Key role of 5‐HT_1A receptors in the modulation of the neuronal network underlying the respiratory rhythm generation in lampreys

Abstract

In mammals, 5-HTexcitatory respiratory effects imply 5-HT 1A receptor-mediated disinhibition of pre-Bötzinger complex neurons. In the lamprey, 5-HT 1A receptors are involved in the neural control of locomotion, but their role in the respiratory regulation, particularly at the level of the putative respiratory rhythm generator, the paratrigeminal respiratory group (pTRG), is not known. We here investigate the respiratory function of inhibitory 5-HT 1A receptors within the pTRG of the isolated brainstem of the adult lamprey. The 5-HT 1A receptor agonists either bath applied or microinjected into the pTRG did not cause significant effects. However, the selective 5-HT 1A receptor antagonist (S)-WAY 100135 bath applied or microinjected into the pTRG induced depressing respiratory effects or even apnoea, thus revealing that 5-HT exerts a 5-HT 1A receptor-mediated potent tonic influence on respiration and contributes to maintain baseline levels of respiratory activity. Microinjections of strychnine or bicuculline, either alone or in combination, into the pTRG prevented (S)-WAY 100135-induced apnoea. In addition, immunohistochemical studies corroborate the present findings suggesting that 5-HT 1A receptors are widely expressed in close apposition to the soma of glycine-immunoreactive cells located within the pTRG region. The results show that in the lamprey respiratory network, 5-HT exerts a tonic influence on respiration by a potent inhibitory control on both GABAergic and glycinergic mechanisms. The observed disinhibitory effects resemble the excitatory respiratory modulation exerted by 5-HT 1A receptor-mediated inhibition of glycinergic and/or GABAergic neurons present in mammals, supporting the notion 3904 | CINELLI Et aL.

Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver

“…Serotonin is a monoamine neurotransmitter, 90% of which has been found in the gastrointestinal tract, synthesized from tryptophan, and secreted from chromaffin cells of the small intestine (Berger et al, 2009). Serotonin is also known to have numerous functions, such as smooth muscle contraction of blood vessels and bronchi, acceleration of peristaltic movement (Berger et al, 2009), respiratory rhythm (Cinelli et al, 2020), regulation of β cells in the pancreas (Berger et al, 2009;Li et al, 2000), liver regeneration (Inoue et al, 2018;Kamimura et al, 2018), liver fibrosis (Kyritsi et al, 2020), protection against intestinal ischemia (Tackett et al, 2019) and food-seeking behavior (He et al, 2020), and its reuptake inhibitors are used as an antidepressant in relation to gastrointestinal symptoms (Salisbury et al, 2020). In addition, serotonin is reportedly involved in the fibrosis of NAFLD (Atallah et al, 2018), the modification of lipid metabolisms (Namkung et al, 2018), the activation of signal from serotonin receptor on the hepatocytes (Choi et al, 2018), and the modulation of autophagy and Notch signal (Martin et al, 2020).…”

The lamprey respiratory network: Some evolutionary aspects

“…The isolated brainstem of the adult lamprey spontaneously generates respiratory neuronal activity in vitro (fictive respiration). Under these experimental conditions, the respiratory frequency is similar to that of spontaneous respiration of intact lampreys in the aquarium at 9− 10 • C (Rovainen, 1977(Rovainen, , 1983Thompson, 1985;Russell, 1986;Bongianni et al, 1999Bongianni et al, , 2002Bongianni et al, , 2006Martel et al, 2007a;Mutolo et al, 2007Mutolo et al, , 2010Mutolo et al, , 2011Cinelli et al, 2013Cinelli et al, , 2014Cinelli et al, , 2016Cinelli et al, , 2017Cinelli et al, , 2020b. Most of the research on respiratory rhythm generation in lampreys comes from in vitro experiments where the input from pTRG to respiratory motoneurons is phasic.…”

“…1B). These bursts, also called 'coughs', occur at lower and irregular frequency (Rovainen, 1977;Thompson, 1985;Martel et al, 2007a) and probably do not originate from the pTRG (see also Hoffman et al, 2016;Cinelli et al, 2017Cinelli et al, , 2020b. These prolonged bursts (slow rhythm) were described for the first time in vitro by Rovainen (1974).…”

“…Rhythm-generating networks are likely present in early vertebrates, but studies in non-mammalian vertebrates are rather limited. A single microcircuit located in a region rostrolateral to the trigeminal motor nucleus is present in the lamprey (Rovainen, 1983(Rovainen, , 1985Russell, 1986;Thompson, 1985;Bongianni et al, 1999Bongianni et al, , 2002Bongianni et al, , 2006Martel et al, 2007a;Mutolo et al, 2007Mutolo et al, , 2010Mutolo et al, , 2011Cinelli et al, 2013Cinelli et al, , 2014Cinelli et al, , 2016Cinelli et al, , 2017Cinelli et al, , 2020b; for review see Bongianni et al, 2016;Milsom, 2018), a jawless fish that diverged from the main vertebrate line about 560 million years ago (Kumar and Hedges, 1998). This neural aggregate, termed the paratrigeminal respiratory group (pTRG), is necessary and sufficient for rhythm generation driving gill movements that can be recorded primarily from the vagus nerve (for review see Bongianni et al, 2016).…”

“…VA, raw vagal nerve activity. Modified from Mutolo et al (2007Mutolo et al ( , 2010 and Cinelli et al (2020b).…”