Chávez Jorge, Alcántara-Alonso Viridiana, García-Luna Cinthia, Soberanes-Chávez Paulina, Grammatopoulos Dimitris, de Gortari Patricia
Molecular Neurophysiology laboratory, Department of Neuroscience, National Institute of Psychiatry "Ramón de la Fuente Muñiz", Mexico City, Mexico 14370.
Translational Medicine, Warwick Medical School, Coventry, United Kingdom CV4 7HL.
eNeuro. 2022 May 11;9(3). doi: 10.1523/ENEURO.0077-22.2022.
Among the modulatory functions of thyrotropin-releasing hormone (TRH), an anorectic behavior in rodents is observed when centrally injected. Hypothalamic PVN neurons receive serotonergic inputs from dorsal raphe nucleus and express serotonin (5HT) receptors such as 5HT, 5HT, 5HT, which are involved in 5HT-induced feeding regulation. Rats subjected to dehydration-induced anorexia (DIA) model show increased PVN TRH mRNA expression, associated with their decreased food intake. We analyzed whether 5HT input is implicated in the enhanced PVN TRH transcription that anorectic rats exhibit, given that 5HT increases TRH expression and release when studied By using mHypoA-2/30 hypothalamic cell cultures, we found that 5HT stimulated TRH mRNA, pCREB and pERK1/2 levels. By inhibiting basal PKA or PKC activities or those induced by 5HT, pCREB or pERK1/2 content did not increase suggesting involvement of both kinases in their phosphorylation. 5HT effect on TRH mRNA was not affected by PKA inhibition, but it diminished in the presence of PKCi suggesting involvement of PKC in 5HT-induced TRH increased transcription. This likely involves 5HT and the activation of alternative transduction pathways than those studied here. In agreement with the data, we found that injecting 5HT antagonists into the PVN of DIA rats reversed the increased TRH expression of anorectic animals, as well as their decreased food intake; also, the agonist reduced food intake of hungry restricted animals along with elevated PVN TRH mRNA levels. Our results support that the anorectic effects of serotonin are mediated by PVN TRH in this model.Interaction between brain peptides and neurotransmitters' pathways regulates feeding behavior, but when altered it could lead to the development of eating disorders, such as anorexia. An abnormal increased TRH expression in hypothalamic PVN results in dehydration-induced anorectic rats, associated to their low food intake. The role of neurotransmitters in that alteration is unknown, and since serotonin inhibits feeding and has receptors in PVN, we analyzed its participation in increasing TRH expression and reducing feeding in anorectic rats. By antagonizing PVN serotonin receptors in anorectic rats, we identify decreased TRH expression and increased feeding, suggesting that the anorectic effects of serotonin are mediated by PVN TRH. Elucidating brain networks involved in feeding regulation would help to design therapies for eating disorders.
在促甲状腺激素释放激素（TRH）的调节功能中，当向啮齿动物中枢注射时可观察到其具有抑制食欲的行为。下丘脑室旁核（PVN）神经元接受来自中缝背核的5-羟色胺能输入，并表达5-羟色胺（5HT）受体，如5HT、5HT、5HT，这些受体参与5HT诱导的进食调节。经历脱水诱导厌食（DIA）模型的大鼠显示PVN中TRH mRNA表达增加，这与其食物摄入量减少有关。鉴于在研究时5HT会增加TRH的表达和释放，我们分析了5HT输入是否与厌食大鼠所表现出的PVN中TRH转录增强有关。通过使用下丘脑mHypoA-2/30细胞培养物，我们发现5HT刺激了TRH mRNA、磷酸化环磷腺苷反应元件结合蛋白（pCREB）和磷酸化细胞外信号调节激酶1/2（pERK1/2）的水平。通过抑制基础蛋白激酶A（PKA）或蛋白激酶C（PKC）的活性或5HT诱导的这些活性，pCREB或pERK1/2的含量没有增加，这表明两种激酶都参与了它们的磷酸化过程。5HT对TRH mRNA的影响不受PKA抑制的影响，但在存在PKC抑制剂（PKCi）的情况下其作用减弱，这表明PKC参与了5HT诱导的TRH转录增加。这可能涉及5HT以及比本文所研究的那些转导途径更多的替代转导途径的激活。与这些数据一致，我们发现向DIA大鼠的PVN中注射5HT拮抗剂可逆转厌食动物TRH表达的增加以及它们食物摄入量的减少；此外，激动剂可减少饥饿受限动物的食物摄入量，并伴有PVN中TRH mRNA水平的升高。我们的结果支持在该模型中5-羟色胺的厌食作用是由PVN中的TRH介导的。脑肽与神经递质途径之间的相互作用调节进食行为，但当这种相互作用发生改变时可能会导致饮食失调的发生发展，如厌食症。下丘脑PVN中TRH表达异常增加会导致脱水诱导的厌食大鼠出现，这与它们低食物摄入量有关。神经递质在这种改变中的作用尚不清楚，并且由于5-羟色胺抑制进食且在PVN中有受体，我们分析了其在厌食大鼠中增加TRH表达和减少进食方面的作用。通过拮抗厌食大鼠PVN中的5-羟色胺受体，我们发现TRH表达降低且进食增加，这表明5-羟色胺的厌食作用是由PVN中的TRH介导的。阐明参与进食调节的脑网络将有助于设计针对饮食失调的治疗方法。
