Department of Biological Sciences, Human and Evolutionary Biology Section, University of Southern California, 3616 Trousdale Parkway, AHF 252, Los Angeles, CA, 90089, United States.
Department of Biological Sciences, Human and Evolutionary Biology Section, University of Southern California, 3616 Trousdale Parkway, AHF 252, Los Angeles, CA, 90089, United States; Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, 90089, United States.
Neuropharmacology. 2020 Nov 1;178:108270. doi: 10.1016/j.neuropharm.2020.108270. Epub 2020 Aug 12.
Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced in the lateral hypothalamus and zona incerta that increases food intake. The neuronal pathways and behavioral mechanisms mediating the orexigenic effects of MCH are poorly understood, as is the extent to which MCH-mediated feeding outcomes are sex-dependent. Here we investigate the hypothesis that MCH-producing neurons act in the nucleus accumbens shell (ACBsh) to promote feeding behavior and motivation for palatable food in a sex-dependent manner. We utilized ACBsh MCH receptor (MCH1R)-directed pharmacology as well as a dual virus chemogenetic approach to selectively activate MCH neurons that project to the ACBsh. Results reveal that both ACBsh MCH1R activation and activating ACBsh-projecting MCH neurons increase consumption of standard chow and palatable sucrose in male rats without affecting motivated operant responding for sucrose, general activity levels, or anxiety-like behavior. In contrast, food intake was not affected in female rats by either ACBsh MCH1R activation or ACBsh-projecting MCH neuron activation. To determine a mechanism for this sexual dimorphism, we investigated whether the orexigenic effect of ACBsh MCH1R activation is reduced by endogenous estradiol signaling. In ovariectomized female rats on a cyclic regimen of either estradiol (EB) or oil vehicle, ACBsh MCH1R activation increased feeding only in oil-treated rats, suggesting that EB attenuates the ability of ACBsh MCH signaling to promote food intake. Collective results show that MCH ACBsh signaling promotes feeding in an estrogen- and sex-dependent manner, thus identifying novel neurobiological mechanisms through which MCH and female sex hormones interact to influence food intake.
黑皮质素-4 受体（MCHR）是一种食欲肽，在外侧下丘脑和未定带中产生，可增加食物摄入。介导 MCH 促食欲作用的神经元途径和行为机制知之甚少，MCH 介导的摄食结果在多大程度上依赖于性别也是如此。在这里，我们假设 MCH 产生神经元在伏隔核壳（ACBsh）中起作用，以促进摄食行为和对美味食物的动机，其作用具有性别依赖性。我们利用 ACBsh MCH 受体（MCH1R）靶向药理学以及双病毒化学遗传方法，选择性地激活投射到 ACBsh 的 MCH 神经元。结果表明，ACBsh MCH1R 激活和激活投射到 ACBsh 的 MCH 神经元均可增加雄性大鼠标准食物和美味蔗糖的消耗，而不会影响蔗糖的动机操作反应、一般活动水平或焦虑样行为。相比之下，无论是 ACBsh MCH1R 激活还是投射到 ACBsh 的 MCH 神经元激活，都不会影响雌性大鼠的食物摄入。为了确定这种性别二态性的机制，我们研究了 ACBsh MCH1R 激活的促食欲作用是否被内源性雌二醇信号减弱。在接受雌二醇（EB）或油载体周期性治疗的去卵巢雌性大鼠中，ACBsh MCH1R 激活仅在油处理的大鼠中增加摄食，表明 EB 减弱了 ACBsh MCH 信号促进食物摄入的能力。集体结果表明，MCH ACBsh 信号以雌激素和性别依赖的方式促进摄食，从而确定了 MCH 和女性性激素相互作用影响食物摄入的新的神经生物学机制。
