Dopamine neuron activity evoked by sucrose and sucrose-predictive cues is augmented by peripheral and central manipulations of glucose availability.

Food deprivation drives eating through multiple signals and circuits. Decreased glucose availability (i.e., cytoglucopenia) drives eating and also increases the value of sucrose. Ventral tegmental area (VTA) dopamine neurons (DANs) contribute to the evaluation of taste stimuli, but their role in integrating glucoprivic signals remains unknown. We monitored VTA DAN activity via Cre-dependent expression of a calcium indicator with in vivo fibre photometry. In ad libitum fed rats, intraoral sucrose evoked a phasic increase in DAN activity. To manipulate glucose availability, we administered (intraperitoneal, lateral or fourth ventricular) the antiglycolytic agent 5-thio-D-glucose (5TG), which significantly augmented the phasic DAN activity to sucrose. 5TG failed to alter DAN activity to water or saccharin, suggesting the response was selective for caloric stimuli. 5TG enhancement of sucrose-evoked DAN activity was stronger after fourth ventricular administration, suggesting a critical node of action within the hindbrain. As 5TG also increases blood glucose, in a separate study, we used peripheral insulin, which stimulates eating, to decrease blood glucose-which was associated with increased DAN activity to intraoral sucrose. DAN activity developed to a cue predictive of intraoral sucrose. While 5TG augmented cue-evoked DAN activity, its action was most potent when delivered to the lateral ventricle. Together, the studies point to central glucose availability as a key modulator of phasic DAN activity to food and food-cues. As glucose sensing neurons are known to populate the hypothalamus and brainstem, results suggest differential modulation of cue-evoked and sucrose-evoked DAN activity.

Thirst recruits phasic dopamine signaling through subfornical organ neurons.

Thirst is a highly potent drive that motivates organisms to seek out and consume balance-restoring stimuli. The detection of dehydration is well understood and involves signals of peripheral origin and the sampling of internal milieu by first order homeostatic neurons within the lamina terminalis-particularly glutamatergic neurons of the subfornical organ expressing CaMKIIa (SFOCaMKIIa). However, it remains unknown whether mesolimbic dopamine pathways that are critical for motivation and reinforcement integrate information from these "early" dehydration signals. We used in vivo fiber photometry in the ventral tegmental area and measured phasic dopamine responses to a water-predictive cue. Thirst, but not hunger, potentiated the phasic dopamine response to the water cue. In euvolemic rats, the dipsogenic hormone angiotensin II, but not the orexigenic hormone ghrelin, potentiated the dopamine response similarly to that observed in water-deprived rats. Chemogenetic manipulations of SFOCaMKIIa revealed bidirectional control of phasic dopamine signaling during cued water reward. Taking advantage of within-subject designs, we found predictive relationships between changes in cue-evoked dopamine response and changes in behavioral responses-supporting a role for dopamine in motivation induced by homeostatic need. Collectively, we reveal a putative mechanism for the invigoration of goal-directed behavior: internal milieu communicates to first order, need state-selective circuits to potentiate the mesolimbic dopamine system's response to cues predictive of restorative stimuli.