title: The rate of fall of blood glucose determines the necessity of forebrain-projecting catecholaminergic neurons for male rat sympathoadrenal responses.
abstract: Different onset rates of insulin-induced hypoglycemia use distinct glucosensors to activate sympathoadrenal counterregulatory responses (CRRs). Glucosensory elements in the portal-mesenteric veins are dispensable with faster rates when brain elements predominate, but are essential for responses to the slower-onset hypoglycemia that is common with insulin therapy. Whether a similar rate-associated divergence exists within more expansive brain networks is unknown. Hindbrain catecholamine neurons distribute glycemia-related information throughout the forebrain. We tested in male rats whether catecholaminergic neurons that project to the medial and ventromedial hypothalamus are required for sympathoadrenal CRRs to rapid- and slow-onset hypoglycemia and whether these neurons are differentially engaged as onset rates change. Using a catecholamine-specific neurotoxin and hyperinsulinemic-hypoglycemic clamps, we found that sympathoadrenal CRRs to slow- but not rapid-onset hypoglycemia require hypothalamus-projecting catecholaminergic neurons, the majority of which originate in the ventrolateral medulla. As determined with Fos, these neurons are differentially activated by the two onset rates. We conclude that 1) catecholaminergic projections to the hypothalamus provide essential information for activating sympathoadrenal CRRs to slow- but not rapid-onset hypoglycemia, 2) hypoglycemia onset rates have a major impact on the hypothalamic mechanisms that enable sympathoadrenal CRRs, and 3) hypoglycemia-related sensory information activates hindbrain catecholaminergic neurons in a rate-dependent manner.
authors.affiliation: Center for NeuroMetabolic Interactions, The Integrated and Evolutionary Biology Graduate Program, and The Department of Biological Sciences, USC Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Jokiaho
authors.affiliation: Center for NeuroMetabolic Interactions, The Integrated and Evolutionary Biology Graduate Program, and The Department of Biological Sciences, USC Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA.
authors.forename: Casey M
authors.initials: CM
authors.lastname: Donovan
authors.affiliation: Center for NeuroMetabolic Interactions, The Integrated and Evolutionary Biology Graduate Program, and The Department of Biological Sciences, USC Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA watts@usc.edu.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Watts
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001786:Blood Glucose / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D059329:Cholinergic Neurons; D004299:Dopamine beta-Hydroxylase / Q000276:immunology; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D015309:Glucose Clamp Technique; D007003:Hypoglycemia; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D016761:Oncogene Proteins v-fos; D016548:Prosencephalon / Q000166:cytology*; D051381:Rats; D017208:Rats, Wistar; D054789:Ribosome Inactivating Proteins, Type 1 / Q000378:metabolism; D000076985:Saporins; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D000906:Antibodies; D001786:Blood Glucose; D002395:Catecholamines; D007074:Immunoglobulin G; D016761:Oncogene Proteins v-fos; D054789:Ribosome Inactivating Proteins, Type 1; D004299:Dopamine beta-Hydroxylase; D000076985:Saporins; D005947:Glucose
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 Dec;301(6):R1815-20
references.pmid: 21957162
references.citation: Endocr Rev. 2001 Aug;22(4):502-48
references.pmid: 11493581
references.citation: J Comp Neurol. 1975 Oct 15;163(4):467-505
references.pmid: 1100685
references.citation: Diabetes. 2005 Nov;54(11):3258-64
references.pmid: 16249453
references.citation: Diabetes. 2011 May;60(5):1582-9
references.pmid: 21411513
references.citation: Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E96-E101
references.pmid: 17374696
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Oct;289(4):R977-81
references.pmid: 16183631
references.citation: Endocrinol Metab Clin North Am. 2010 Sep;39(3):641-54
references.pmid: 20723825
references.citation: Diabetes. 2007 Apr;56(4):1120-6
references.pmid: 17251273
references.citation: Brain Res Bull. 1988 Dec;21(6):905-12
references.pmid: 3224284
references.citation: Physiol Behav. 2006 Apr 15;87(4):700-6
references.pmid: 16492385
references.citation: J Comp Neurol. 2007 Jun 10;502(5):768-82
references.pmid: 17436292
references.citation: J Clin Invest. 1997 Jan 15;99(2):361-5
references.pmid: 9006005
references.citation: Diabetes. 1997 Sep;46(9):1521-5
references.pmid: 9287058
references.citation: J Comp Neurol. 2002 Jul 1;448(3):217-29
references.pmid: 12115705
references.citation: Diabetes. 2008 May;57(5):1380-6
references.pmid: 18292347
references.citation: Ann Intern Med. 1994 Mar 15;120(6):512-7
references.pmid: 8311375
references.citation: Am J Physiol Endocrinol Metab. 2010 May;298(5):E971-7
references.pmid: 20304763
references.citation: Neurosci Lett. 1984 May 4;46(2):215-8
references.pmid: 6738915
references.citation: J Neuroendocrinol. 2012 Dec;24(12):1517-26
references.pmid: 22831701
references.citation: Brain Res. 1998 Sep 14;805(1-2):41-54
references.pmid: 9733914
references.citation: Diabetes. 2004 May;53(5):1230-6
references.pmid: 15111491
references.citation: J Neurosci. 2006 Nov 1;26(44):11442-53
references.pmid: 17079674
references.citation: Physiol Behav. 2006 Nov 30;89(4):501-10
references.pmid: 16828817
references.citation: J Neurosci. 2011 Dec 14;31(50):18479-91
references.pmid: 22171049
references.citation: Pancreas. 2005 Aug;31(2):142-7
references.pmid: 16025001
references.citation: Front Neuroendocrinol. 2010 Jan;31(1):32-43
references.pmid: 19836412
references.citation: Am J Physiol. 1984 Aug;247(2 Pt 1):E206-14
references.pmid: 6380307
references.citation: J Neurosci. 2007 Jul 4;27(27):7344-60
references.pmid: 17611287
references.citation: Diabetes. 2004 Oct;53(10):2521-8
references.pmid: 15448079
references.citation: Diabetes. 2011 Dec;60(12):3154-8
references.pmid: 22013013
references.citation: Diabetes. 2014 Aug;63(8):2866-75
references.pmid: 24727435
references.citation: Endocrinology. 2011 Nov;152(11):4019-32
references.pmid: 21878511
references.citation: Diabetes. 2004 Mar;53(3):549-59
references.pmid: 14988237
references.citation: Diabetes. 2003 Nov;52(11):2767-73
references.pmid: 14578295
references.citation: Endocrinology. 2011 Jul;152(7):2552-7
references.pmid: 21521751
references.citation: Life Sci. 1977 Sep 1;21(5):625-36
references.pmid: 904439
references.citation: Brain Res. 1987 Dec 15;465(1-2):257-66
references.pmid: 3440206
references.citation: Diabetes Technol Ther. 2005 Dec;7(6):849-62
references.pmid: 16386091
references.citation: Diabetes Nutr Metab. 2002 Oct;15(5):308-12; discussion 313-4
references.pmid: 12625475
references.citation: J Comp Neurol. 2010 May 1;518(9):1460-99
references.pmid: 20187136
references.citation: Endocrinology. 2003 Apr;144(4):1357-67
references.pmid: 12639919
references.citation: J Comp Neurol. 2001 Apr 2;432(2):197-216
references.pmid: 11241386
references.citation: Eur J Neurosci. 2011 Jul;34(2):272-82
references.pmid: 21692881
references.citation: Am J Physiol Regul Integr Comp Physiol. 2001 Feb;280(2):R563-9
references.pmid: 11208588
references.citation: J Neurosci. 1994 Aug;14(8):4825-30
references.pmid: 8046453
references.citation: Neurosci Biobehav Rev. 1986 Fall;10(3):295-315
references.pmid: 3095717