Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit

Abstract

The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCKNTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCKNTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4RPVH) cells, which are also responsive to CCK. Optogenetic activation of CCKNTS axon terminals within the PVH reveal the satiating function of CCKNTS neurons to be mediated by a CCKNTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCKNTS neurons and reveal a sufficient and discrete NTS to hypothalamus circuit controlling appetite.DOI: http://dx.doi.org/10.7554/eLife.12225.001

A tale of two circuits: CCK NTS neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions

“…Injection of the otherwise inert ligand, clozapine-N-oxide (CNO), was used to activate neurons expressing the DREADD receptor in vivo . Two independent studies have confirmed the ability of CNO to increase the firing rate in CCK NTS neurons expressing hM3Dq using ex vivo electrophysiology (D'Agostino et al, 2016; Roman et al, 2016). After allowing 2 weeks for viral expression of the receptor, animals were food-restricted and injected (i.p) with either saline or CNO (0.8 mg/kg) during the light cycle.…”

“…By manipulating the activity of genetically identified cells within a specific region of the brain in vivo , researchers have uncovered several pathways that are directly involved in an animal’s motivation to eat or not to eat [for reviews see: (Graebner et al, 2015; Krashes and Kravitz, 2014; Sternson and Roth, 2014)]. Recently, we and others have elucidated a role for CCK-expressing neurons in the NTS in the cessation of feeding (D'Agostino et al, 2016; Roman et al, 2016). CCK is a well-studied peptide known for its role in suppressing feeding behavior both peripherally and centrally (Della Fera and Baile, 1979; Moran and Schwartz, 1994; Schick et al, 1990); however, the CCK-producing cells of the NTS have only recently received attention for their role in appetite suppression.…”

“…Two such regions receiving especially dense innervation from CCK NTS neurons are the PBN and PVH. When CCK NTS neurons or their axon terminals in either of these two regions are stimulated, mice eat less, even in energy-depleted states (D'Agostino et al, 2016; Roman et al, 2016). …”

Gut-Brain Cross-Talk in Metabolic Control

“…These then act in a paracrine fashion on their receptors located on the surface of local vagal afferent fibers in the intestine that project to the NTS; these vagal neurons thus convert nutrient-dependent changes in the gut-hormonal milieu into electro-chemical information that is relayed to the NTS (Berthoud and Morrison, 2008). Neurons in the NTS integrate the incoming vagal information with other neuroendocrine signals, including locally synthesized GLP-1 and CCK, such that the magnitude of the incoming responses to the gut-derived signals can be enhanced or suppressed before being relayed from the NTS to other brain areas (Barrera et al, 2011; D’Agostino et al, 2016; Herbert and Saper, 1990; Larsen et al, 1997). Thus, multiple layers of perpetual gut-derived information on nutrient availability and metabolic balance highlights that mammals, including Homo sapiens , have evolved a highly complex metabolic control system.…”

The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

“…IP injection of CCK induces c-fos expression in the brainstem and PVN, where oxytocin neurons are selectively activated [80,81]. Chemogenetic activation of NTS neurons elicit c-fos-positive neurons in the PVN and reduce food intake and BW in mice [82]. Taking these reports into consideration, postprandial secretion of the gut hormone contributes to suppressing appetite by mediating the vagal afferent NTS-PVN oxytocin neurons.…”