Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure

“…GLP-1 signaling pathways are implicated in the central control of food intake, glucose homeostasis, and HPA axis and autonomic responses to stress (Holst, 2007; Imeryuz et al., 1997; Kinzig et al., 2003; Nakade et al., 2007; Rinaman, 1999a; Sandoval et al., 2008; Tang-Christensen et al., 2001;…”

“…are implicated in the central control of food intake, glucose homeostasis, and HPA axis and autonomic responses to stress (Holst, 2007; Imeryuz et al., 1997; Kinzig et al., 2003; Nakade et al., 2007; Rinaman, 1999a; Sandoval et al., 2008; Tang-Christensen et al., 2001; Turton et al., 1996).”

“H129 undergoes anterograde transneuronal transport in cebus monkeys after inoculation of primary motor cortex (Kelly and Strick, 2003; Zemanick et al., 1991) and in mice after inoculation of tooth pulp (Barnett et al., 1995) or the vitreous body of the eye (Sun et al., 1996).”

“…description of the central projections of NST neurons effectively reveals most CNS recipients of viscerosensory information (Bailey et al., 2006; Horst et al., 1989; Horst and Streefland, 1994; Ricardo and Koh, 1978), albeit without identifying the central targets of organ-specific sensory signals.”

“The PBN has at least 12 distinct subnuclei, some of which project to central targets that do not receive direct input from the NST (Fulwiler and Saper, 1984;Herbert et al., 1990;Moga et al., 1990;Saper and Loewy, 1980).”

“(Gerfen and Sawchenko, 1984), into the caudal visceral NST. Coronal brain sections (35 µm thick) were cut from the caudal medulla through the rostral extent of the corpus callosum, and a one-in-six series was processed for immunoperoxidase localization of PhAL.”

“…NST neurons that project to the hypothalamus and limbic forebrain are NA neurons of the overlapping A2/C2 cell groups (Sawchenko and Swanson, 1981; Sawchenko and Swanson, 1982a; Sawchenko and Swanson, 1982b), with remaining projection neurons primarily comprising smaller and separate populations…”

“…NST neurons that project to the hypothalamus and limbic forebrain are NA neurons of the overlapping A2/C2 cell groups (Sawchenko and Swanson, 1981; Sawchenko and Swanson, 1982a; Sawchenko and Swanson, 1982b), with remaining projection neurons primarily comprising smaller and separate populations…”

“The PBN has at least 12 distinct subnuclei, some of which project to central targets that do not receive direct input from the NST (Fulwiler and Saper, 1984;Herbert et al., 1990;Moga et al., 1990;Saper and Loewy, 1980).”

“The PBN has at least 12 distinct subnuclei, some of which project to central targets that do not receive direct input from the NST (Fulwiler and Saper, 1984;Herbert et al., 1990;Moga et al., 1990;Saper and Loewy, 1980).”

“However, the mNTS does not directly project to the HPC (Rinaman, 2010; Hsu et al., 2015a).”

“Indeed, the vmNTS, where the VN projects its terminals, connects to many brainstem and forebrain regions, but not to the HPC directly (35, 36).”

“…to their vital role in processing visceral sensory signals and modulating vagal motor outflow (Rogers et al., 1995; Grill and Hayes, 2012), NTS neurons modulate hypothalamic neuroendocrine secretion, food intake, and other motivated behaviors (Maniscalco and Rinaman, 2018; Rinaman, 2010, 2019).”

“regions is said to modulate behavioral arousal, and coordinate endocrine [268–273] and behavioral responses to stress (including infection and inflammation) [272, 273].”

“Its neurons overlap axon terminal fields that deliver viscerosensory information from the nucleus of the solitary tract (Geerling & Loewy, 2006b; Herbert et al., 1990;Rinaman, 2010) andanoral-sensory subregionof the spinal trigeminal nucleus (Dallel et al., 2004).”

“As reviewed elsewhere (Andresen et al., 2007; Maley, 1996; Riche et al., 1990; Rinaman, 2007, 2010; Sawchenko et al., 1990), different subpopulations of cNTS neurons express different combinations of amino acid, peptide and biogenic amine signalling molecules.”

“…by the expression of the catecholamine synthesis enzyme TH, receives ‘‘higher order’’ influences through one or more additional interneurons and integrative inputs rather than direct blood pressure inputs from baroreceptors afferents (Chan and Sawchenko 1994, 1995, 1998; Rinaman 2010, 2011).”

“GLP-1R expression by PrRP+ neurons could contribute to local modulatory effects on Ca signaling within the local somatodendritic compartment of PrRP neurons, and/or distal axo-axonic interactions that affect release of norepinephrine and PrRP within CNS target regions that receive axonal input from both cNTS neural po…”

“, 2013), where GLP1-positive axon terminals are concentrated (Rinaman, 2010).”

“GLP-1 fibers and receptors are present in the LS [3,27,28], as well, and recent experimental data from our laboratory showed that GLP-1 in the LS influences food intake [29].”

“…of C2816 or saline in the ventromedial, dorsomedial and paraventricular nuclei of the hypothalamus (VMH, DMH, PVH) and the nucleus tract of the solitarius (NTS) and the area postrema (AP) in the caudomedial brainstem (Blevins, Stanley, & Reidelberger, 2000; Rinaman, 2010; Secher et al., 2014).”

“…eating upon the reward properties of specific foods or food-associated stimuli, and the so-called reward circuitry has been well established in the brain (see reviews in Berthoud 2004; Figlewicz and Sipols 2010; Petrovich 2013; Richard et al. 2013; Rinaman 2010; Zheng and Berthoud 2007).”

“…two products (i.e., GLP-1 and GLP-2) are generated in the same caudal brainstem neurons and transported anterogradely into axon terminals that make asymmetric (i.e., excitatory-type) synaptic contacts with central neural targets in the hypothalamus (Sarkar et al. 2003) and other brain regions.”

“The NTS also sends projections to nuclei within the forebrain that are involved in the regulation of food intake including the paraventricular nucleus (PVN) and arcuate nucleus of the hypothalamus [30].”

“The neurons in the NTS have ascending axons projecting to a large number of brain areas, including brain areas involved in food intake regulation and mood, such as the hypothalamus and amygdala (Ricardo and Koh, 1978; Rinaman, 2007, 2010).”

“GLP-1 is also a neuropeptide produced by brainstem neurons in the nucleus of the tractus solitarius (NTS) which project widely to subcortical areas containing the GLP-1 receptor (Merchenthaler et al., 1999; Rinaman, 2010).”

“Axonal projections from NTS neurons then communicate monosynaptically and polysynaptically with various hindbrain, midbrain, and forebrain nuclei involved in energy balance regulation (see [10,11] for review).”

“Centrally, GLP-1 is produced by neurons in the caudal NTS, which project throughout the brain to several feeding-relevant regions and are activated by nutrient ingestion, gastric distension, CCK, and vagal afferent stimulation (Larsen et al., 1997; Rinaman, 2010).”

“The A2 noradrenergic population plays a role in both the execution and inhibition of feeding behaviors, though the preponderance of studies to date emphasizes its role in suppression of feeding (Rinaman 2010, 2011; Roman et al. 2016; Wellman 2000).”

“hypothalamus to drive appropriate physiological responses to incoming signals [3].”

“forebrain, modulating arousal and pain perception (Rinaman 2010; Ossipov et al. 2010).”

“Further, this effect is associated with altered NA α2 autoreceptor binding in the caudal medullary DVC, suggesting altered negative feedback control over stress-responsive NA neurons [84] that are heavily involved in local coordination of vagal motor outflow [169–172]} and other behavioral functions, such as inhibitio…”

“GLP-1 producing neurons in the NTS projected to lateral and medial PBN in rodents (151, 152) and consistently, GLP-1Rs have been found to be expressed in the lateral PBN (lPBN) (153).”

“…ventral tegmental area (dopamine), as well as targets in the midbrain and forebrain including hypothalamic and amygdalar subnuclei, portions of the basal ganglia (e.g., nucleus accumbens) and the hippocampus via the septal nuclei (Rinaman, 2003, 2010; Rinaman & Schwartz, 2004; Suarez et al., 2018).”

“In rats and mice, PPG neurons project to the PVT, and neurons here express GLP-1 receptors (Cork et al., 2015; Gu et al., 2013; Llewellyn-Smith et al., 2013; Merchenthaler et al., 1999; Rinaman, 2010).”

“posterior and anterior pituitary and projects to nuclei with sympathetic or parasympathetic efferents((86,90,91)).”

“This effect on appetite is not only attributed to the delayed gastric emptying but also to its influence on the hypothalamus as a neurotransmitter, particularly on the lateral hypothalamus, and the paraventric‐ ular and arcuate nucleus (16,17).”

“Likewise, rats exposed to enhanced maternal care during the postnatal period show reduced activation of nuclei targeted by ascending NTS projections in response to a visceral stressor (Koehnle and Rinaman, 2010).”

“Anterograde and retrograde labeling studies indicate substantial connectivity, often bidirectional, between the caudal NTS and most of the CNS (Herbert et al., 1990; Spyer, 1990; Hermes et al., 2006; Geerling et al., 2010; Rinaman, 2010; Alheid et al., 2011; Alhadeff et al., 2012).”

“For example, GLP-1 neurons reside within the NTS and have been shown to send projections to the septal area [67,68], but whether this pathway is the sole source of LS GLP-1 is unclear.”

“Emerging evidence suggests an important role of NTS projections to hypothalamic and limbic regions of the brain in many physiologic processes as well (Lee et al., 2011; Maniscalco and Rinaman, 2017; Rinaman, 2010).”

“It is conceivable that the right side of the mesolimbic pathway of the MC animals (VTA and NAC), due to elevated level of the m = (CH)/mas(CH3) ratio, is likely to be particularly vulnerable to changes in the level of fatty acid unsaturation.”

“This result is consistent with what can be gleaned from photomicrographs and brief descriptions in previous reports (Karimnamazi et al., 2002; Rinaman, 2010; Whitehead et al., 2000).”

“We examined Glp-1r gene expression as Glp-1r mRNA is distributed in LC and central GLP-1 signaling plays a key role in modulating feeding behaviors (Merchenthaler et al., 1999; Moran, 2009; Rinaman, 2010).”

“…vagus, nucleus ambiguous, parabrachial nucleus, paraventricular nucleus of hypothalamus, to participate in the regulation of blood pressure, taste, respiration, visceral activity and stress responses (Rinaman, 2010; Alheid et al., 2011; Cutsforth-Gregory and Benarroch, 2017; Myers et al., 2017).”

“Vagal efferents terminating in the cNTS and the relative permeability of the blood brain barrier in the brain stem allow the combined visceral sensation and circulating nutrients to modulate activity of broader brain pathways [58,59].”

“…to the paraventricular hypothalamus include GCG þ , TH þ (which includes DBH þ (A2) and PNMT þ (C2)), POMC þ , and CCK þ neurons [39,43,76 e 78], and activating this circuit reduces food intake, indicating their role of relaying ingestive cues detected from the gastrointestinal tract to…”

“These GLP-1 neurons within the NTS have rich axonal innervation to the hypothalamus [52, 53].”

“The NTS is important for sensing glucose levels and it responds to hypoglycemia by stimulating food intake, inducing release of stress hormones and increasing sympathetic tone (Renner et al., 2010; Rinaman, 2010; Wu et al., 2012).”

“…and brainstem regions that regulate affective, appetitive, cardiores-piratory, and neuroendocrine functions (Beckstead, Morse, and Norgren 1980; Geerling and Loewy 2006; Herbert, Moga, and Saper 1990; Holt 2022; Loewy and Burton 1978; Quillet et al. 2023; Rinaman 2010; Ter Horst et al. 1989).”

“Distinct groups of NTS neurons then send this information to multiple brain centers, such as the dorsomotor nucleus of the vagus, the PBL, ARC, and the paraventricular hypothalamic nucleus (PVH; Rinaman, 2010; Trapp and Cork, 2015; D’Agostino et al., 2016; Travagli and Anselmi, 2016).”

“…of signals arising from the gastrointestinal tract (mechanical, chemical, nutrient), and in turn projects by noradrenergic and peptidergic neurotransmission to other brain regions involved in the control of energy balance, including the hypothalamic and limbic forebrain nuclei (Rinaman 2010).”

“…coeruleus (LC), the main source of NA in the central nervous system, have been shown to send projections to the VTA (Mejias-Aponte et al., 2009, Rinaman, 2010, 2011; Jones and Moore, 1977, Phillipson, 1979, Simon et al., 1979, Geisler and Zahm, 2005, Mejias-Aponte et al., 2009 for detailed…”

“Because we know that GLP-1-producing neurons in the hindbrain are activated by gastric distention (36), and that they project to the LS (24), these neurons may be the source for that gut sensory information.”

“…tissues, including human, rat and mice brain regions related to reward and addiction (Merchenthaler et al., 1999; Alvarez et al., 2005; Pannacciulli et al., 2007; Rinaman, 2010; Seino et al., 2010; Suchankova et al., 2015; Jensen et al., 2018; Eser et al., 2020; ErenYazicioglu et al., 2021).”

“Thus, manipulating the vagus nerve may regulate motivational and reward behaviors by affecting dopamine release to the striatum, medial prefrontal cortex (mPFC), or other brain regions [79-81].”

“T from the nucleus of the solitary tract (McDonald et al., 1999; Rinaman and Schwartz, 2004; Rinaman, 2010).”

“…the results obtained by Kim et al. Part of the neural pathway involved in the eating-suppressing effect of CCK has already been established in literature: The pathway starts from the vagus nerve and involves NTS, PBN, and CeA (Becskei et al., 2007; D ’ Agostino et al., 2016; Rinaman, 2010).”

“Additionally, the activation of GLP-1 receptors in the area postrema in the brainstem modulates dopaminergic activity to reduce food intake and modulate activity in the ARC of the hypothalamus [170,171].”

“The NTS has been shown to target circuits involved in control of energy homeostasis such as the paraventricular nucleus of the hypothalamus (PVN) (Figure 2; Rinaman, 2010).”

“Previously, we found a significant increase of FOS in DMN, SON and PVN of neonatal rabbit pups after ingestion of a large volume of milk (Caba et al., 2003, 2008).”

“…non-specific axon tracers to explore neural pathways associated with inputs or outputs of the NTS throughout the brain (Ricardo and Koh, 1978; Shioya and Tanaka, 1989; Herbert et al., 1990; Yu and Gordon, 1996; Tanaka et al., 1997; Rinaman, 2010; Ganchrow et al., 2014; Gasparini et al., 2020).”

“These signals – mostly originated from the gustatory stimulation, gastric distension or presence of peptides and peripheral hormones such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and leptin – are transmitted to the NTS through vagal afferents and other cranial nerves, such as glossopharyngeal, facial…”

“The NTS has an established role as a center that receives, integrates, and relays visceral gastrointestinal, gustatory, cardiovascular, and respiratory information to higher centers (Bradley and Grabauskas, 1998; Rinaman, 2010; Zhang and Mifflin, 2010; Zoccal et al., 2014).”

“In addition to modulating reward, nicotine also stimulates a stress response, modulates cardiovascular and gastric reflexes, inhibits food intake, and reduces body weight (3, 12, 30, 34, 40, 49, 81, 92), all behaviors and reflexes influenced by neurons in the nucleus of the solitary tract (NTS) in the hindbrain (1, 10…”

“In addition to the interface between hindbrain GLP-1 and the SFO and OVLT, GLP-1 fibers and receptors are present in the VTA [108, 111, 117].”

“The NTS of the dorsal medulla oblongata plays an essential role in regulating cardiovascular functions, affects the activity of hypothalamic SON and PVN neurons [42, 43], and reduces food intake and body weight [44].”

“…sends projections throughout the brain to regions involved in autonomic regulation and motivated behaviour, including the paraventricular nucleus of the hypothalamus (PVN), bed nucleus of the stria terminalis, central amygdala, parabrachial nucleus, and dorsomedial hypothalamus (Rinaman, 2010).”

“This neuronal group projects to the lateral parabrachial nucleus (LPBN), the median preoptic nucleus (which is part of the AV3V region), the SFO, and the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus (10, 16, 35, 41, 43, 46).”

“GLP-1R mRNA and GLP- 1-containing fibers were detected in the PBN (Merchenthaler, Lane, and Shughrue 1999; Rinaman 2010) (Figure 5).”

“Importantly, GLP-1R are expressed throughout the meso - limbic DA system, and GLP-1 containing neurons extend directly into the VTA and NAc [7 –9 ].”