Brain Center, Department of Translational Neuroscience, University Medical Center Utrecht and University Utrecht, the Netherlands.
Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Biol Psychiatry. 2021 Dec 15;90(12):843-852. doi: 10.1016/j.biopsych.2021.02.017. Epub 2021 Feb 23.
Leptin reduces the motivation to obtain food by modulating activity of the mesolimbic dopamine (DA) system upon presentation of cues that predict a food reward. Although leptin directly reduces the activity of ventral tegmental area (VTA) DA neurons, the majority of leptin receptor (LepR)-expressing DA neurons do not project to the nucleus accumbens, the projection implicated in driving food reward seeking. Therefore, the precise locus of leptin action to modulate motivation for a food reward is unresolved.
We used transgenic mice expressing Cre recombinase under the control of the LepR promoter, anatomical tracing, optogenetics-assisted patch-clamp electrophysiology, in vivo optogenetics with fiber photometric calcium measurements, and chemogenetics to unravel how leptin-targeted neurocircuitry inhibits food reward seeking.
A large number of DA neurons projecting to the nucleus accumbens are innervated by local VTA LepR-expressing GABA (gamma-aminobutyric acid) neurons. Leptin enhances the activity of these GABA neurons and thereby inhibits nucleus accumbens-projecting DA neurons. In addition, we find that lateral hypothalamic LepR-expressing neurons projecting to the VTA are inhibited by leptin and that these neurons modulate DA neurons indirectly via inhibition of VTA GABA neurons. In accordance with such a disinhibitory function, optogenetically stimulating lateral hypothalamic LepR projections to the VTA potently activates DA neurons in vivo. Moreover, we found that chemogenetic activation of lateral hypothalamic LepR neurons increases the motivation to obtain a food reward only when mice are in a positive energy balance.
We identify neurocircuitry through which leptin targets multiple inputs to the DA system to reduce food reward seeking.
瘦素通过调节中脑边缘多巴胺（DA）系统的活动，减少了对预测食物奖励线索的获取食物的动机。尽管瘦素直接降低腹侧被盖区（VTA）DA 神经元的活性，但大多数表达瘦素受体（LepR）的 DA 神经元并不投射到伏隔核，而投射到伏隔核的神经元与驱动食物奖励寻求有关。因此，瘦素调节食物奖励动机的确切作用部位尚未解决。
我们使用在 LepR 启动子控制下表达 Cre 重组酶的转基因小鼠，通过解剖追踪、光遗传学辅助膜片钳电生理学、活体光纤光度钙测量和化学遗传学来揭示瘦素靶向神经回路如何抑制食物奖励寻求。
大量投射到伏隔核的 DA 神经元被局部 VTA LepR 表达 GABA（γ-氨基丁酸）神经元支配。瘦素增强了这些 GABA 神经元的活性，从而抑制了伏隔核投射的 DA 神经元。此外，我们发现，投射到 VTA 的下丘脑外侧 LepR 表达神经元受到瘦素的抑制，这些神经元通过抑制 VTA GABA 神经元间接调节 DA 神经元。与这种抑制功能一致，光遗传学刺激下丘脑外侧 LepR 投射到 VTA 强烈激活体内的 DA 神经元。此外，我们发现，化学遗传学激活下丘脑外侧 LepR 神经元仅在小鼠处于正能量平衡时才会增加获取食物奖励的动机。
我们确定了瘦素靶向 DA 系统多个输入以减少食物奖励寻求的神经回路。
