Orexin/Hypocretin and Histamine Cross-Talk on Hypothalamic Neuron Counts in Mice.

Chiara Berteotti,Alessandro Silvani,Gabriele Matteoli,Hiroshi Ohtsu,Jian-Sheng Lin,Viviana Lo Martire,Cristiano Bombardi,Stefano Bastianini,Giovanna Zoccoli,Sara Alvente

doi:10.3389/fnins.2021.660518

Abstract

The loss of hypothalamic neurons that produce wake-promoting orexin (hypocretin) neuropeptides is responsible for narcolepsy type 1 (NT1). While the number of histamine neurons is increased in patients with NT1, results on orexin-deficient mouse models of NT1 are inconsistent. On the other hand, the effect of histamine deficiency on orexin neuron number has never been tested on mammals, even though histamine has been reported to be essential for the development of a functional orexin system in zebrafish. The aim of this study was to test whether histamine neurons are increased in number in orexin-deficient mice and whether orexin neurons are decreased in number in histamine-deficient mice. The hypothalamic neurons expressing L-histidine decarboxylase (HDC), the histamine synthesis enzyme, and those expressing orexin A were counted in four orexin knock-out mice, four histamine-deficient HDC knock-out mice, and four wild-type C57BL/6J mice. The number of HDC-positive neurons was significantly higher in orexin knock-out than in wild-type mice (2,502 ± 77 vs. 1,800 ± 213, respectively, one-tailed t-test, P = 0.011). Conversely, the number of orexin neurons was not significantly lower in HDC knock-out than in wild-type mice (2,306 ± 56 vs. 2,320 ± 120, respectively, one-tailed t-test, P = 0.459). These data support the view that orexin peptide deficiency is sufficient to increase histamine neuron number, supporting the involvement of the histamine waking system in the pathophysiology of NT1. Conversely, these data do not support a significant role of histamine in orexin neuron development in mammals.

Highlights

The interactions between the orexin (de Lecea et al, 1998; Sakurai et al, 1998) and histamine neuron systems are an open topic of investigation of substantial scientific and potential clinical relevance (Sundvik and Panula, 2015)
The estimated total number of histidine decarboxylase (HDC)-positive tuberomammillary nucleus (TMN) neurons per brain was 39% higher in KO-ORX than in WT mice (P = 0.011, one-tailed t-test) (Figure 1C), and the increase in KO-ORX mice remained significant when assessed on raw neuron counts without the Abercrombie correction (1279 ± 40 vs. 940 ± 111, P = 0.014, one-tailed t-test)
The anteroposterior location of HDC-positive neurons in the TMN evidenced a significant interaction between distance from bregma along the rostro-caudal axis and mouse group (P = 0.002, twoway ANOVA) (Figure 1D)

Summary

Introduction

The interactions between the orexin (hypocretin) (de Lecea et al, 1998; Sakurai et al, 1998) and histamine neuron systems are an open topic of investigation of substantial scientific and potential clinical relevance (Sundvik and Panula, 2015). Two independent studies (John et al, 2013; Valko et al, 2013) reported an increased number of histamine neurons at autopsy in the brains of patients with NT1. These results keep open the question whether orexin peptide deficiency is sufficient to increase histamine neuron number, given that patients lose orexin co-transmitters (Bonnavion et al, 2016) and may suffer from consequences of an autoimmune insult to the hypothalamus (Kornum, 2020). One study (Valko et al, 2013) found a significant 53% increase in histamine neurons in adult orexin knock-out mice (KO-ORX) compared to wild-type (WT) control mice, whereas the other study (John et al, 2013) did not find significantly altered numbers of histamine neurons

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