Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania.
Biol Psychiatry. 2017 Dec 1;82(11):828-838. doi: 10.1016/j.biopsych.2016.12.028. Epub 2017 Jan 10.
The pancreatic- and brain-derived hormone amylin promotes negative energy balance and is receiving increasing attention as a promising obesity therapeutic. However, the neurobiological substrates mediating amylin's effects are not fully characterized. We postulated that amylin acts in the lateral dorsal tegmental nucleus (LDTg), an understudied neural processing hub for reward and homeostatic feeding signals.
We used immunohistochemical and quantitative polymerase chain reaction analyses to examine expression of the amylin receptor complex in rat LDTg tissue. Behavioral experiments were performed to examine the mechanisms underlying the hypophagic effects of amylin receptor activation in the LDTg.
Immunohistochemical and quantitative polymerase chain reaction analyses show expression of the amylin receptor complex in the LDTg. Activation of LDTg amylin receptors by the agonist salmon calcitonin dose-dependently reduces body weight, food intake, and motivated feeding behaviors. Acute pharmacological studies and longer-term adeno-associated viral knockdown experiments indicate that LDTg amylin receptor signaling is physiologically and potentially preclinically relevant for energy balance control. Finally, immunohistochemical data indicate that LDTg amylin receptors are expressed on gamma-aminobutyric acidergic neurons, and behavioral results suggest that local gamma-aminobutyric acid receptor signaling mediates the hypophagia after LDTg amylin receptor activation.
These findings identify the LDTg as a novel nucleus with therapeutic potential in mediating amylin's effects on energy balance through gamma-aminobutyric acid receptor signaling.
胰腺和脑源性激素胰淀素促进负能平衡，作为一种有前途的肥胖治疗方法，受到越来越多的关注。然而，介导胰淀素作用的神经生物学基础尚未完全阐明。我们假设胰淀素在外侧背侧脑桥核（LDTg）中起作用，LDTg 是一个研究较少的用于奖励和稳态摄食信号的神经处理中枢。
我们使用免疫组织化学和定量聚合酶链反应分析来检查大鼠 LDTg 组织中胰淀素受体复合物的表达。进行行为实验以研究 LDTg 中胰淀素受体激活对摄食减少的作用机制。
免疫组织化学和定量聚合酶链反应分析显示胰淀素受体复合物在 LDTg 中表达。激动剂鲑鱼降钙素激活 LDTg 中的胰淀素受体，可剂量依赖性地降低体重、食物摄入和摄食行为。急性药理学研究和更长期的腺相关病毒敲低实验表明，LDTg 中的胰淀素受体信号对能量平衡控制具有生理和潜在的临床前相关性。最后，免疫组织化学数据表明 LDTg 中的胰淀素受体表达在γ-氨基丁酸能神经元上，行为结果表明，LDTg 中的胰淀素受体激活后，局部γ-氨基丁酸受体信号介导摄食减少。
这些发现确定 LDTg 为一个新的核团，通过γ-氨基丁酸受体信号在调节胰淀素对能量平衡的作用方面具有治疗潜力。
