{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T09:03:18Z","timestamp":1784797398457,"version":"3.55.0"},"reference-count":42,"publisher":"The Endocrine Society","issue":"8","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000041","name":"American Diabetes Association","doi-asserted-by":"publisher","award":["118IBS156"],"award-info":[{"award-number":["118IBS156"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DK114187"],"award-info":[{"award-number":["DK114187"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In diabetic patients, hypoglycemia-associated autonomic failure (HAAF) is a potentially lethal condition that results in attenuation of critical protective responses to low blood glucose, following repeated prior hypoglycemic episodes. The underlying mechanism(s) of HAAF is not fully understood. We previously demonstrated that activation of catecholamine (CA) neurons in the ventrolateral medulla (VLM) is both required and sufficient to elicit key protective responses to glucose deficit. Here we test the hypothesis that repeated selective activation of VLM CA neurons is sufficient to induce HAAF, even in the absence of glucose deficit. Using stereotaxic injections of an adeno-associated virus in female TH-Cre transgenic rats, we transfected rostral C1 CA neurons to express hM3D(Gq). In these rats, we found that a single clozapine-N-oxide (CNO) injection evoked robust hyperglycemia, with a magnitude and time course similar to those evoked by the glucoprivic agent, 2-deoxy-D-glucose (2DG). However, following repeated CNO injections in these same rats, the hyperglycemic response evoked by either CNO or 2DG were significantly attenuated. Moreover, plasma epinephrine levels, and Fos expression in VLM CA neurons and in the adrenal medulla, also were attenuated following repeated CNO injections. This constellation of effects is similar to those that define HAAF. Taken together our results suggest that repeated stimulation of VLM CA neurons mimics and could be a cause of the impairment of counterregulatory responses associated with pathogenesis of HAAF.<\/jats:p>","DOI":"10.1210\/endocr\/bqag074","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T11:52:22Z","timestamp":1782388342000},"source":"Crossref","is-referenced-by-count":0,"title":["Repeated chemogenetic activation of C1 catecholamine neurons reduces subsequent glucoprivic responses and mimics HAAF"],"prefix":"10.1210","volume":"167","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3585-886X","authenticated-orcid":false,"given":"Ai-Jun","family":"Li","sequence":"first","affiliation":[{"name":"Programs in Neuroscience, Washington State University , Pullman, WA 99164-7620 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Wang","sequence":"additional","affiliation":[{"name":"Programs in Neuroscience, Washington State University , Pullman, WA 99164-7620 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert C","family":"Ritter","sequence":"additional","affiliation":[{"name":"Programs in Neuroscience, Washington State University , Pullman, WA 99164-7620 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne M","family":"Appleyard","sequence":"additional","affiliation":[{"name":"Programs in Neuroscience, Washington State University , Pullman, WA 99164-7620 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"2026072304311428000_bqag074-B1","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/S1054-3589(08)60827-3","article-title":"Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus","volume":"42","author":"Cryer","year":"1998","journal-title":"Adv Pharmacol"},{"issue":"4","key":"2026072304311428000_bqag074-B2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1210\/TEAM.9781936704200.ch2","article-title":"2. Hypoglycemia detection","volume":"3","author":"Routh","year":"2012","journal-title":"Transl Endocrinol Metab"},{"key":"2026072304311428000_bqag074-B3","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1201\/9781315120171-9","volume-title":"Appetite and Food Intake: Central Control","author":"Ritter","year":"2017"},{"issue":"3","key":"2026072304311428000_bqag074-B4","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1210\/er.2018-00226","article-title":"Central mechanisms of glucose sensing and counterregulation in defense of hypoglycemia","volume":"40","author":"Stanley","year":"2019","journal-title":"Endocr Rev"},{"issue":"3","key":"2026072304311428000_bqag074-B5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.2337\/diab.41.3.255","article-title":"Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious cycle","volume":"41","author":"Cryer","year":"1992","journal-title":"Diabetes"},{"issue":"8","key":"2026072304311428000_bqag074-B6","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.2337\/diab.46.8.1328","article-title":"Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans","volume":"46","author":"Davis","year":"1997","journal-title":"Diabetes"},{"issue":"4397","key":"2026072304311428000_bqag074-B7","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1126\/science.451558","article-title":"The forebrain is not essential for sympathoadrenal hyperglycemic response to glucoprivation","volume":"204","author":"DiRocco","year":"1979","journal-title":"Science"},{"issue":"4606","key":"2026072304311428000_bqag074-B8","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1126\/science.6344221","article-title":"Insulin elicits ingestion in decerebrate rats","volume":"221","author":"Flynn","year":"1983","journal-title":"Science"},{"issue":"4506","key":"2026072304311428000_bqag074-B9","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1126\/science.6264602","article-title":"Glucoreceptors controlling feeding and blood glucose: location in the hindbrain","volume":"213","author":"Ritter","year":"1981","journal-title":"Science"},{"issue":"1-2","key":"2026072304311428000_bqag074-B10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0006-8993(99)02327-6","article-title":"Localization of hindbrain glucoreceptive sites controlling food intake and blood glucose","volume":"856","author":"Ritter","year":"2000","journal-title":"Brain Res"},{"issue":"2","key":"2026072304311428000_bqag074-B11","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/cne.1097","article-title":"Immunotoxic destruction of distinct catecholamine subgroups produces selective impairment of glucoregulatory responses and neuronal activation","volume":"432","author":"Ritter","year":"2001","journal-title":"J Comp Neurol"},{"issue":"4","key":"2026072304311428000_bqag074-B12","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1210\/en.2002-221076","article-title":"Immunotoxin lesion of hypothalamically projecting norepinephrine and epinephrine neurons differentially affects circadian and stressor-stimulated corticosterone secretion","volume":"144","author":"Ritter","year":"2003","journal-title":"Endocrinology"},{"issue":"3","key":"2026072304311428000_bqag074-B13","doi-asserted-by":"crossref","first-page":"R751","DOI":"10.1152\/ajpregu.00800.2005","article-title":"Attenuation of homeostatic responses to hypotension and glucoprivation after destruction of catecholaminergic rostral ventrolateral medulla neurons","volume":"291","author":"Madden","year":"2006","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"3","key":"2026072304311428000_bqag074-B14","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/0165-0173(82)90010-8","article-title":"The organization of noradrenergic pathways from the brainstem to the paraventricular and supraoptic nuclei in the rat","volume":"257","author":"Sawchenko","year":"1982","journal-title":"Brain Res"},{"issue":"1","key":"2026072304311428000_bqag074-B15","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/0006-8993(83)91196-4","article-title":"Noradrenergic projections to the spinal cord of the rat","volume":"263","author":"Westlund","year":"1983","journal-title":"Brain Res"},{"issue":"4","key":"2026072304311428000_bqag074-B16","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/cne.902590408","article-title":"Organization of central adrenergic pathways: I. Relationships of ventrolateral medullary projections to the hypothalamus and spinal cord","volume":"259","author":"Tucker","year":"1987","journal-title":"J Comp Neurol"},{"issue":"5","key":"2026072304311428000_bqag074-B17","doi-asserted-by":"crossref","first-page":"bqae021","DOI":"10.1210\/endocr\/bqae021","article-title":"Lesion of NPY receptor-expressing neurons in perifornical lateral hypothalamus attenuates glucoprivic feeding","volume":"165","author":"Choi","year":"2024","journal-title":"Endocrinology"},{"issue":"5","key":"2026072304311428000_bqag074-B18","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.neuron.2011.10.028","article-title":"Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement","volume":"72","author":"Witten","year":"2011","journal-title":"Neuron"},{"issue":"1","key":"2026072304311428000_bqag074-B19","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1210\/en.2017-00630","article-title":"Selective pharmacogenetic activation of catecholamine subgroups in the ventrolateral medulla elicits key glucoregulatory responses","volume":"159","author":"Li","year":"2018","journal-title":"Endocrinology"},{"key":"2026072304311428000_bqag074-B20","volume-title":"The Rat Brain in Stereotaxic Coordinates","author":"Paxinos","year":"2007"},{"issue":"12","key":"2026072304311428000_bqag074-B21","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.2337\/db20-0402","article-title":"Repeated pharmacogenetic catecholamine neuron activation in the ventrolateral medulla attenuates subsequent glucoregulatory responses","volume":"69","author":"Li","year":"2020","journal-title":"Diabetes"},{"issue":"8","key":"2026072304311428000_bqag074-B22","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1210\/en.2015-1138","article-title":"Hindbrain catecholamine neurons activate orexin neurons during systemic glucoprivation in male rats","volume":"156","author":"Li","year":"2015","journal-title":"Endocrinology"},{"issue":"1-2","key":"2026072304311428000_bqag074-B23","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0006-8993(98)00655-6","article-title":"Subgroups of hindbrain catecholamine neurons are selectively activated by 2-deoxy-D-glucose induced metabolic challenge","volume":"805","author":"Ritter","year":"1998","journal-title":"Brain Res"},{"issue":"5","key":"2026072304311428000_bqag074-B24","doi-asserted-by":"crossref","first-page":"E802","DOI":"10.1152\/ajpendo.00466.2010","article-title":"Rostroventrolateral medullary neurons modulate glucose homeostasis in the rat","volume":"299","author":"Verberne","year":"2010","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"11","key":"2026072304311428000_bqag074-B25","doi-asserted-by":"crossref","first-page":"4019","DOI":"10.1210\/en.2010-1458","article-title":"Minireview: the value of looking backward: the essential role of the hindbrain in counterregulatory responses to glucose deficit","volume":"152","author":"Ritter","year":"2011","journal-title":"Endocrinology"},{"issue":"2","key":"2026072304311428000_bqag074-B26","doi-asserted-by":"crossref","first-page":"602","DOI":"10.2337\/db10-1374","article-title":"Adrenergic mediation of hypoglycemia-associated autonomic failure","volume":"60","author":"Ramanathan","year":"2011","journal-title":"Diabetes"},{"issue":"11","key":"2026072304311428000_bqag074-B27","doi-asserted-by":"crossref","first-page":"3416","DOI":"10.1210\/clinem\/dgaa539","article-title":"Plasma epinephrine contributes to the development of experimental hypoglycemia-associated autonomic failure","volume":"105","author":"Lontchi-Yimagou","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"2026072304311428000_bqag074-B28","doi-asserted-by":"crossref","first-page":"R1792","DOI":"10.1152\/ajpregu.00777.2006","article-title":"Localized glucoprivation of hindbrain sites elicits corticosterone and glucagon secretion","volume":"292","author":"Andrew","year":"2007","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"2","key":"2026072304311428000_bqag074-B29","doi-asserted-by":"crossref","first-page":"223","DOI":"10.2337\/diab.40.2.223","article-title":"Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans","volume":"40","author":"Heller","year":"1991","journal-title":"Diabetes"},{"issue":"5","key":"2026072304311428000_bqag074-B30","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1210\/jc.2003-031289","article-title":"Plasma metanephrine levels are decreased in type 1 diabetic patients with a severely impaired epinephrine response to hypoglycemia, indicating reduced adrenomedullary stores of epinephrine","volume":"89","author":"De Galan","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"2026072304311428000_bqag074-B31","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.2337\/diabetes.53.10.2542","article-title":"Hypothalamic ATP-sensitive K+ channels play a key role in sensing hypoglycemia and triggering counterregulatory epinephrine and glucagon responses","volume":"53","author":"Evans","year":"2004","journal-title":"Diabetes"},{"issue":"5","key":"2026072304311428000_bqag074-B32","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/0031-9384(93)90279-O","article-title":"Sympathoadrenal responses to glucoprivation and lipoprivation in rats","volume":"53","author":"Scheurink","year":"1993","journal-title":"Physiol Behav"},{"issue":"3","key":"2026072304311428000_bqag074-B33","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1172\/JCI118839","article-title":"Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans","volume":"98","author":"Davis","year":"1996","journal-title":"J Clin Invest"},{"issue":"9","key":"2026072304311428000_bqag074-B34","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.2337\/diabetes.52.9.2198","article-title":"Cortisol acts through central mechanisms to blunt counterregulatory responses to hypoglycemia in conscious rats","volume":"52","author":"Sandoval","year":"2003","journal-title":"Diabetes"},{"issue":"2","key":"2026072304311428000_bqag074-B35","doi-asserted-by":"crossref","first-page":"R413","DOI":"10.1152\/ajpregu.00674.2003","article-title":"Brain region- dependent effects of dexamethasone on counterregulatory responses to hypoglycemia in conscious rats","volume":"288","author":"Sandoval","year":"2005","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"5","key":"2026072304311428000_bqag074-B36","doi-asserted-by":"crossref","first-page":"R1426","DOI":"10.1152\/ajpregu.2001.281.5.R1426","article-title":"PVN activation is suppressed by repeated hypoglycemia but not antecedent corticosterone in the rat","volume":"281","author":"Evans","year":"2001","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"3","key":"2026072304311428000_bqag074-B37","doi-asserted-by":"crossref","first-page":"E455","DOI":"10.1152\/ajpendo.2001.281.3.E455","article-title":"Effects of antecedent hypoglycemia, hyperinsulinemia, and excess corticosterone on hypoglycemic counterregulation","volume":"281","author":"Shum","year":"2001","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"8","key":"2026072304311428000_bqag074-B38","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.2337\/diabetes.52.8.2083","article-title":"Cortisol elevations comparable to those that occur during hypoglycemia do not cause hypoglycemia-associated autonomic failure","volume":"52","author":"Raju","year":"2003","journal-title":"Diabetes"},{"issue":"7","key":"2026072304311428000_bqag074-B39","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1523\/JNEUROSCI.1046-12.2013","article-title":"Selective optogenetic activation of rostral ventrolateral medullary catecholaminergic neurons produces cardiorespiratory stimulation in conscious mice","volume":"33","author":"Abbott","year":"2013","journal-title":"J Neurosci"},{"issue":"5","key":"2026072304311428000_bqag074-B40","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1002\/cne.21140","article-title":"Efferent projections of rat rostroventrolateral medulla C1 catecholamine neurons: implications for the central control of cardiovascular regulation","volume":"499","author":"Card","year":"2006","journal-title":"J Comp Neurol"},{"key":"2026072304311428000_bqag074-B41","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.brainres.2011.12.058","article-title":"Sympathetic premotor neurones project to and are influenced by neurones in the contralateral rostral ventrolateral medulla of the rat in vivo","volume":"1439","author":"McMullan","year":"2012","journal-title":"Brain Res"},{"issue":"4","key":"2026072304311428000_bqag074-B42","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1111\/ejn.12232","article-title":"Rostroventrolateral medulla neurons with commissural projections provide input to sympathetic premotor neurons: anatomical and functional evidence","volume":"38","author":"Turner","year":"2013","journal-title":"Eur J Neurosci"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqag074\/68627710\/bqag074.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/167\/8\/bqag074\/68627710\/bqag074.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/167\/8\/bqag074\/68627710\/bqag074.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T08:31:25Z","timestamp":1784795485000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqag074\/8718995"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":42,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,7,8]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqag074","relation":{},"ISSN":["1945-7170"],"issn-type":[{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,8]]},"published":{"date-parts":[[2026,6,26]]},"article-number":"bqag074"}}