Activated Wake Systems in Narcolepsy Type 1

Abstract

ObjectiveNarcolepsy 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‐releasing hormone (CRH)‐positive neurons in the paraventricular nucleus (PVN). We assessed the remaining CRH neurons in NT1 to determine whether they co‐express vasopressin (AVP) to reflect upregulation. We also systematically assessed other wake‐systems, since current NT1 treatments target histamine, dopamine, and norepinephrine pathways.MethodsIn 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‐synthesizing enzyme, histidine decarboxylase (HDC) in the hypothalamic tuberomammillary nucleus (TMN); the rate‐limited‐synthesizing enzyme, tyrosine hydroxylase (TH), for dopamine in the mid‐brain and for norepinephrine in the locus coeruleus (LC).ResultsIn NT1, there was: a 234% increase in the percentage of CRH cells co‐expressing 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‐positive neurons in the substantia nigra compacta; while the density of TH‐positive LC neurons was unchanged.InterpretationOur 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‐expressing AVP neurons are less vulnerable. ANN NEUROL 2023

The Changed Nocturnal Sleep Structure and Higher Anxiety, Depression, and Fatigue in Patients with Narcolepsy Type 1

“…Recent studies had found a reduced number of neurons expressing and hyperactivity of the remaining CRH neurons in the paraventricular nucleus (PVN) of the hypothalamus in patients with NT1. 53 , 54 CRH increased the rate-limiting enzymes of biosynthesis for NE and 5-HT, which in turn inhibited the activation of NE and 5-HT. 55 Antagonists of CRH1 receptors showed antidepressant-like effects, confirming the relationship between CRH and anxiety and depression.…”

Narcolepsy Type 1: Should We Only Target Hypocretin Receptor 2?

“…Furthermore, the relationship between anxiety and depressive symptoms in NT1 is yet to be fully understood. In a post-mortem study, there was a surprisingly substantial reduction in the number of CRH-positive neurons in the paraventricular nucleus in NT1 [27]. The CRH signal was preserved in other brain areas.…”

“…Of note, there is a difference between acute stress response and chronic stress levels. In a follow-up study, almost all of the 12% 'surviving' paraventricular CRH neurons expressed vasopressin [27]. This peptide also plays an essential role in the HPA axis and strongly potentiates the action of CRH on cortisol release.…”

White matter integrity in narcolepsy: the structural blueprint for functional complaints?

“…In idiopathic RBD, REM sleep without atonia arises from the dysfunctioning of REM-regulating pontomedullary nuclei, primarily through glutamatergic neurons in the subcoeruleus [ 16 ]. Changes in neuron counts outside the hypothalamus have so far not been identified in narcolepsy type 1 [ 17 , 18 ], and loss of hypocretinergic innervation of brainstem REM circuits and the basal ganglia seems a more reasonable hypothesis for RBD symptoms in narcolepsy type 1. Different underlying pathophysiology could account for the nuanced distinctions in RBD phenotypes, such as the typically younger onset in narcolepsy compared to idiopathic RBD [ 15 ].…”