Liu Xiaoning, Yang Helin, Xu Wenguang, Wang Xuezhe, Tang Wenhui, Wang Xiaoxuan, Jiao Yang, Luan Xinchi, Li Pengmeng, Guo Feifei
Department of Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China.
Department of Pathology, Women and Children's Hospital, Qingdao University, Qingdao, Shandong, China.
Front Nutr. 2024 Dec 20;11:1468874. doi: 10.3389/fnut.2024.1468874. eCollection 2024.
The ventral tegmental area (VTA), a pivotal hub in the brain's reward circuitry, receives inputs from the lateral hypothalamic area (LHA). However, it remains unclear whether melanin-concentrating hormone (MCH) and orexin-A (OX-A) neurons in the LHA exert individual or cooperative influence on palatable food consumption in the VTA. This study aims to investigate the modulatory role of MCH and OX-A in hedonic feeding within the VTA of high-fat diet (HFD) mice.
Male mice were subjected to an 8-week high-fat diet. To visualize the projections from the LHA to VTA, we employed fluorescent gold retrograde tracing combined with immunofluorescence staining. Immunofluorescence staining or enzyme-linked immunosorbent assay was used to detect the activity of the VTA neurons, expression of OX-A or MCH in the LHA, as well as the activity of their receptors (OXR1 and MCHR1) in the VTA following a sucrose preference test. Single-unit extracellular electrical discharge recordings were conducted to assess the effects of OX-A and MCH on VTA neurons in HFD mice. Additionally, chemogenetic inhibition of MCH neurons and immunofluorescence staining were utilized to observe the regulatory roles of MCH in changes of hedonic feeding induced by OX-A in HFD mice.
Sucrose intake resulted in lower activation of VTA neurons in the HFD mice compared to CON mice, while OX-Aergic and MCHergic neurons project from the LHA to the VTA. Although sucrose intake increased the expression of OX-A and MCH in HFD mice, it led to diminished activation of OXR1-positive and MCHR1-positive VTA neurons compared to CON mice. Extracellular single-unit recording revealed that MCH significantly suppressed the firing rate of OX-A-responsive neurons in the VTA. MCH attenuated the hedonic feeding response induced by OX-A in HFD mice, and administration of MCHR1 antagonist (SNAP94847) significantly potentiated the effect of OX-A. Chemogenetic inhibition of MCH neurons improved the activity of OXR1-expressing neurons, which could be reversed by pretreatment with an OXR1 antagonist (SB334867). Furthermore, chemogenetic inhibition of MCH enhanced hedonic feeding behavior, which was counteracted by SB334867 treatment in HFD mice.
Melanin-concentrating hormone could attenuate the hedonic feeding behavior induced by orexin-A in the VTA of HFD mice.
腹侧被盖区（VTA）是大脑奖赏回路的关键枢纽，接受来自下丘脑外侧区（LHA）的输入。然而，LHA中的促黑素细胞激素（MCH）和食欲素A（OX-A）神经元对VTA中美味食物消耗是发挥单独作用还是协同作用仍不清楚。本研究旨在探讨MCH和OX-A在高脂饮食（HFD）小鼠VTA内享乐性进食中的调节作用。
雄性小鼠接受为期8周的高脂饮食。为了可视化从LHA到VTA的投射，我们采用了荧光金逆行追踪结合免疫荧光染色。免疫荧光染色或酶联免疫吸附测定用于检测VTA神经元的活性、LHA中OX-A或MCH的表达，以及蔗糖偏好试验后VTA中其受体（OXR1和MCHR1）的活性。进行单细胞胞外放电记录以评估OX-A和MCH对HFD小鼠VTA神经元的影响。此外，利用MCH神经元的化学遗传学抑制和免疫荧光染色来观察MCH在HFD小鼠中OX-A诱导的享乐性进食变化中的调节作用。
与对照组小鼠相比，蔗糖摄入导致HFD小鼠VTA神经元的激活降低，而OX-A能和MCH能神经元从LHA投射到VTA。虽然蔗糖摄入增加了HFD小鼠中OX-A和MCH的表达，但与对照组小鼠相比，它导致OXR1阳性和MCHR1阳性VTA神经元的激活减少。胞外单细胞记录显示，MCH显著抑制了VTA中对OX-A有反应的神经元的放电频率。MCH减弱了HFD小鼠中OX-A诱导的享乐性进食反应，给予MCHR1拮抗剂（SNAP94847）显著增强了OX-A的作用。MCH神经元的化学遗传学抑制改善了表达OXR1的神经元的活性，这可以通过用OXR1拮抗剂（SB334867）预处理来逆转。此外，MCH的化学遗传学抑制增强了享乐性进食行为，在HFD小鼠中，SB334867治疗可抵消这种行为。
促黑素细胞激素可减弱HFD小鼠VTA中食欲素A诱导的享乐性进食行为。
