{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:28:13Z","timestamp":1789518493675,"version":"build-2803163510"},"reference-count":52,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:00:00Z","timestamp":1689724800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Narcolepsy type 1 (NT1) is assumed to be caused solely by a lack of hypocretin (orexin) neurotransmission. Recently, however, we found an 88% reduction in corticotropin\u2010releasing hormone (CRH)\u2010positive neurons in the paraventricular nucleus (PVN). We assessed the remaining CRH neurons in NT1 to determine whether they co\u2010express vasopressin (AVP) to reflect upregulation. We also systematically assessed other wake\u2010systems, since current NT1 treatments target histamine, dopamine, and norepinephrine pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In postmortem tissue of people with NT1 and matched controls, we immunohistochemically stained and quantified neuronal populations expressing: CRH and AVP in the PVN, and CRH in the Barrington nucleus; the key neuronal histamine\u2010synthesizing enzyme, histidine decarboxylase (HDC) in the hypothalamic tuberomammillary nucleus (TMN); the rate\u2010limited\u2010synthesizing enzyme, tyrosine hydroxylase (TH), for dopamine in the mid\u2010brain and for norepinephrine in the locus coeruleus (LC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In NT1, there was: a 234% increase in the percentage of CRH cells co\u2010expressing AVP, while there was an unchanged integrated optical density of CRH staining in the Barrington nucleus; a 36% increased number of histamine neurons expressing HDC, while the number of typical human TMN neuronal profiles was unchanged; a tendency toward an increased density of TH\u2010positive neurons in the substantia nigra compacta; while the density of TH\u2010positive LC neurons was unchanged.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings suggest an upregulation of activity by histamine neurons and remaining CRH neurons in NT1. This may explain earlier reports of normal basal plasma cortisol levels but lower levels after dexamethasone suppression. Alternatively, CRH neurons co\u2010expressing AVP neurons are less vulnerable. 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