Energy homeostasis and motivated behaviors are coordinated by peripheral metabolic signals and central reward circuitry. Circulating triglycerides (TG) have been implicated as neuromodulators of mesolimbic dopamine function and reward processing. The authors sought to determine whether central TG availability directly shapes the in vivo activity of nucleus accumbens (NAc) dopamine D2 receptor-expressing spiny projection neurons (D2R-SPNs) during appetitive behaviors, and whether effects depend on dietary history or current metabolic state.
To monitor activity of identified D2R-SPNs in behaving animals, the study used in vivo fiber photometry in Drd2-Cre mice. Calcium dynamics of D2R-SPNs were recorded across two behavioral contexts reported in the source: appetitive Pavlovian conditioning with a reward-predictive conditioned stimulus (CS+), and refeeding after fasting. Central TG levels were acutely elevated by carotid infusion to assess direct central effects of circulating lipids. Comparisons were made between lean chow-fed mice and mice exposed to a high-fat diet (HFD), and across feeding states (fed, food-restricted or fasted) to evaluate metabolic state dependence.
During Pavlovian conditioning, D2R-SPNs progressively developed robust neural responses to the reward-predictive cue (CS+) over the course of learning. In contrast to cue-evoked activity, the neuronal activity associated with reward consumption remained stable throughout the learning sessions. These observations indicate that D2R-SPNs in the NAc selectively increased encoding of predictive cues during appetitive learning while maintaining consistent responses during consumption.
Acute elevation of central TG levels via carotid infusion did not alter D2R-SPN activity or behavioral performance in lean chow-fed mice. This lack of effect was observed irrespective of whether the chow-fed animals were in a fed or food-restricted state. Thus, in animals without an obesogenic dietary history, increasing central TG availability acutely did not modulate D2R-SPN calcium signals during the tested appetitive paradigms nor did it change the measured behavioral outputs reported by the authors.
In animals previously exposed to a high-fat diet (HFD), the influence of central TG differed from chow-fed mice and depended on the current metabolic state. Specifically, carotid infusion of TG suppressed cue-evoked D2R-SPN activity in food-restricted HFD mice. Importantly, this suppression of cue-evoked neural responses occurred without detectable changes in reward consumption or the behavioral outputs reported in the experiments. These findings indicate that obesogenic dietary history can unmask a sensitivity of accumbal D2R-SPNs to circulating lipids that is contingent on the animal's metabolic state.
Consistent with the cue-evoked findings, TG infusion significantly reduced refeeding-evoked activation of D2R-SPNs in fasted mice that had been exposed to HFD. By contrast, neuronal responses evoked by novelty were not affected by central TG delivery. Together, these results suggest that TG modulation of D2R-SPN activity is selective for certain reward-related stimuli (predictive cues and refeeding) and spares other stimulus-driven responses such as novelty in the paradigms described.
The data summarized in the source support a model in which circulating lipids act as context-dependent modulators of identified accumbal neurons. Obesogenic dietary exposure (HFD) interacts with the animal's immediate metabolic state (food-restricted or fasted) to reveal a sensitivity of D2R-SPNs to central TG. This interaction reshapes how predictive cues and feeding-related events are encoded at the level of D2R-expressing projection neurons in the NAc, while leaving consummatory behavior measurements and novelty responses largely unaffected in the reported experiments.
This work is presented as a preprint and has not been peer-reviewed. The summary above reports findings and experimental design elements as described in the source. Specific methodological details, quantitative measurements, statistical outcomes, sample sizes, and additional experimental controls were not detailed in the abstract-level content provided here; readers should consult the full preprint and supplementary material for complete experimental parameters and full data reporting.