The dynamic regulation of appetitive behavior through lateral hypothalamic orexin and melanin concentrating hormone expressing cells

Abstract

The lateral hypothalamic area (LHA) is a heterogeneous brain structure extensively studied for its potent role in regulating energy balance. The anatomical and molecular diversity of the LHA permits the orchestration of responses to energy sensing cues from the brain and periphery. Two of the primary cell populations within the LHA associated with integration of this information are Orexin (ORX) and Melanin Concentrating Hormone (MCH). While both of these non-overlapping populations exhibit orexigenic properties, the activities of these two systems support feeding behavior through contrasting mechanisms. We describe the anatomical and functional properties as well as interaction with other neuropeptides and brain reward and hedonic systems. Specific outputs relating to arousal, food seeking, feeding, and metabolism are coordinated through these mechanisms. We then discuss how both the ORX and MCH systems harmonize in a divergent yet overall cooperative manner to orchestrate feeding behavior through transitions between various appetitive states, and thus offer novel insights into LHA allostatic control of appetite.

Figure 1:. LHA MCH and ORX expressing neurons in the LHA.

Fluorescent labelling of MCH (red) and ORX (green) expressing cells indicates that these neurons form discrete but commingled populations in the LHA. Representative image taken at approximately ~1.7m posterior to bregma from a pMCH-cre mouse crossed with a tdTomato reporter line. Immunohistochemistry was employed to label ORX protein (AlexaFlour 488/ green) and amplify the tdTomato signal (AlexaFluor 568/ red). DMH = dorsomedial hypothalamus; fx = fornix; PeF = perifornical area; VMH = ventromedial hypothalamus; ZI = zona incerta.

Figure 2:. LHA ORX and MCH neuronal projections.

(a) ORX cells project within hypothalamic regions including the arcuate nucleus of the hypothalamus. LHA ORX cells innervate hindbrain regions both through direct connections (solid arrows) to the brainstem as well as indirect ventral tegmental area innervation (dashed arrow). These cells also project to forebrain and limbic regions such as the cortex, amygdala, hippocampus, and thalamus. ORX1 and ORX2 specific projection patterns to specific brain regions are denoted with associated labels. (b) MCH cells project within hypothalamic regions including the arcuate nucleus of the hypothalamus. LHA MCH cells project to the brainstem, cortex, bed nucleus of stria terminalis, lateral septum, nucleus accumbens, and limbic structures such as the thalamus and hippocampus (solid arrows) and debated projection to VTA (dashed arrow). Abbreviations: ACB = nucleus accumbens; AMY= amygdala; ARC = arcuate nucleus of the hypothalamus; BNST = bed nucleus of stria terminalis; HIPP = hippocampus; LS= lateral septum; MCH = melanin concentrating hormone; ORX = orexin; ORX1 = orexin1 receptor; ORX2= orexin 2 receptor; THAL = thalamus VTA = ventral tegmental area.

Figure 3.. ORX to MCH transitions mediating the appetitive behavioral sequence from food-seeking to consumption.

ICV infusion of MCH [185, 186] increases feeding, as does stimulation of MCH neurons during consumption. Likewise, infusion [183, 184] or chemogenetic stimulation [188] of ORX increases feeding. Knockout of MCH1-R in mice disrupts overeating in cue-potentiated feeding [196] Similarly, antagonism of the OX1R receptor in rats also disrupts cue-potentiated feeding. High frequency gamma oscillations from the lateral septum have the potential to provide input to both ORX and MCH neurons in the LHA; these high frequency oscillations stimulate MCH neurons while silencing ORX neurons [78]. Low blood glucose stimulates orexin neurons [94, 95, 97, 171]. (5) Orexin neurons display increased activation that coincides with food anticipatory activity [166]. MCH neurons are primarily either unaffected or inhibited by ORX [75], although a small (≈ 30%) subpopulation is excited by ORX [21]. MCH neurons are more active during periods of low activity and their activation supports REM sleep [218]. Stimulation of orexin neurons increases overall arousal, as well as feeding-specific behaviors like foraging and food anticipatory activity [112]. Ghrelin, a hunger signal produced in the gut, excites ORX neurons, but appears to have no effect on MCH neurons [111, 112]. MCH neurons can inhibit orexin neurons and appear to do so especially effectively under increased activation of orexin neurons [77]. MCH may support the continued ingestion of food by enhancing its reward value [200]. ICV infusion of ORX-A increased responding for food reward in a progressive ratio task [172], whereas disruption of ORX signaling through ORX antagonism disrupts operant responding under fasted [170] and free-feeding [172]. Orexin neuron activity peaks in anticipation of food consumption but decreases rapidly once consumption is initiated [199]. MCH neurons are excited by glucose [99, 100]. In the absence of food availability, presentation of a food-paired cue results in ORX, but not MCH, neuron excitation [197]. MCH1-R antagonism disrupts operant responding for a sucrose, but not saccharin reward [219]. Fry and dinner plate illustrations were modified from Smart Servier Medical Art on May 20th, 2020, available online at https://smart.servier.com/category/general-items/food/

Figure 4.. Potential physiological mechanisms underlying ORX to MCH rapid behavioral state transitions for food-seeking and consumption.

(a) Under conditions of hunger, the accompanying low glucose levels stimulates ORX and inhibits MCH. Further, the gastric peptide ghrelin stimulates LHA ORX either indirectly via stimulation of first-order NPY-AGRP neurons in ARC and inhibition of α-MSH and CART signals, or directly via GHSRs in LHA. Increased ghrelin and stimulation of ORX enhances VTA DA, facilitating signaling to ventral striatal ACB MSNs. MCH firing may be inhibited by ORX-dependent increases in GABAergic inhibition and potentially via DA. Finally, lower oscillation frequencies (<10 Hz), ORX cells show a proclivity for stimulation, which could be mediated via LS input. (b) As ORX activity increases, MCH can inhibit LHA ORX in an activity-dependent manner. Increased glucose levels following food consumption further attenuate ORX signaling while heightening activity in LHA MCH cells. The CB1 receptor can also respectively inhibit and excite ORX and MCH cells. This general decrease in ORX activity has the potential to disinhibit MCH cell firing. Activity of MCH leads to increases in reward and hedonic pathways in the brain, such as ACB. Abbreviations: ACB = nucleus accumbens; ARC = arcuate nucleus of the hypothalamus; AGRP = agouti-related peptide; α-MSH = α-melanin-stimulating hormone; CART = cocaine and amphetamine related transcript; CB1 = cannabinoid receptor type 1; DA = dopamine; D1/D2 = dopamine D1-like, D2-like receptors; LS = lateral septum; MCH = melanin concentrating hormone; MSNs = medium spiny neurons; NPY = neuropeptide Y. Solid arrows indicate known excitatory (red) and inhibitory (blue) interactions; dashed red arrows = assumed excitatory (red) and inhibitory (blue) interactions that require further pathway characterization.