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21Интегративная физиология, 2020, т. 1, № 3 Integrative Physiology, 2020, vol. 1, no. 3 _www.intphysiology.ru
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UDC 612.328 DOI: 10.33910/2687-1270-2020-1-3-160-168
Thyrotropin releasing hormone (TRH) in the brainstem: Role of Pavlov's vagally mediated cephalic phase of gastric secretion
Y. TacheH1
1 University of California, Los Angeles, 115 Wilshire Blvd, Los Angeles 11301, USA
Abstract. Pavlov's seminal observation that sham feeding in dogs stimulates gastric acid secretion through the vagus nerve pioneered the concept of the cephalic phase of digestion. This has been subsequently extended to a wide range of mammals including humans. In the last decades, experimental evidence in rats established that the three amino acid peptide thyrotropin-releasing hormone (TRH) expressed in the brainstem plays a key role in the vagal stimulation of digestive secretory-motor function. The dorsal motor nucleus of the vagus (DMN) neurons expresses TRH receptor subtype 1 (TRH-R1) and receives input of TRH containing fibers arising from TRH synthesizing neurons in medullary raphe nuclei. The activation of TRH-TRH-R1 signaling excites the firing of DMN neurons leading to the activation of vagal efferent discharges and gastric myenteric cholinergic neurons. This results in a vagally mediated and atropine-sensitive stimulation of gastric secretory and propulsive motor function, along with duodenal and pancreatic secretion. Importantly, the blockade of TRH or TRH-R1 in the brainstem inhibits the gastric acid response to sham feeding in rats. Collectively, these convergent data support the physiological relevance of medullary TRH-TRH-R1 signaling as the end effector of the vagally mediated stimulation of digestive process in the cephalic phase.
Keywords: dorsal vagal complex, cephalic phase, gastric secretion, thyrotropin releasing hormone (TRH), TRH receptor, sham feeding, vagus.
Author
Yvette Taché,
Scopus AuthorID: 35430815800, e-mail: ytache@mednet.ucla.edu For citation: Taché, Y. (2020) Thyrotropin releasing hormone (TRH) in the brainstem: Role of Pavlov's vagally mediated cephalic phase of gastric secretion. Integrative Physiology, vol. 1, no. 3, pp. 160-168. DOI: 10.33910/2687-1270-2020-1-3160-168
Received 29 May 2020; reviewed 9 June 2020; accepted 9 June 2020. Funding: The author' work was supported by the NIHDDK grant DK 33061, the Center grant DK 41301 (Animal Core), VA Merit Award and VA Research Career Scientist Award.
Copyright: © The Author (2020). Published by Herzen State Pedagogical University of Russia. Open access under CC BY-NC License 4.0.
Introduction
At the beginning of the last century, Ivan Pavlov pioneered contributions to the field of integrative physiology by providing experimental evidence of the existence of a "psychic" stimulation of gastric acid secretion now known as the cephalic phase of digestion (Pavlov 1910). This was achieved by developing an experimental model in dogs equipped with an esophagus and gastric fistula whereby sham feeding consisting of swallowing food without reaching the stomach was shown to stimulate gastric acid secretion. Pavlov (1910) also found that in dogs with gastric intact and vagally denervated pouches (Heidenhain pouch) the gastric response to the vision and smell of food
along with gustative input in the oral cavity required the integrity of the vagus nerve.
Thereafter, the cephalic phase has been extended to a wide range of experimental mammals (Zafra et al. 2006). In humans, the gastric acid secretion initiated by meal expectations, visual, olfactory, and gustatory stimuli contributes up to 50% of the postprandial gastric secretory output and is mediated by vagal cholinergic pathways (Feldman, Richardson 1986). Subsequent investigations also showed that, in addition to acid, the cephalic phase encompasses the stimulation of a vast number of gastrointestinal (GI) digestive processes (Kat-schinski et al. 1992; Power, Schulkin 2008). Among those, the saliva is the first secretion to be increased by cephalic stimuli and the presence of food
in the mouth (Mattes 1997). Others relevant important secretory components are the enhanced GI hormone release, namely, gastrin (Goldschmiedt et al. 1990; Kovacs et al. 1997), ghrelin (Simonian et al. 2005), leptin (Sobhani et al. 2002) localized in the gastric mucosa within the gastric G, X/A, and mucosal cells respectively (Rindi et al. 2004), insulin (Guemes et al. 2019) and pancreatic polypeptide (Simonian et al. 2005) secreted from the pancreatic endocrine cells, as well as enzyme and bicarbonate from exocrine pancreatic secretion (Ohara et al. 1988). Concomitantly with the secretions, sham feeding increases GI motility (Rogers et al. 1993; Power, Schulkin 2008). The anticipatory GI secretory-motor responses induced by the cephalic phase are integrative and adaptive in nature to prime the gut to optimize the digestive, metabolic and absorptive processes under conditions of impending nutrient ingestion (Giduk et al. 1987; Katschinski 2000; Power, Schulkin 2008; Smeets et al. 2010).
Contrasting with the extended characterization of the peripheral GI changes evoked by the cephalic phase (Smeets et al. 2010), the underlying chemical coding in the brain mediating the vagally mediated response lagged behind. This was largely due to the lack of methodological approaches in dogs or humans to investigate the activation of these circuitries particularly in the brainstem (DelParigi et al. 2005). By contrast, a number of experimental studies in rodents have unraveled transmitters involved in vagal regulation of GI function in the brainstem (Hornby et al. 1991; Taché et al. 1995; Powley et al. 2000).
The present review will focus on convergent neuroanatomical and functional evidence accumulated during the past decades in rats supporting a role of thyrotropin releasing hormone (TRH)-TRH receptor 1 (TRH-R1) signaling in the brainstem in the vagal dependent stimulation of GI function and the possible physiological relevance as local medullary effector of the vagally mediated cephalic phase of digestion.
Hindbrain TRH-TRH receptor signaling and gastric vagal myenteric activation
We made the initial observation in rats that TRH injected the hindbrain cerebrospinal fluid at the level of the cisterna magna induces a rapid and potent increase of gastric acid secretion through vagal and atropine-sensitive pathways while peripherally administered, the peptide had no effect (Taché et al. 1980). This provided the first evidence of the central action of a peptide to induce a vagal stimulation of gastric secretion (Taché et al. 1981). However, to delineate the physiological relevance
of this observation in the vagal stimulation of gastric function several criteria had to be fulfilled. Namely, TRH should be present in fibers/terminals projecting on preganglionic vagal motor neurons of the dorsal motor nucleus of the vagus (DMN) innervating the gut. TRH receptors (TRH-R) should be expressed in DMN neurons and TRH-TRH-R activation should induce activation of vagal efferent fibers activity that innervate target cells involved in stimulating GI function. Importantly, blockade of TRH and/or TRH-R within the dorsal vagal complex (DVC) should inhibit the vagal dependent stimulation of gastric function evoked by stimuli acting through brain-vagal pathways as those recruited during the cephalic phase. So far, TRH-TRH-R signaling in the brainstem is the only ligand-receptor interaction for which these combined neuroanatomical, electrophysiological and functional criteria have been fulfilled (Taché et al. 1993; 2006; 2014).
Brain distribution by immunostaining showed that dense TRH-immunoreactive (IR) fibers are present in the rat DVC composed of the nucleus tractus solitarius (NTS) and DMN (fig. 1A). Electron microscopic studies further provided neuroanatomical evidence that TRH-IR localized in the DVC nerve terminals create asymmetric synaptic (excitatory) contacts on dendrites of DMN neurons contributing vagal efferent innervation of the stomach in rodents (Rinaman et al. 1989; Rinaman, Mise-lis 1990). Of translational relevance, TRH-IR fibers innervating the DMN in humans constitute the most prominent network compared to twelve other peptides immunostained under the same conditions (Fodor et al. 1994). Additional brainstem mapping studies with the combined use of knife cut and tracing methods have identified that TRH-IR fibers localized in the DVC do not originate from the hypothalamus but from TRH expressing neurons located in medullary raphe nuclei. Namely, the raphe obscurus (Rob), raphe pallidus (Rpa), and parapyramidal region synthetizing TRH containing neurons send direct projections to the DVC in rats (Lynn et al. 1991) and rabbits (Iwase et al. 1988) (fig. 1B-C).
The abundance of TRH-IR fibers and terminals in the DVC is paired with the presence of TRH-R expression. The initial autoradiography studies showed that TRH binding sites have the highest density within the medial column of the DMN (Manaker, Rizio 1989; Bayliss et al. 1994) (fig. 1D) where neurons contributing to the vagal efferent innervation to the stomach are most prominently localized (Powley et al. 1991; Holst et al. 1997). The subsequent cloning of G-protein coupled membrane bound proteins TRH-R subtype 1
(TRH-R1) and TRH-R2 in rodents (Gershengorn, Osman 1996) showed that only the TRH-R1 mRNA subtype is expressed in the DMN and NTS (Barnes et al. 2010). The TRH-R2 is found mainly in cortical and thalamic areas implicated in the processing of somatosensory signals (Heuer et al. 2000; O'Dowd et al. 2000).
The activation of TRH-R1 by exogenously applied TRH on in vitro rat brainstem slice preparations or in vivo results in the excitation of gastric projecting DMN neurons in rats and guinea pigs (McCann et al. 1989; Raggenbass et al. 1990; Travagli et al. 1992; Livingston, Berger 1993). This represents a direct excitatory action by TRH on DMN neurons since synaptic blockade and glutamate or muscarinic antagonists did not alter the response (McCann et al. 1989; Raggenbass et al. 1990; Travagli et al. 1992; Livingston, Berger 1993). Along with the activation of preganglionic vagal motor neurons, there is a robust increase in efferent discharges in the cervical or ventral gastric branch of the vagus evoked by TRH or the stable TRH agonist — dimethyl proline TRH (RX-77368) — injected into the cerebrospinal fluid of anesthetized rats (So-miya, Tonoue 1984; O-Lee et al. 1997). Additionally, RX-77368 injected intracisternally, at a dose that stimulates efferent activity in the gastric branch of the vagus (fig. 2A), activates 90% of submucosal and myenteric cholinergic neurons located in the gastric corpus and antrum in rats (Miampamba et al. 2001; 2011; Yuan et al. 2005). This was demonstrated in conscious rats by double immunostaining of gastric enteric neurons with Fos, the nuclear marker of synaptic activation and PGP 9.5, a neuronal marker (Krammer et al. 1993), or peripheral acetyl cholinergic transferase (Yuan et al. 2005) (fig. 2B) that was blocked by hexamethonium (Miampamba et al. 2001). Collectively, these data indicate that TRH injection into the brainstem increases vagal efferent outflow to the stomach leading to a nicotinic-mediated activation of gastric enteric postganglionic cholinergic neurons in rats (fig. 2).
Brainstem TRH and the stimulation of gastrointestinal function
To assess whether the endogenous TRH circuitry in the medulla oblongata plays a physiological role in the vagal activation, we used low doses of kainic acid to activate TRH synthesizing neurons located in the medullary raphe nuclei or parapyramidal region and innervating the DVC (Taché et al. 1995). This resulted in a vagal-dependent, atropine-sensitive stimulation of gastric acid and pepsin secretion, mucosal blood flow and motility mimicking the gastric responses to microinjection of TRH
or a TRH stable agonist into the DMN in rats and cats (Taché et al. 1984; Yang et al. 1993; 2000; Kaneko et al. 1998; Kiraly et al, 1998;White et al.1991; Garrick et al. 1994). It also resulted in stimulation of pancreatic secretion (Okumura et al. 1995; Yang et al. 2002; Yoneda et al. 2005). Moreover, polyclonal TRH antibody selectively microinjected bilaterally into the DVC to neutralize endogenous TRH or antisense oligodeoxynucleotides pretreatment given intracisternally to block TRH-R1 prevented the stimulation of gastric acid secretion, motility, and blood flow induced by the microinjection of kainic acid into the Rpa, Rob or parapyramidal region (Yang et al. 1993; 2000; Kaneko, Yang, Oh-ning, Taché 1995; Kaneko, Kaunitz, Taché 1998; Garrick et al. 1994; Sivarao et al. 1997).
Next, we assess in rats whether the TRH-TRH-R1 signaling pathway plays a role as part of hindbrain mechanisms stimulating the vagus under conditions of central-vagally mediated gastric secretion. Martínez et al. (Martínezet al. 2002) developed a new model of gastric acid secretion in response to sham feeding induced by exposing fasted rats to sensory, visual and olfactory stimuli of smell and vision of Purina Chow without accessing to it. This induced an elevation of basal acid secretion within 10 min after the onset of sham-feeding reaching a peak increase of 130% over baseline at 20 min followed by a decline to basal levels thereafter. Moreover, the intracisternal injection of TRH-R1 antisense oligodeoxynucleotides given at doses that suppress gastric acid output stimulated by intracisternal TRH, blocked the acid response to the sight and smell of food while a TRH-R1 mismatched oligodeoxynucleotide had no effect under similar experimental conditions (Martínez et al. 2002) (fig. 3).
Of interest is also the demonstration that TRH in the brainstem-induce vagal stimulation of gastric secretory and motor function can be inhibited by several peptides innervating the DVC including those that play a role in the immune (interleukin-1, tumor necrosis factor-a) or stress (corticotrophin releasing factor, urocortin 1) responses, as well as other peptides innervating the DVC through their projections from the paraventricular nucleus of the hypothalamus (gastrin releasing peptide/bombesin) or central amygdala (calcitonin gene related peptide/ adrenomedullin) (Morrow et al. 1995; Hughes et al. 1984; Martínez, Taché 2000; Hermann et al. 1999; Heymann et al. 1991; Chen et al. 2002; Taché, Bonaz 2007). It may be speculated that the centrally mediated inhibitory action of these peptides may have significance to curtail the cephalic phase of digestion under conditions of infections, stress, pain or fear, although it remains to be investigated.
Fig. 1. TRH/TRH-R1 signaling pathways in the rat brain stem. Neuroanatomical evidence for a physiological role of brain medullary TRH. (A): Drawing of dense distribution of TRH-IR fibers in rats dorsal vagal complex (DVC) rostrocaudal to the obex. (B): TRH synthetizing neurons shown by in situ hybridization in the rat raphe obscurus (Rob), pallidus (Rpa) and bilateral parapyramidal nuclei (paPy). (C): Schematic representation of the rat medulla and projections of TRH synthetizing neurons to the dorsal motor nucleus. (D): High expression of TRH binding sites in the dorsal motor nucleus (X) including the medial portion projecting to the stomach
Fig. 2. Intracisternal injection of TRH analog activates efferent spike activity in the gastric branch of the vagus in urethane anesthetized rats (A) and gastric myenteric cholinergic neurons in conscious rats as showed by double labeling of Fos, a marker of neuronal activation, and peripheral acetyl cholinergic transferase as a marker of cholinergic neurons (B). (From O-Lee et al. 1997 and Yuan et al. 2005)
Fig. 3. The psychic phase of gastric secretion demonstrated in dogs by Pavlov and reproduced in rats by a sham feeding-induced increase in gastric acid output: suppression by selective blockade of TRH receptor 1 in the brainstem supporting a role of TRH signaling in the cephalic phase. (From Martínez et al. 2002)
Perspectives
Convergent experimental evidence supports that TRH synthesizing neurons in medullary raphe nuclei projecting to the DVC and TRH-R1 recep-
tors in the DVC have a physiological relevance in the vagal cholinergic dependent regulation of GI and pancreatic secretion and other vagally mediated gut response during the cephalic phase (fig. 4).
Fig. 4. Schematic representation of TRH interacting with TRH 1 receptor expressed on dorsal motor nucleus neurons as well as stimulation of gastric, pancreatic and intestinal function through the activation of vagal pathways
The DVC receives direct projections from forebrain sites including the parabrachial nucleus, mesencephalic periaqueductal gray, paraventricular and dorsomedial nucleus of the hypothalamus, lateral hypothalamus, central nucleus of amygdala, bed nucleus of stria terminalis, insular cortex, anterior cingulate cortex, and orbi-tofrontal cortex (Van der Kooy et al. 1984). It also gets input from gustatory afferents in the oral cavity (Van der Kooy et al. 1984). These circuits offer potential pathways by which sensory information of gustatory, olfactory, or visual nature
involved in the cephalic phase can influence neurons of the DVC. Whether the activation of TRH-TRH-R1 signaling in the brainstem represents a common final effector mechanism activated by forebrain and hindbrain neuronal circuit recruited during the cephalic phase warrant further investigations.
Conflict of interest
The author confirms that this article content has no conflict of interest.
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