Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden.
Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
Mol Metab. 2019 Feb;20:178-193. doi: 10.1016/j.molmet.2018.11.005. Epub 2018 Nov 27.
The supramammillary nucleus (SuM) is nestled between the lateral hypothalamus (LH) and the ventral tegmental area (VTA). This neuroanatomical position is consistent with a potential role of this nucleus to regulate ingestive and motivated behavior. Here neuroanatomical, molecular, and behavior approaches are utilized to determine whether SuM contributes to ingestive and food-motivated behavior control.
Through the application of anterograde and retrograde neural tract tracing with novel designer viral vectors, the current findings show that SuM neurons densely innervate the LH in a sex dimorphic fashion. Glucagon-like peptide-1 (GLP-1) is a clinically targeted neuro-intestinal hormone with a well-established role in regulating energy balance and reward behaviors. Here we determine that GLP-1 receptors (GLP-1R) are expressed throughout the SuM of both sexes, and also directly on SuM LH-projecting neurons and investigate the role of SuM GLP-1R in the regulation of ingestive and motivated behavior in male and female rats.
SuM microinjections of the GLP-1 analogue, exendin-4, reduced ad libitum intake of chow, fat, or sugar solution in both male and female rats, while food-motivated behaviors, measured using the sucrose motivated operant conditioning test, was only reduced in male rats. These data contrasted with the results obtained from a neighboring structure well known for its role in motivation and reward, the VTA, where females displayed a more potent response to GLP-1R activation by exendin-4. In order to determine the physiological role of SuM GLP-1R signaling regulation of energy balance, we utilized an adeno-associated viral vector to site-specifically deliver shRNA for the GLP-1R to the SuM. Surprisingly, and in contrast to previous results for the two SuM neighboring sites, LH and VTA, SuM GLP-1R knockdown increased food seeking and adiposity in obese male rats without altering food intake, body weight or food motivation in lean or obese, female or male rats.
Taken together, these results indicate that SuM potently contributes to ingestive and motivated behavior control; an effect contingent on sex, diet/homeostatic energy balance state and behavior of interest. These data also extend the map of brain sites directly responsive to GLP-1 agonists, and highlight key differences in the role that GLP-1R play in interconnected and neighboring nuclei.
穹窿上核（SuM）位于外侧下丘脑（LH）和腹侧被盖区（VTA）之间。这种神经解剖位置表明该核可能在调节摄食和动机行为方面发挥作用。目前，通过应用新型设计的病毒载体进行顺行和逆行神经束追踪，研究发现 SuM 神经元以性别二态的方式密集地支配 LH。胰高血糖素样肽-1（GLP-1）是一种临床靶向神经肠激素，在调节能量平衡和奖励行为方面具有明确的作用。在这里，我们确定 GLP-1 受体（GLP-1R）在两性的 SuM 中均有表达，并且直接在 SuM LH 投射神经元上表达，并研究 SuM GLP-1R 在调节雄性和雌性大鼠摄食和动机行为中的作用。
SuM 内注射 GLP-1 类似物 exendin-4 可减少雄性和雌性大鼠的自由摄食量，包括 Chow、脂肪或糖水，但只有雄性大鼠的食物动机行为，通过蔗糖动机操作测试测量，才会减少。这些数据与来自一个以其在动机和奖励方面的作用而闻名的邻近结构（VTA）的结果形成对比，在 VTA 中，雌性对 exendin-4 激活 GLP-1R 的反应更为强烈。为了确定 SuM GLP-1R 信号调节能量平衡的生理作用，我们使用腺相关病毒载体将 GLP-1R 的 shRNA 特异性递送至 SuM。令人惊讶的是，与 SuM 两个邻近部位（LH 和 VTA）的先前结果相反，SuM GLP-1R 敲低增加了肥胖雄性大鼠的食物寻求和肥胖程度，而不会改变瘦或肥胖、雄性或雌性大鼠的食物摄入、体重或食物动机。
总之，这些结果表明 SuM 强烈参与摄食和动机行为控制；这种作用取决于性别、饮食/体内能量平衡状态以及感兴趣的行为。这些数据还扩展了对 GLP-1 激动剂直接反应的脑区图谱，并强调了 GLP-1R 在相互连接和相邻核中的作用的关键差异。
