Labeled lines for fat and sugar reward combine to promote overeating

Abstract

Food is a powerful natural reinforcer that guides feeding decisions. The vagus nerve conveys internal sensory information from the gut to the brain about nutritional value; however, the cellular and molecular basis of macronutrient-specific reward circuits are poorly understood. Here, we monitor in vivo calcium dynamics to provide direct evidence of independent vagal sensing pathways for detection of dietary fats and sugars. Using activity-dependent genetic capture of nutrient-specific vagal neurons activated in response gut infusions, we demonstrate the existence of separate hard-wired reward circuits for fat and sugar that are necessary and sufficient for nutrient-specific reinforcement. Even after controlling for calories, combined activation of fat and sugar circuits increases dorsal striatal dopamine levels and overeating compared to fat or sugar alone. This work provides new insight on the complex sensory circuitry that mediates motivated behavior and suggests that a subconscious internal drive to consume obesogenic diets (e.g., those high in both fat and sugar) may impede conscious dieting efforts.

High sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight

“…In accordance, we found that SucrW 12Wk feeding increased AgRP neuronal activity and caloric intake without significantly altering bodyweight or body composition. These changes in neuronal firing mirror HFDinduced changes to AgRP neuronal firing rate in DIO mice [24,31], though to a lesser extent, likely driven by functional differences in fat-and sugar-sensitive afferents to the hypothalamus and AgRP neurons [33][34][35]77] or even disparate circuitries for hedonic and nutritional sugar preference [40]. Interestingly, fasting failed to further increase the F AP of AgRP neurons suggesting that (1) AgRP neurons are refractory to additional relevant stimuli, or (2) this rate represents a ceiling beyond which AgRP neurons are not able to sustain action potential firing.…”

Separate orexigenic hippocampal ensembles shape dietary choice by enhancing contextual memory and motivation

“…Dietary preferences are largely learned 69 and this process involves reward-based associations. 46, 52, 69, 70 In light of the increased preference for nutrients caused by dHPC neurons (Fig 2), we hypothesize that these neurons are involved in reinforcement learning. To address this, we assessed the role of nutrient-responsive dHPC neurons in a flavor-nutrient conditioning task, in which animals are trained to prefer a novel non-nutritive flavor that has been experimentally paired to an intragastric infusion of nutrient (Fig 4A).…”

“…46 Thus, we inquired whether separate populations of dHPC neurons are recruited in response to fat and sugar. We used a Fos TRAP mouse 51 with a previously validated approach 46 to compare neuronal activity in response to two separate nutrient infusions in the same mouse (Fig 1K). These mice express an inducible Cre recombinase, iCreER T2 , under the control of an activity-dependent Fos promoter ( Fos TRAP mice), enabling permanent genetic access to neuronal populations based on their activation to a specific, time-restricted stimulus.…”

“…Prior work from our lab provides evidence that fats and sugars are sensed by two separate populations of vagal sensory neurons. 46 Notably, the deletion of these separate vagal populations was shown to impair learned preferences in a nutrient-specific manner. 46 Furthermore, segregated cellular responses to fats or sugars in central reward circuits downstream of vagal sensory neurons were observed, 46 suggesting the existence of separate hardwired signaling mechanisms for different nutrient reward.…”

“…Subsets of vagal sensory neurons in the nodose ganglia (NG) are activated in response to intestinal nutrients, and these NG neurons are necessary to mediate the reinforcing value of fat and sugar. 46 Although vagal sensory fibers terminate in the nucleus tractus solitarius (NTS) of the hindbrain, there is evidence of a polysynaptic circuit connecting the gut via the NTS to the HPC. 47 Furthermore, vagal stimulation increases HPC activity in mice 48 and in humans 49 while deletion of gut-innervating vagal sensory neurons impairs HPC-dependent contextual episodic memory.…”