regulate immune function via hypothalamic and sympathetic pathways.
abstract: We previously have shown that cerebellar fastigial nucleus (FN) modulates immune function, but pathways or mechanisms underlying this immunomodulation require clarification. Herein, an anterograde and retrograde tracing of nerve tracts between the cerebellar FN and hypothalamus/thalamus was performed in rats. After demonstrating a direct cerebellar FN-hypothalamic/thalamic glutamatergic projection, 6-diazo-5-oxo-L-norleucine (DON), an inhibitor of glutaminase that catalyzes glutamate synthesis, was injected bilaterally in the cerebellar FN and simultaneously, D,L-threo-β-hydroxyaspartic acid (THA), an inhibitor of glutamate transporters on cell membrane, was bilaterally injected in the lateral hypothalamic area (LHA) or the ventrolateral (VL) thalamic nucleus. DON treatment in the FN alone decreased number of glutamatergic neurons that projected axons to the LHA and also diminished glutamate content in both the hypothalamus and the thalamus. These effects of DON were reduced by combined treatment with THA in the LHA or in the VL. Importantly, DON treatment in the FN alone attenuated percentage and cytotoxicity of natural killer (NK) cells and also lowered percentage and cytokine production of T lymphocytes. These DON-caused immune effects were reduced or abolished by combined treatment with THA in the LHA, but not in the VL. Simultaneously, DON treatment elevated level of norepinephrine (NE) in the spleen and mesenteric lymphoid nodes, and THA treatment in the LHA, rather than in the VL, antagonized the DON-caused NE elevation. These findings suggest that glutamatergic neurons in the cerebellar FN regulate innate and adaptive immune functions and the immunomodulation is conveyed by FN-hypothalamic glutamatergic projections and sympathetic nerves that innervate lymphoid tissues.
authors: Department of Physiology, School of Medicine, and Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province, 226001, China.
authors: Bei-Bei
authors: BB
authors: Cao
authors: Yan
authors: Y
authors: Huang
authors: Yong-Ying
authors: YY
authors: Jiang
authors: Yi-Hua
authors: YH
authors: Qiu
authors: Yu-Ping
authors: YP
authors: Peng
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001369:Axons / Q000187:drug effects; D002529:Cerebellar Nuclei / Q000166:cytology* / Q000276:immunology*; D003980:Diazooxonorleucine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D005972:Glutaminase / Q000037:antagonists & inhibitors; D007026:Hypothalamic Area, Lateral / Q000276:immunology / Q000502:physiology; D007031:Hypothalamus / Q000276:immunology* / Q000502:physiology*; D007109:Immunity / Q000502:physiology*; D007267:Injections; D007694:Killer Cells, Natural / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000276:immunology* / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects; D013788:Thalamus / Q000276:immunology / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D003980:Diazooxonorleucine; C011274:3-hydroxyaspartic acid; D001224:Aspartic Acid; D018698:Glutamic Acid; D005972:Glutaminase
references: Brain Behav Immun. 2014 May;38:263-71
references: 24583232
references: Brain Res Rev. 2006 Aug 30;52(1):93-106
references: 16497381
references: Prog Brain Res. 2000;124:141-72
references: 10943123
references: Physiol Behav. 2011 Aug 3;104(2):257-65
references: 21402087
references: Neurosci Lett. 1998 Nov 27;257(2):89-92
references: 9865934
references: Cerebellum. 2003;2(4):263-9
references: 14964685
references: Annu Rev Immunol. 2002;20:125-63
references: 11861600
references: J Physiol. 1993 Nov;471:209-21
references: 8120804
references: Brain Behav Immun. 2013 Jan;27(1):80-90
references: 23046722
references: Cytokine. 2001 Dec 21;16(6):205-9
references: 11884023
references: Brain Behav Immun. 2007 Aug;21(6):736-45
references: 17467231
references: J Neuroimmunol. 2009 Aug 18;213(1-2):100-11
references: 19559489
references: Neuroimmunomodulation. 2007;14(6):344-53
references: 18463421
references: Brain Behav Immun. 2007 Aug;21(6):727-35
references: 17604598
references: J Leukoc Biol. 2006 Jun;79(6):1093-104
references: 16531560
references: Cell Immunol. 2008 Mar-Apr;252(1-2):27-56
references: 18308299
references: J Immunol. 1997 Nov 15;159(10):4857-67
references: 9366411
references: Neuroimmunomodulation. 2015;22(3):138-51
references: 24800755
references: J Comp Neurol. 1981 Apr 1;197(2):217-36
references: 7276233
references: J Neuroimmunol. 2001 Nov 1;120(1-2):50-7
references: 11694319
references: Histol Histopathol. 1994 Jul;9(3):603-14
references: 7981506
references: Neuro Endocrinol Lett. 2010;31(5):635-44
references: 21173746
references: Mol Psychiatry. 2005 Mar;10(3):239-50
references: 15685252
references: Alcohol Clin Exp Res. 2013 Nov;37(11):1901-9
references: 23889735
references: Immunol Rev. 2012 Jul;248(1):36-55
references: 22725953
references: J Comp Neurol. 1990 Sep 1;299(1):106-22
references: 1698835
references: J Neuroimmunol. 2014 Jul 15;272(1-2):16-28
references: 24837703
references: Front Integr Neurosci. 2013 Aug 13;7:56
references: 23964208
references: J Immunol. 2001 Jan 1;166(1):232-40
references: 11123297
references: J Anat. 2001 Jan;198(Pt 1):37-45
references: 11215766
references: Neuro Endocrinol Lett. 2012;33(4):393-400
references: 22936265
references: Int J Neurosci. 2003 Feb;113(2):259-77
references: 12751435
references: Nat Rev Immunol. 2011 Dec 09;12(1):24-34
references: 22158414
references: Vitam Horm. 2013;93:263-76
references: 23810011
references: Brain Res Bull. 2006 Dec 11;71(1-3):10-7
references: 17113922
references: Haematol Rep. 2006 Sep;2(10):9-13
references: 20890454
references: Physiol Res. 2011;60 Suppl 1:S71-82
references: 21777027
references: Brain Behav Immun. 2012 Feb;26(2):195-200
references: 21855626
references: Brain Behav Immun. 1995 Mar;9(1):47-60
references: 7620210
references: J Immunol. 1997 May 1;158(9):4200-10
references: 9126981
references: J Comp Neurol. 2008 May 10;508(2):286-314
references: 18322920
references: Amino Acids. 2013 Jul;45(1):55-71
references: 22160285
references: Annu Rev Neurosci. 2009;32:413-34
references: 19555291
references: Cerebellum. 2011 Sep;10 (3):495-503
references: 21132574
references: Arthritis Res Ther. 2006;8(5):R138
references: 16889669
references: J Neuroimmunol. 2006 Mar;172(1-2):38-58
references: 16375977
references: Brain Res Bull. 1992 Jun;28(6):897-907
references: 1638416
references: Eur J Neurosci. 2011 Jan;33(1):95-109
references: 21073550
references: Cerebellum. 2012 Dec;11(4):905-16
references: 22302669
references: J Immunol. 2003 Mar 15;170(6):3024-8
references: 12626556
references: J Nutr. 2001 Sep;131(9 Suppl):2498S-504S; discussion 2523S-4S
references: 11533301
references: Neurosci Res. 2005 Mar;51(3):275-84
references: 15710491
references: J Neuroimmunol. 2013 Apr 15;257(1-2):1-6
references: 23411096
references: Int Rev Neurobiol. 1997;41:83-107
references: 9378614