Frontiers in Integrative Neuroscience (Jul 2014)
Flavor vs Energy Sensing in Brain Reward Circuits
Abstract
Sweetness functions as a potent natural reinforcer in several species, from flies to rodents to primates including humans. The appreciation of flavored stimuli is greatly enhanced when sweetness is added, the obvious example being sugar-sweetened flavored beverages (the major source of excess added calories in US diets). Different sweet substances are nevertheless attributed greater incentive value than others, with glucose-containing sugars appearing as the uppermost sweet reward. Food choices are indeed prominently determined by nutritional value, with caloric content being highly predictive of both preference and intake. Specifically, for most species studied, glucose-containing sugars are known to exert exquisitely strong effects on food choice via post-ingestive signals. Despite the relevance of the issue to public health, the identity of the physiological signals underlying glucose’s rewarding effects remains incompletely understood. Recently, however, some progress has been achieved in this front: the concept is emerging that the metabolic utilization of glucose moieties contained in sugars drives activity in brain reward circuitries (thereby presumably driving robust intake). Specifically, disruption of glucose utilization in mice was shown to produce an enduring inhibitory effect on artificial (non-nutritive) sweetener intake, an effect that did not depend on sweetness perception or aversion [1]. Indeed, such an effect was not observed in mice presented with a less palatable, yet caloric, glucose solution. It is also remarkable that hungry mice shift their preferences away from artificial sweeteners in favor of glucose solutions, especially when the sugar is experienced in a food-depleted state. However, the most striking effect associated with sweet appetite appears to be the strong selectivity of certain brain circuitries to the energy content of the solutions, irrespective of sweetness per se. Indeed, it has been shown that glucose intake produces significantly greater levels of dopamine efflux compared to artificial sweetener intake in dorsal striatum, whereas disrupting glucose oxidation suppresses dorsal striatum dopamine efflux; conversely, inhibiting striatal dopamine receptor signalling during glucose intake in sweet-naïve animals resulted in reduced, artificial sweetener-like intake of glucose during subsequent glucoprivation [1]. This is consistent with data using physiological preparations demonstrating that intravenous administration of the glucose anti-metabolite 2-deoxy-D-glucose robustly suppresses dopamine efflux in dorsal striatum, an effect annulled by subsequent infusions of glucose via the same route [2]. Of note is the fact that the same study demonstrates that glucose utilization rates control both nutrient choice in tasteless mutant mice. Overall, these results point to the notion that glucose oxidation controls intake levels of sweet tastants by regulating the midbrain dopaminergic nigro-striatal pathway, and suggest that glucose utilization is one critical physiological signal involved in the control of goal-directed sweetener intake [1]. It is equally striking, on the other hand, that the other major midbrain dopaminergic system, the mesolimbic pathway, is considerably less selective in their responses to sweeteners: sweetness and energy appear to independently stimulate dopamine release into the nucleus accumbens of ventral striatum, in the absence of any apparent additive effects; in fact, while artificial sweeteners cause dopamine to be released in ventral striatum of wild-type mice, sugar (bot not sweeteners) induces similar effluxes in ventral striatum of tasteless mutant mice [3]. Such nigro-striatal selectivity to energy-containing sweeteners may have a deeper behavioral meaning: dopamine release into dorsal striatum is not only critical for motivation to eat [4], but also for the formation of compulsive behavioral habits (whereas the nucleus accumbens seem to play a much lesser role in inflexible behavioral actions, [5]). Thus, our findings suggest that sugar metabolism is a critical signal involved in the formation of behavioral habits linked to sugar overconsumption. The observations above bring about the problem of which physiological signaling pathways may link peripheral glucose sensors to dopaminergic neurons. Our more recent experiments indicate that glucose infusions into the portal vein are sufficient to induce robust dopamine release into dorsal striatum. This suggests that hepatoportal glucose sensors, known to regulate a number of physiological functions including enhancement of glucose utilization [6], may directly influence dopaminergic activity via the modulation of glucose utilization rates. It is also of note that neither glucose-induced flavor preferences [7] nor portal glucose-induced Fos activity in forebrain [8] seem to depend on vagal afferents; this brings to light a potentially critical role for spinal afferents innervating the hepatoportal system in linking peripheral glucose sensing to brain reward circuits [8]. These findings obviously do not rule out a potential role for brain glucosensing in linking glucose ingestion to dopaminergic activity: Early studies show that hindbrain catecholamine neurons detect glucose deficits [9] and may influence dopamine cells directly. Potentially important may be the activity of KATP ion channels expressed on neurons sending afferents to midbrain dopamine cells [10], not to mention the possibility that Substantia nigra compacta cells may sense glucose directly [11]. Finally, it is intriguing that sugar metabolism seems to control nutrient reinforcement in invertebrate species including Drosophila, since tasteless mutant flies were shown to develop preferences for metabolizable sugars but not for their non-metabolizable analogues (Burke & Waddell 2011; Dus et al. 2011). It thus appears that the metabolic control of sugar reward is a highly conserved mechanism whose manifestation ranges from flies to rodents and to humans. Future research must determine the molecular and circuit bases for the existence of a sugar-monitoring system at the service of mammal reward neural pathways.
Keywords
