nutrients Review Central Neurocircuits Regulating Food Intake in Response to Gut Inputs—Preclinical Evidence Kirsteen N. Browning * and Kaitlin E. Carson Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-717-531-8267 Abstract: The regulation of energy balance requires the complex integration of homeostatic and hedonic pathways, but sensory inputs from the gastrointestinal (GI) tract are increasingly recognized as playing critical roles. The stomach and small intestine relay sensory information to the central nervous system (CNS) via the sensory afferent vagus nerve. This vast volume of complex sensory information is received by neurons of the nucleus of the tractus solitarius (NTS) and is integrated with responses to circulating factors as well as descending inputs from the brainstem, midbrain, and forebrain nuclei involved in autonomic regulation. The integrated signal is relayed to the adjacent dorsal motor nucleus of the vagus (DMV), which supplies the motor output response via the efferent vagus nerve to regulate and modulate gastric motility, tone, secretion, and emptying, as well as intestinal motility and transit; the precise coordination of these responses is essential for the control of meal size, meal termination, and nutrient absorption. The interconnectivity of the NTS implies that many other CNS areas are capable of modulating vagal efferent output, emphasized by the many CNS disorders associated with dysregulated GI functions including feeding. This review will summarize the role of major CNS centers to gut-related inputs in the regulation of gastric function Citation: Browning, K.N.; Carson, with specific reference to the regulation of food intake. K.E. Central Neurocircuits Regulating Food Intake in Response to Gut Keywords: brainstem; vagus; feeding; gastrointestinal Inputs—Preclinical Evidence. Nutrients 2021, 13, 908. https:// doi.org/10.3390/nu13030908 1. Introduction Academic Editor: Christine Feinle-Bisset Sensory information from the gastrointestinal (GI) tract is relayed centrally via neural and humoral pathways; the central nervous system (CNS) integrates this large volume Received: 23 January 2021 of sensory afferent information and coordinates a precise series of efferent responses to Accepted: 7 March 2021 regulate food and caloric intake including the modulation of gastric motility, tone, and Published: 11 March 2021 emptying, as well as intestinal motility, transit, secretion and absorption. This efferent output is regulated meticulously in order to maintain homeostasis based on current energy Publisher’s Note: MDPI stays neutral needs and visceral sensory stimuli. The advent of novel and emerging molecular and with regard to jurisdictional claims in genetic labeling techniques implies that, as a field, we are in a better position to be able to published maps and institutional affil- potentially delineate the exact phenotype of neurons involved in distinct aspects of nutrient iations. signaling, and to interrogate and manipulate those neurocircuits with spatial and temporal precision. Characterizing the central neurocircuits involved following activation of gut inputs, including their phenotypes, activation characteristics, and connectomes, will be important to understand the physiology and pathophysiology of food intake. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. 1.1. Afferent Inputs This article is an open access article GI sensory information is relayed centrally via both vagal and spinal afferents. Spinal distributed under the terms and afferents, particularly those within the splanchnic nerves, relay low- or high-threshold conditions of the Creative Commons mechanical and chemical information centrally and are considered primarily to be involved Attribution (CC BY) license (https:// in nociceptive processing [1,2]. In contrast, the majority of interoceptive information is creativecommons.org/licenses/by/ relayed centrally via vagal afferents, the cell bodies of which reside in the nodose and 4.0/). Nutrients 2021, 13, 908. https://doi.org/10.3390/nu13030908 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, x FOR PEER REVIEW 2 of 19 Nutrients 2021, 13, 908 2 of 18 volved in nociceptive processing [1,2]. In contrast, the majority of interoceptive infor- mation is relayed centrally via vagal afferents, the cell bodies of which reside in the nodose and jugular ganglion. The central terminals of most of the gastrointestinal vagal afferents terminatejugular ganglion. within the The brainstem central terminalsat the level of of most the nucleus of the gastrointestinal tractus solitarus vagal (NTS), afferents with a minorityterminate of within terminals the brainstemfound in the at thearea level post ofrema the nucleus(AP), the tractus dorsal solitarus motor nucleus (NTS), withof the a vagusminority (DMV), of terminals and the foundtrigeminal in the islands area postrema [3]. Vagal (AP), afferent the dorsal signaling motor is critical nucleus for of the the regulationvagus (DMV), of food and intake the trigeminal and selective islands surgical [3]. denervation Vagal afferent of GI signaling vagal afferents is critical has for been the shownregulation to increase of food intakemeal size and and selective blunt surgical the response denervation to peripheral of GI vagal administration afferents has of been GI peptidesshown to implicating increase meal vagal size afferent and blunt signaling the response in the regulation to peripheral of food administration intake [4] (Figure of GI 1).peptides implicating vagal afferent signaling in the regulation of food intake [4] (Figure1). FigureFigure 1. 1. SchematicSchematic representation representation of of the the neuroanatomi neuroanatomicalcal connections connections between between the the gastrointestinal gastrointestinal (GI)(GI) tract tract and and brainstem brainstem vagal vagal nuclei nuclei involved involved in in the the regulation regulation of of food food intake. intake. Sensory Sensory information information fromfrom the the GI GI tract tract is isrelayed relayed centrally centrally via via the theaffe afferentrent vagus vagus which which responds responds both bothdirectly directly (via neu- (via ropods)neuropods) and andindirectly indirectly (via (viaparacrine paracrine signaling) signaling) to gastrointestinal to gastrointestinal stimulation. stimulation. At the At level the level of the of dorsalthe dorsal hindbrain, hindbrain, afferent afferent vagal vagal inputs inputs enter enterthe brainstem the brainstem via the via tractus the tractus solitarius solitarius (TS) and (TS) termi- and nate on neurons of the nucleus of the tractus solitarius (NTS). The integrated signal is relayed from terminate on neurons of the nucleus of the tractus solitarius (NTS). The integrated signal is relayed the NTS to the adjacent dorsal motor nucleus of the vagus (DMV) via catecholaminergic, glutama- from the NTS to the adjacent dorsal motor nucleus of the vagus (DMV) via catecholaminergic, tergic, and predominantly gamma aminobutyric acid (GABA)-ergic, synapses. The DMV contains preganglionicglutamatergic, parasympathetic and predominantly motoneurons gamma aminobutyric that relayed the acid resulting (GABA)-ergic, output signal synapses. to the The GI DMVtract viacontains the efferent preganglionic motor vagus. parasympathetic EEC—enteroendocrine motoneurons cells; that CC—central relayed the resulting canal. output signal to the GI tract via the efferent motor vagus. EEC—enteroendocrine cells; CC—central canal. Gastric vagal afferents can be distinguished on the basis of their preferred response Gastric vagal afferents can be distinguished on the basis of their preferred response modality; mechanosensitive afferents, for example, innervate the GI smooth muscle and modality; mechanosensitive afferents, for example, innervate the GI smooth muscle and are activated by distention and stretch in response to food ingestion (reviewed in [5]). are activated by distention and stretch in response to food ingestion (reviewed in [5]). Recent studies have also shown that these tension-sensitive afferents can be further dis- Recent studies have also shown that these tension-sensitive afferents can be further distin- tinguished based upon their neurochemical phenotype, with glucagon-like peptide 1 re- guished based upon their neurochemical phenotype, with glucagon-like peptide 1 receptor ceptor (GLP-1R) positive afferents innervating the stomach and oxytocin (OXT) positive (GLP-1R) positive afferents innervating the stomach and oxytocin (OXT) positive afferents afferents innervating the intestine [6]. Their distinct neurochemical phenotypes allow for innervating the intestine [6]. Their distinct neurochemical phenotypes allow for selective selective experimental manipulation; optogenetic stimulation of these mechanosensitive experimental manipulation; optogenetic stimulation of these mechanosensitive afferents, afferents,for example, for example, mimics central mimics responses central response to gastrics stretch,to gastric including stretch, including the activation the activation of distinct ofNTS distinct populations NTS population and reduceds and food reduced intake. food intake. Mucosal afferents, in contrast, innervate the mucosal layer but do not make direct con- tact with the GI lumen. They are responsive to mucosal stroking and chemosensation and may play a role in the detection