Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Biological Sciences, Human and Evolutionary Biology Section, University of Southern California, Los Angeles, California.
Biol Psychiatry. 2024 May 15;95(10):938-950. doi: 10.1016/j.biopsych.2023.07.011. Epub 2023 Jul 28.
A better understanding of the neural mechanisms regulating impaired satiety to palatable foods is essential to treat hyperphagia linked with obesity. The satiation hormone amylin signals centrally at multiple nuclei including the ventral tegmental area (VTA). VTA-to-medial prefrontal cortex (mPFC) projections encode food reward information to influence behaviors including impulsivity. We hypothesized that modulation of VTA-to-mPFC neurons underlies amylin-mediated decreases in palatable food-motivated behaviors.
We used a variety of pharmacological, behavioral, genetic, and viral approaches (n = 4-16/experiment) to investigate the anatomical and functional circuitry of amylin-controlled VTA-to-mPFC signaling in rats.
To first establish that VTA amylin receptor (calcitonin receptor) activation can modulate mPFC activity, we showed that intra-VTA amylin decreased food-evoked mPFC cFos. VTA amylin delivery also attenuated food-directed impulsive behavior, implicating VTA amylin signaling as a regulator of mPFC functions. Palatable food activates VTA dopamine and mPFC neurons. Accordingly, dopamine receptor agonism in the mPFC blocked the hypophagic effect of intra-VTA amylin, and VTA amylin injection reduced food-evoked phasic dopamine levels in the mPFC, supporting the idea that VTA calcitonin receptor activation decreases dopamine release in the mPFC. Surprisingly, calcitonin receptor expression was not found on VTA-to-mPFC projecting neurons but was instead found on GABAergic (gamma-aminobutyric acidergic) interneurons in the VTA that provide monosynaptic inputs to this pathway. Blocking intra-VTA GABA signaling, through GABA receptor antagonists and DREADD (designer receptor exclusively activated by designer drugs)-mediated GABAergic neuronal silencing, attenuated intra-VTA amylin-induced hypophagia.
These results indicate that VTA amylin signaling stimulates GABA-mediated inhibition of dopaminergic projections to the mPFC to mitigate impulsive consumption of palatable foods.
更好地了解调节美味食物饱腹感的神经机制对于治疗与肥胖相关的过食症至关重要。饱足激素胰淀素在包括腹侧被盖区（VTA）在内的多个核团中发出中枢信号。VTA 到内侧前额叶皮层（mPFC）的投射编码食物奖励信息，以影响包括冲动行为在内的行为。我们假设，VTA 到 mPFC 神经元的调制是胰淀素介导的美味食物动机行为减少的基础。
我们使用了多种药理学、行为学、遗传学和病毒学方法（n=4-16/实验）来研究大鼠中胰淀素控制的 VTA 到 mPFC 信号的解剖和功能回路。
首先，为了确定 VTA 胰淀素受体（降钙素受体）的激活可以调节 mPFC 的活性，我们发现 VTA 内的胰淀素减少了食物诱发的 mPFC cFos。VTA 胰淀素传递也减弱了食物导向的冲动行为，暗示 VTA 胰淀素信号作为 mPFC 功能的调节剂。美味食物激活 VTA 多巴胺和 mPFC 神经元。因此，mPFC 中的多巴胺受体激动剂阻断了 VTA 内胰淀素的致食作用，而 VTA 内的胰淀素注射降低了 mPFC 中食物诱发的相位多巴胺水平，支持了 VTA 降钙素受体激活降低 mPFC 中多巴胺释放的观点。令人惊讶的是，降钙素受体在 VTA 到 mPFC 投射神经元上没有表达，而是在 VTA 中的 GABA 能（γ-氨基丁酸能）中间神经元上表达，这些中间神经元对这条通路提供单突触输入。通过 VTA 内 GABA 受体拮抗剂和 DREADD（专门由设计药物激活的受体）介导的 GABA 能神经元沉默阻断 VTA 内 GABA 信号，减弱了 VTA 内胰淀素诱导的摄食减少。
这些结果表明，VTA 胰淀素信号刺激 GABA 介导的抑制多巴胺能投射到 mPFC，以减轻美味食物的冲动消费。
