Lesion of NPY Receptor-expressing Neurons in Perifornical Lateral Hypothalamus Attenuates Glucoprivic Feeding.

Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain.

CCK-sensitive C fibers activate NTS leptin receptor-expressing neurons via NMDA receptors.

The hormone leptin reduces food intake through actions in the peripheral and central nervous systems, including in the hindbrain nucleus of the solitary tract (NTS). The NTS receives viscerosensory information via vagal afferents, including information from the gastrointestinal tract, which is then relayed to other central nervous system (CNS) sites critical for control of food intake. Leptin receptors (lepRs) are expressed by a subpopulation of NTS neurons, and knockdown of these receptors increases both food intake and body weight.

Chemogenetic activation of ventral medullary astrocytes enhances feeding and corticosterone release in response to mild glucoprivation.

To investigate the role of glial cells in the regulation of glucoprivic responses in rats, a chemogenetic approach was used to activate astrocytes neighboring catecholamine (CA) neurons in the ventromedial medulla (VLM) where A1 and C1 CA cell groups overlap (A1/C1). Previous results indicate that activation of CA neurons in this region is necessary and sufficient for feeding and corticosterone release in response to glucoprivation. However, it is not known whether astrocyte neighbors of CA neurons contribute to glucoregulatory responses.

Linking drug and food addiction via compulsive appetite.

Background And Purpose: 'Food addiction' is the subject of intense public and research interest. However, this nosology based on neurobehavioural similarities among obese individuals, patients with eating disorders and those with substance use disorders (drug addiction) remains controversial. We thus sought to determine which aspects of disordered eating are causally linked to preclinical models of drug addiction.

Leptin Sensitizes NTS Neurons to Vagal Input by Increasing Postsynaptic NMDA Receptor Currents.

Leptin signaling within the nucleus of the solitary tract (NTS) contributes to the control of food intake, and injections of leptin into the NTS reduce meal size and increase the efficacy of vagus-mediated satiation signals. Leptin receptors (LepRs) are expressed by vagal afferents as well as by a population of NTS neurons. However, the electrophysiological properties of LepR-expressing NTS neurons have not been well characterized, and it is unclear how leptin might act on these neurons to reduce food intake.

NPY2 receptor activation in the dorsal vagal complex increases food intake and attenuates CCK-induced satiation in male rats.

Neuropeptide Y (NPY), peptide YY (PYY), and their cognate receptors (YR) are expressed by subpopulations of central and peripheral nervous system neurons. Intracerebroventricular injections of NPY or PYY increase food intake, and intrahypothalamic NPY1 or NPY5 receptor agonist injections also increase food intake. In contrast, injection of PYY in the periphery reduces food intake, apparently by activating peripheral Y2R.

NMDA-type glutamate receptors participate in reduction of food intake following hindbrain melanocortin receptor activation.

Hindbrain injection of a melanocortin-3/4 receptor agonist, MTII, reduces food intake primarily by reducing meal size. Our previously reported results indicate that N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the nucleus of the solitary tract (NTS) play an important role in the control of meal size and food intake. Therefore, we hypothesized that activation of NTS NMDARs contribute to reduction of food intake in response to fourth ventricle or NTS injection of MTII.

Frequency-dependent facilitation of synaptic throughput via postsynaptic NMDA receptors in the nucleus of the solitary tract.

Hindbrain NMDA receptors play important roles in reflexive and behavioural responses to vagal activation. NMDA receptors have also been shown to contribute to the synaptic responses of neurons in the nucleus of the solitary tract (NTS), but their exact role remains unclear. In this study we used whole cell patch-clamping techniques in rat horizontal brain slice to investigate the role of NMDA receptors in the fidelity of transmission across solitary tract afferent-NTS neuron synapses.

Central vagal afferent endings mediate reduction of food intake by melanocortin-3/4 receptor agonist.

Injection of the melanocortin-3/4 receptor agonist melanotan-II (MTII) into the nucleus of the solitary tract (NTS) produces rapid and sustained reduction of food intake. Melanocortin-4 receptors (MC4Rs) are expressed by vagal afferent endings in the NTS, but it is not known whether these endings participate in MTII-induced reduction of food intake. In experiments described here, we evaluated the contribution of central vagal afferent endings in MTII-induced reduction of food intake.

Vagal afferent NMDA receptors modulate CCK-induced reduction of food intake through synapsin I phosphorylation in adult male rats.

Vagal afferent nerve fibers transmit gastrointestinal satiation signals to the brain via synapses in the nucleus of the solitary tract (NTS). Despite their pivotal role in energy homeostasis, little is known about the cellular mechanisms enabling fleeting synaptic events at vagal sensory endings to sustain behavioral changes lasting minutes to hours. Previous reports suggest that the reduction of food intake by the satiation peptide, cholecystokinin (CCK), requires activation of N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the NTS, with subsequent phosphorylation of ERK1/2 (pERK1/2) in NTS vagal afferent terminals.

CCK-induced reduction of food intake and hindbrain MAPK signaling are mediated by NMDA receptor activation.

The dorsal vagal complex of the hindbrain, including the nucleus of the solitary tract (NTS), receives neural and humoral afferents that contribute to the process of satiation. The gut peptide, cholecystokinin (CCK), promotes satiation by activating gastrointestinal vagal afferents that synapse in the NTS. Previously, we demonstrated that hindbrain administration of N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonists attenuate reduction of food intake after ip CCK-8 injection, indicating that these receptors play a necessary role in control of food intake by CCK.

Circulating GLP-1 and CCK-8 reduce food intake by capsaicin-insensitive, nonvagal mechanisms.

Previous reports suggest that glucagon-like peptide (GLP-1), a peptide secreted from the distal small intestine, is an endocrine satiation signal. Nevertheless, there are conflicting reports regarding the site where circulating GLP-1 acts to reduce food intake. To test the hypothesis that vagal afferents are necessary for reduction of food intake by circulating GLP-1, we measured intake of 15% sucrose during intravenous GLP-1 infusion in intact, vagotomized, and capsaicin-treated rats.

Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors.

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed.

A tale of two endings: modulation of satiation by NMDA receptors on or near central and peripheral vagal afferent terminals.

Glutamate is the neurotransmitter responsible for fast excitatory transmission from vagal afferents to second order neurons in the NTS. Antagonism of NMDA-type glutamate receptors in the NTS increases food intake and attenuates reduction of food intake by vagally mediated satiation signals, such as cholecystokinin. Although, the cellular location(s) of NMDA receptors that participate in satiation is uncertain, recent findings suggest that attenuation of satiation by NMDA receptor antagonists is due, at least in part, to their action on primary vagal afferents themselves.

Increased hypothalamic signal transducer and activator of transcription 3 phosphorylation after hindbrain leptin injection.

Reduction of food intake and body weight by leptin is attributed largely to its action in the hypothalamus. However, the signaling splice variant of the leptin receptor, LRb, also is expressed in the hindbrain, and leptin injections into the fourth cerebral ventricle or dorsal vagal complex are associated with reductions of feeding and body weight comparable to those induced by forebrain leptin administration. Although these observations suggest direct hindbrain action of leptin on feeding and body weight, the possibility that hindbrain leptin administration also activates the Janus kinase/signal transducer and activator of transcription 3 (STAT3) signaling in the hypothalamus has not been investigated.

Blockade of hindbrain NMDA receptors containing NR2 subunits increases sucrose intake.

We have previously shown that blockade of N-methyl-d-aspartate (NMDA) receptors in the caudal brain stem delays satiation and increases food intake. NMDA receptors are heterodimers made up of distinct, but different, ion channel subunits. The NR2 subunits of the NMDA receptor contain the binding site for glutamate.

Vagal afferent neurons projecting to the stomach and small intestine exhibit multiple N-methyl-D-aspartate receptor subunit phenotypes.

Previous reports suggest that NMDA receptors participate in control of food intake via vagal afferent neurons that innervate the upper gastrointestinal (GI) tract. While messenger RNA coding for the NR1 NMDA receptor subunit is present in a majority of vagal afferent neurons of nodose ganglia (NG), immunoreactivity for other NMDA receptor subunits (NR2B, NR2C and NR2D) are expressed in more limited subpopulations of vagal afferents. To determine whether vagal afferent neurons that project to the stomach or duodenum exhibit distinct NMDA receptor subunit phenotypes, we examined immunoreactivity (IR) for NMDA receptor NR1, NR2B, NR2C and NR2D subunits in NG neurons that were labeled by injections of the retrograde tracer Fast Blue (FB) into the wall of the stomach or duodenum.

Modulation of vagal afferent excitation and reduction of food intake by leptin and cholecystokinin.

The gut-peptide, cholecystokinin (CCK), reduces food intake by acting at CCK-1 receptors on vagal afferent neurons, whereas the feeding effects of the adipokine hormone, leptin, are associated primarily with its action on receptors (ObRb) in the hypothalamus. Recently, however, ObRb mRNA has been reported in vagal afferent neurons, some of which also express CCK-1 receptor, suggesting that leptin, alone or in cooperation with CCK, might activate vagal afferent neurons, and influence food intake via a vagal route. To evaluate these possibilities we have been examining the cellular and behavioral effects of leptin and CCK on vagal afferent neurons.

N-methyl-D-aspartate receptor subunit phenotypes of vagal afferent neurons in nodose ganglia of the rat.

Most vagal afferent neurons in rat nodose ganglia express mRNA coding for the NR1 subunit of the heteromeric N-methyl-D-aspartate (NMDA) receptor ion channel. NMDA receptor subunit immunoreactivity has been detected on axon terminals of vagal afferents in the dorsal hindbrain, suggesting a role for presynaptic NMDA receptors in viscerosensory function. Although NMDA receptor subunits (NR1, NR2B, NR2C, and NR2D) have been linked to distinct neuronal populations in the brain, the NMDA receptor subunit phenotype of vagal afferent neurons has not been determined.

Cholecystokinin1 receptors mediate the increase in Fos-like immunoreactivity in the rat myenteric plexus following intestinal oleate infusion.

Intestinal infusion of nutrients, such as glucose and oleic acid, increase Fos-like immunoreactivity (Fos-LI) in both the enteric nervous system and neurons of the dorsal vagal complex (DVC) of the hindbrain. To test the hypothesis that increased Fos-LI in enteric neurons and the DVC, following intestinal nutrient infusions is mediated by cholecystokinin(1) receptors (CCK(1)), we counted enteric and DVC neurons that expressed Fos-LI following intestinal infusion of oleate or glucose, with and without pretreatment with the CCK(1) receptor antagonist, lorglumide. Both oleate and glucose infusions increased Fos-LI in the DVC.

Reduced CCK-induced Fos expression in the hindbrain, nodose ganglia, and enteric neurons of rats lacking CCK-1 receptors.

Many of the actions of cholecystokinin (CCK) are mediated by CCK-1 receptors, expressed by enteric and vagal afferent neurons. Otsuka Long-Evans Tokushima Fatty rats (OLETF) do not express CCK-1 receptors, and do not exhibit the vagally mediated responses to CCK. To determine whether the OLETF rat's failure to respond to CCK is correlated with failure of CCK to activate enteric and vagal neurons, we quantified neuronal Fos immunoreactivity in the dorsal vagal complex of the hindbrain, the nodose ganglia, and the ganglia of the myenteric and submucosal plexuses of the duodenum following intraperitoneal injection of CCK-8 (20 microg/kg).

Intestinal infusions of oleate and glucose activate distinct enteric neurons in the rat.

Nutrients entering the small intestine trigger a variety of neural and endocrine reflexes that involve specific afferents, efferents and interneurons, many of which are located within the enteric nervous system (ENS). We hypothesized that intestinal nutrient stimuli might activate specific subpopulations of these neurons. To test this hypothesis, we utilized immunohistochemical detection of nuclear c-fos expression in the myenteric and submucosal plexuses of the rat small intestine following intraintestinal infusions of oleate or glucose.

Gastrointestinal mechanisms of satiation for food.

Satiation for food comprises the physiological processes that result in the termination of eating. Satiation is evoked by physical and chemical qualities of ingested food, which trigger afferent signals to the brain from multiple sites in the GI tract, including the stomach, the proximal small intestine, the distal small intestine and the colon. The physiological nature of each signal's contribution to satiation and overall control of food intake is likely to vary, depending on the level of the GI tract from which the signal arises.