Institute of Experimental Medicine, Budapest, Hungary; János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary.
Institute of Experimental Medicine, Budapest, Hungary; INRAE Centre Val de Loire, CNRS, IFCE, Université de Tours, UMR 85 Physiologie de la Reproduction et des Comportements, France.
Life Sci. 2021 Dec 1;286:120037. doi: 10.1016/j.lfs.2021.120037. Epub 2021 Oct 9.
Median raphe region (MRR) is an important bottom-up regulatory center for various behaviors as well as vegetative functions, but detailed descriptions and links between the two are still largely unexplored.
Pharmacogenetics was used to study the role of MRR in social (sociability, social interaction, resident intruder test) and emotional behavior (forced swim test) parallel with some vegetative changes (biotelemetry: core body temperature). Additionally, to validate pharmacogenetics, the effect of clozapine-N-oxide (CNO), the ligand of the artificial receptor, was studied by measuring (i) serum and brainstem concentrations of CNO and clozapine; (ii) MRR stimulation induced neurotransmitter release in hippocampus; (iii) CNO induced changes in body temperature and locomotor activity.
MRR stimulation decreased locomotion, increased friendly social behavior in the resident intruder test and enhanced depressive-like behavior. The latter was accompanied by diminished decrease in core body temperature. Thirty minutes after CNO injection clozapine was predominant in the brainstem. Nonetheless, peripheral CNO injection was able to induce glutamate release in the hippocampus. CNO had no immediate (<30 min) or chronic (repeated injections) effect on the body temperature or locomotion.
We confirmed the role of MRR in locomotion, social and depressive-like behavior. Most interestingly, only depressive-like behavior was accompanied by changed body temperature regulation, which was also observed in human depressive disorders previously. This indicates clinical relevance of our findings. Despite low penetration, CNO acts centrally, but does not influence the examined basic parameters, being suitable for repeated behavioral testing.
中缝核区域（MRR）是各种行为以及植物性功能的重要的自下而上的调节中枢，但详细的描述和两者之间的联系在很大程度上仍未得到探索。
我们使用遗传药理学来研究 MRR 在社会（社交性、社交互动、群居入侵测试）和情绪行为（强迫游泳测试）中的作用，同时研究一些植物性功能变化（生物遥测学：核心体温）。此外，为了验证遗传药理学，我们通过测量（i）血清和脑干中的 CNO 和氯氮平浓度；（ii）MRR 刺激诱导海马中的神经递质释放；（iii）CNO 诱导体温和运动活动的变化，研究了人工受体配体氯氮平-N-氧化物（CNO）的作用。
MRR 刺激减少了运动，增加了群居入侵测试中的友好社交行为，并增强了抑郁样行为。后者伴随着核心体温下降的减少。CNO 注射 30 分钟后，脑干部位以氯氮平为主。尽管如此，外周 CNO 注射能够诱导海马中的谷氨酸释放。CNO 对体温或运动没有即时（<30 分钟）或慢性（重复注射）影响。
我们证实了 MRR 在运动、社交和抑郁样行为中的作用。最有趣的是，只有抑郁样行为伴随着体温调节的改变，这在以前的人类抑郁障碍中也观察到过。这表明我们的发现具有临床相关性。尽管穿透性低，CNO 仍在中枢起作用，但不影响所检查的基本参数，适合重复行为测试。
