Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Australia.
Monash Biomedical Imaging Facility, Monash University, Clayton, Australia.
Elife. 2022 Jan 12;11:e72668. doi: 10.7554/eLife.72668.
Agouti-related peptide (AgRP) neurons increase motivation for food, however, whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase () in mice. We hypothesised that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgPP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 min in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.
阿黑皮素原相关肽（AgRP）神经元会增加对食物的动力，然而，AGRP 神经元对稳态代谢的感知是否通过与多巴胺奖励系统相互作用来增强动力，这一点尚未探索。作为代谢感知受损的模型，我们使用了特异性敲除 AgRP 神经元中的肉碱乙酰转移酶（）的小鼠。我们假设，AGRP 神经元中的代谢感知对于通过调节伏隔核或纹状体多巴胺释放来增加食物奖励的动力是必需的。研究证实，AGRP 神经元中的缺失（KO）损害了离体葡萄糖感应，以及对外周葡萄糖注射或反复美味食物呈现和消耗的体内反应。AGRP 神经元中代谢感知的受损减少了急性多巴胺释放（秒）对美味食物的消耗，以及在操作反应期间，通过核伏隔核中的 GRAB-DA 光度测定法进行评估，但在背纹状体中则不然。AGRP 神经元中代谢感知的受损抑制了放射性标记的 18F-fDOPA 在背纹状体中约 30 分钟后的积累，但在核伏隔核中则不然。AGRP 神经元中代谢感知的受损抑制了饥饿状态下的蔗糖奖励的操作性反应。因此，AGRP 神经元中的代谢感知对于适当的时间整合和将稳态饥饿感知传递到纹状体中的多巴胺信号传递是必需的。
