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).”

“Stimulants increased insulin levels in a PCP-induced model of schizophrenia (179) Glucagon-like peptide-1 (GLP-1) (180) Small intestine Oral taste buds Some anorexic effects appear to be exerted at the level of the mesolimbic reward system (181) Exendin, a GLP-1 receptor agonist modulates behavioural activation by amp…”

“…(DMV) to evoke vago-vagal reflexes, to other hindbrain sites to control sympathetic outflow, and to more rostral sites to control behavior, autonomic outflow, and neuroendocrine responses (Ghosal et al., 2017; Grill and Hayes, 2012; Rinaman, 2010; Trapp and Cork, 2015; Travagli and Anselmi, 2016).”

“Likewise, we cannot completely eliminate the possibility that Fluorogold was taken up by fibers of passage that were damaged during drug injection into the VTA and NAc.”

“Many of these mechanistic roles in NTS processing of energy-balance signals has been reviewed elsewhere (see Berthoud, 2004; Grill, 2010; Moran and Ladenheim, 2011; Powley, 2000; Rinaman, 2010; Ritter, 2004; Schwartz, 2010 for review).”

“For motor activity measurements (after VTA and NAc EX4 microinjections), rats were placed in chambers 60 min before VTA or NAc EX4 (0.1 g/0.5 l) injection and 60 min spontaneous X-Y plane and rearing postinjection activity were measured and analyzed in 10 min bins.”

“Moreover, neurons in VTA and/or nucleus accumbens (NAc) express glucagon-like peptide-1 (11,12), ghrelin (13,14), leptin (15,16), insulin (17), orexin (18), and melanocortin receptors (19).”

“Classic tract tracings have revealed that neurons in the ARC and NTS receive inputs from, and project to, broad brain areas (Makara and Hodacs, 1975; Ricardo and Koh, 1978; Schwaber et al., 1982; Chronwall, 1985; Gruber et al., 1987; Sim and Joseph, 1991; Magoul et al., 1993; Rinaman, 2010).”

“Vagally mediated satiation signals are likely transmitted to hippocampal neurons via yet unidentified polysynaptic pathways, given that there are no known monosynaptic pathways between medial nucleus of the solitary tract (mNTS) and hippocampal neurons (68,69).”

“(B) At the week 26 rescan, DAT availability in striatum, caudate, and putamen was significantly lower in the exenatide group compared with the placebo group [striatum, F(1,13) = 4.”

“These cells are located primarily in the nucleus of the solitary tract (NTS) and project throughout the brain to many feeding-relevant areas (Rinaman, 2010).”

“Neurons within central vagal neurocircuits, particularly NTS neurons, have dense reciprocal connections with the hypothalamus which are critically important in the integration and regulation of several autonomic reflexes (Rinaman, 2007; Rinaman, 2010; Spyer et al., 1997; van der Kooy et al., 1984).”

“, 1999) and endogenous GLP-1-containing-fibers from the NTS specifically target these reward areas (Rinaman, 2010; Alhadeff et al., 2012).”

“Repeated-measures analysis of variance (ANOVA) analyses across days revealed a significant day × group interaction (F[1,13]= 5.”

“One of the primary integration nodes within the brain for meal-related and metabolic signals from the periphery is the nucleus of the solitary tract (NTS) (Grill and Hayes, 2012; Rinaman, 2010; Schwartz, 2010; Wu et al., 2012).”

“Indeed, neurons in VTA and/or NAc express receptors for several peptides and hormones that regulate homeostatic food signals, such as glucagon-like peptide or GLP-1 (Alhadeff et al., 2012; Rinaman, 2010), ghrelin (Abizaid et al., 2006; Jerlhag et al., 2007), leptin (Figlewicz et al., 2003; Leshan et al., 2010), insuli…”

“Moreover, GLP-1 containing neurons from the NTS target reward related areas expressing GLP-1 receptors, such as the ventral tegmental area and nucleus accumbens [3,4,30,31].”

“Additionally, the A2/C2 CA neurons in the NTS also directly project to the CRH and TRH neurons in the hypothalamus and stimulate CRH and TRH neuronal activity [39].”

“Acc [8,9,17,30].”

“Perhaps the most notable feature about the projections originating from the medulla to the PAG/DR is that they appear to target all subdivisions while selectively avoiding the DL column (Blomqvist and Craig, 1991; Herbert and Saper, 1992a; Mantyh, 1982a; Rinaman, 2010).”

“Since A2/C2 neurons of the NTS have been extensively examined for their hypothalamic projections, we focused on this region (Ricardo and Koh, 1978; Rinaman, 2010, 2011; Sawchenko and Swanson, 1981, 1982a, 1982b; Ter Horst et al., 1989).”

“The NTS is a heterogeneous brain structure comprising distinct and segregated cell populations, including noradrenergic and peptidergic neurons, that integrate and modulate autonomic function, energy balance, and motivated feeding behaviors (Grill and Hayes, 2012; Rinaman, 2010).”

“These inputs allow the NTS to contribute to metabolic homeostasis, affecting not only cardiorespiratory function, but also food intake and digestion (Rinaman, 2010; Zoccal et al., 2014).”

“Despite the presence of GLP-1R mRNA (Merchenthaler et al, 1999) and terminals of GLP-1immunopositive fibers (Rinaman, 2010) in the PBN, a direct analysis of lPBN GLP-1R signaling in the control of feeding behavior remains unexplored.”

“Within the CNS, hindbrain GLP-1 neurons project to numerous brain regions relevant to metabolic regulation in mice (Figure 1) (Burcelin et al., 2009; Ghosal et al., 2017; Llewellyn-Smith et al., 2011; Rinaman, 2010).”

“A variety of sensory information from the gastrointestinal tract, including satiation and satiety, is transmitted to the brain via the vagal afferent nerve (Rinaman, 2010).”

“Our result differs from other studies in which small numbers of GLP-1-containing terminals were found in the nucleus accumbens (Rinaman, 2010) and a significant projection of GLP-1-expressing neurons to the nucleus accumbens was observed by retrograde tracing (Dossat et al., 2011).”

“A variety of sensory information derived from the gastrointestinal tract is transmitted to the nucleus of the tractus solitaries (NTS) in the medulla oblongata via the vagal afferent nerve, terminating in hypothalamic nuclei implicated in the control of feeding (Rinaman 2010).”

“…cells (Cork et al, 2015; Merchenthaler et al, 1999) and GLP-1 immunopositive fibers are located within the PVT, which suggests possible GLP-1 innervation from preproglucagon (PPG) neurons in the caudal nucleus tractus solitarius (NTS; Gu et al, 2013; Llewellyn-Smith et al, 2011; Rinaman, 2010).”

“Indeed, although it is well known that NTS neurons project to a variety of regions throughout the hindbrain, midbrain, and forebrain (Norgren, 1978; Rinaman, 2010), the target projection sites of NTS GLP-1R-expressing neurons and the downstream circuits mediating the effects described here remain…”

“GLP-1 is a potent incretin that is synthesized and secreted by L cells predominantly located in the distal gut and by a subset of neurons in the nucleus tractus solitarius (NTS) (Larsen et al., 1997; Merchenthaler et al., 1999; Rinaman, 2010).”

“NTS GLP-1 neurons projectwidely to brain regions including the ventral tegmental area (VTA) and the nucleus accumbens (NAc) [12–17].”

“Attenuated dopamine release in the NAc was reported following systemic Ex4 administration (Egecioglu et al, 2013a; Egecioglu et al, 2013c).”

“Together, these intracellular signaling pathways interact to control for the feeding effects produced by mNTS GLP-1R activation, as a disruption of any one of these signaling pathways is sufficient to attenuate the food intake–suppressive effects produced by hindbrain GLP-1R activation.”

“Following a meal, CCKNTS neurons become activated and relay visceral input from the vagus to brain regions known to mediate changes in feeding (Rinaman, 2010).”

“In contrast to VLM CA neurons, which send heavy projections to the HPA axis and the sympathetic nervous system (Kvetnansky et al., 2009; Moore and Bloom, 1979; Rinaman, 2010), the LC sends intense projections to high cognitive centers such as the hippocampus and the cortex but sends few inputs to the PVN or the spinal…”

“NTS GLP-1producing neurons project directly to the mesolimbic VTA (Rinaman, 2010; Dossat et al., 2011; Alhadeff et al., 2012; Dickson et al., 2012).”

“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript NTS terminals appear relatively dense in the regions surrounding, rather than within the facial nucleus (e.g. Rosin et al., 2006; Rinaman, 2010).”

“One circuit of interest is the GLP-1-producing neurons from the NTS that target the LDTg, VTA, and NAc (Figure 2) (Rinaman, 2010).”

“For example, selective pharmacological antagonism of GLP-1 PHYSIOLOGY • Volume 33 • March 2018 • www.physiologyonline.org 159 receptors (GLP-1R) within the VTA, NAc, or LHA increases food intake (3, 76) and motivation for sucrose reward (243), whereas GLP-1R agonists reduce food palatability and motivation (70).”

“GLP-1 and noradrenergic PrRP neurons comprise only a small subset of all cNTS neurons that are sensitive to visceral sensory feedback, but they collectively provide most neural output from the cNTS to the hypothalamus and limbic forebrain, and are implicated in mediating endocrine and behavioral stress responses (Rina…”

“Vagal afferents synapse on NTS neurons, which, in turn, connect to a network of structures, including the amygdala, paraventricular nucleus (PVN), lateral hypothalamus, and parabrachial nucleus (22, 31, 32).”

“Although the presence of GLP-1 fibers and receptors in the LS was previously documented, this is the first demonstration of a role for this pathway in feeding behavior (10, 23, 29).”

“NTS GLP-1 neurons project throughout the brain to many areas typically considered to play a role in energy homeostasis, including the ARC, PVN, and LH, but these cells also project to nuclei associated with reward and motivation such as the VTA and the NAc [34-37].”

“By contrast, given the very wide distributed expression of GLP-1R throughout the brain [40,41], what is likely to be different across the CNS is the phenotype of neurons that express the GLP-1R.”

“GLP-1- producing neurons of the nucleus of the solitary tract project directly to the VTA and the shell and core regions of the nucleus accumbens (Rinaman, 2010; Alhadeff et al., 2012).”

“Since noradrenergic A2 neurons and GLP1 neurons together provide the bulk of ascending projections from the cNST to higher brain regions (Rinaman 2010; Sawchenko and Swanson 1982), the presence of VGLUT2 immunolabeling in nerve terminals arising from the cNST confirms and extends previous findings…”

“In turn, these meal-sensitive NTS neurons project to additional brainstem sites such as the lateral parabrachial nucleus (lPB), hypothalamic sites such as the PVH, and cortical sites such as the insular cortex (97).”

“…hormonal, and somatic feedback from body to brain, tuning stress responsiveness, and regulating glucose homeostasis and other aspects of energy balance (Zagon et al., 1999; Rinaman, 2003b, 2007, 2010, 2011; Berthoud et al., 2006; Grill and Hayes, 2009, 2012; Grill, 2010; Zhang et al., 2010).”

“…and others http://joe.endocrinology-journals.org © 2017 Society for Endocrinology Printed in Great Britain Published by Bioscientifica Ltd. 235:1 amygdala and the bed nucleus of stria terminalis (BNST), establishing connections between metabolism and eating behaviors (Nestler 2005, Rinaman 2010).”

“, 2016), and food intake/energy expenditure, appetite control by cholecystokinin concerned with NTS-PVH projection (Rinaman, 2010; D’Agostino et al., 2016).”

“In addition to expressing GLP-1Rs ( 10 , 11 ), the VTA also receives direct monosynaptic projections from GLP-1–producing preprogluca-gon (PPG) neurons in the nucleus tractus solitarius (NTS) ( 12 , 13 ).”

“Although activation of GLP-1R sensitive NTS afferents to reward areas including NAc, VTA and LDTg, might provide a possible downstream circuitry for the ability of Ex4-NTS to attenuate alcohol-mediated behaviors, other downstream brain areas should also be considered as potential mediators (Llewellyn-Smith et al., 201…”

“However, the NTS is comprised of heterogeneous cell populations [89, 139, 150] and thus further studies investigating the exact role of each of these populations in cocaine-mediated behaviors must be investigated.”

“, 100 μg/kg BW) dose of CCK [30], and GLP-1 axonal projections target the mpPVN [29, 31, 57], suggesting an additional role for GLP-1 signaling in CCK-induced stimulation of the HPA axis.”

“Consistent with these findings, leptin acts on receptors in the VTA to modulate meso-accumbal dopamine transmission and reduce feeding (Baldo and Kelley, 2007; Fulton et al, 2006; Hommel et al, 2006).”

“Despite the presence of GLP-1 terminals within the anterior BST (Rinaman 2010), the specific contribution of BST GLP-1 signaling to anxiety-like behavior has not been determined.”

“Thus, NST neurons are critically involved in receiving and processing GI satiety signals that terminate ingestive consummatory behaviors, thereby limiting meal size (13).”

“While physiological state information can be relayed to the mesolimbic system directly via hormones, the VTA and NAc also receive extensive neuronal projections from a multitude of neural substrates that are involved in processing homeostatic information.”

“The NTS contains projections to several regions of the brain including the hypothalamus (Berthoud et al., 2004; Rinaman, 2010).”

“Gut sensory information is also transmitted via afferent vagal fibres, terminating in hypothalamic nuclei with orexigenic functions (Rinaman, 2010).”

“…attenuation invovles presynaptic (Hayes et al., 2010; Hisadome et al., 2010; Vrang et al., 2007) GLP-1 receptor dependent connectivity from the NTS to the above mentioned areas participating in AUD development (Alhadeff et al., 2012; Merchenthaler et al., 1999; Reiner et al., 2018; Rinaman, 2010).”

“Besides numerous brainstem territories including the PBN, the projections of the NTS have also been traced to a series of forebrain structures: the bed nucleus of the stria terminalis, the paraventricular, dorsomedial, and arcuate nuclei of the hypothalamus, the central amygdaloid nucleus, and the periventricular nucl…”

“The notion is also consolidated by prior studies demonstrating extensive projections from NTS to the three serially arrayed regions (Geerling and Loewy, 2006; Rinaman, 2010; Alheid et al., 2011), whereas the phenotype of NTS projection neurons remains unknown.”