Curtis Genevieve R, Carpenter Brody A, Pirino Breanne E, Hawks Annie, Li George, Barson Jessica R
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, P.A. 19129.
Res Sq. 2024 Apr 2:rs.3.rs-4145128. doi: 10.21203/rs.3.rs-4145128/v1.
Binge eating disorder, characterized by the overconsumption of food in a discrete time period, is the most common eating disorder in the United States, but its neurological basis is not fully understood. The paraventricular nucleus of the thalamus (PVT) is a limbic brain region implicated in eating, and the anorexigenic neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), is densely expressed in the PVT. This study sought to examine the possible involvement of PACAP in the PVT in binge-type eating. First, a model of binge-type eating was established in mice. Male and female C57BL/6J mice were given limited access to Milk Chocolate Ensure Plus or had access only to chow and water. Under this model, while males and females both engaged in binge-type eating with Ensure, females engaged in this behavior to a greater degree than males. Next, the role of PACAP in the PVT was defined in relation to binge-type eating. Using quantitative real-time PCR, females were found to have higher baseline levels of PVT PACAP mRNA than males, but only males showed an increase in levels of PACAP after a history of binge-type eating, and only males showed a reduction in levels of PACAP immediately prior to a binge session. Using chemogenetics in PACAP-Cre transgenic mice on a C57BL/6J background, activation of PVT PACAP cells with a Cre-dependent Gq-DREADD was found to reduce binge-type eating, significantly in male but not female mice. These results indicate that PVT PACAP is involved in binge-type eating in a sex-dependent manner, with a decrease in PVT PACAP levels preceding binge-type eating in male mice, and enhanced PVT PACAP cell activity suppressing binge-type eating in male mice. Together, these results suggest that the PACAP system could be targeted in specific patient populations to help treat binge eating disorder.
暴饮暴食症的特征是在一段特定时间内过度进食，它是美国最常见的饮食失调症，但其神经学基础尚未完全明确。丘脑室旁核（PVT）是一个与进食有关的边缘脑区，而厌食神经肽垂体腺苷酸环化酶激活多肽（PACAP）在PVT中大量表达。本研究旨在探讨PACAP在PVT中与暴饮暴食型进食可能存在的关联。首先，在小鼠中建立了暴饮暴食型进食模型。给雄性和雌性C57BL/6J小鼠限量提供巧克力味安素营养奶昔，或者只提供普通食物和水。在这个模型中，雄性和雌性小鼠都会用安素进行暴饮暴食型进食，但雌性小鼠的这种行为比雄性小鼠更明显。接下来，确定了PACAP在PVT中与暴饮暴食型进食相关的作用。通过定量实时PCR发现，雌性小鼠PVT中PACAP mRNA的基线水平高于雄性小鼠，但只有雄性小鼠在经历暴饮暴食型进食后PACAP水平有所升高，且只有雄性小鼠在暴饮暴食前即刻PACAP水平有所降低。在C57BL/6J背景的PACAP-Cre转基因小鼠中使用化学遗传学方法，发现用依赖Cre的Gq-DREADD激活PVT中的PACAP细胞可减少暴饮暴食型进食，在雄性小鼠中效果显著，而在雌性小鼠中则不然。这些结果表明，PVT中的PACAP以性别依赖的方式参与暴饮暴食型进食，雄性小鼠在暴饮暴食型进食前PVT中PACAP水平下降，而增强PVT中PACAP细胞的活性可抑制雄性小鼠的暴饮暴食型进食。总之，这些结果表明，PACAP系统可以作为特定患者群体的治疗靶点，以帮助治疗暴饮暴食症。
