Kaplan Kara, Echert Ashley E, Massat Ben, Puissant Madeleine M, Palygin Oleg, Geurts Aron M, Hodges Matthew R
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
J Appl Physiol (1985). 2016 May 1;120(9):1070-81. doi: 10.1152/japplphysiol.01015.2015. Epub 2016 Feb 11.
Genetic deletion of brain serotonin (5-HT) neurons in mice leads to ventilatory deficits and increased neonatal mortality during development. However, it is unclear if the loss of the 5-HT neurons or the loss of the neurochemical 5-HT led to the observed physiologic deficits. Herein, we generated a mutant rat model with constitutive central nervous system (CNS) 5-HT depletion by mutation of the tryptophan hydroxylase 2 (Tph2) gene in dark agouti (DA(Tph2-/-)) rats. DA(Tph2-/-) rats lacked TPH immunoreactivity and brain 5-HT but retain dopa decarboxylase-expressing raphe neurons. Mutant rats were also smaller, had relatively high mortality (∼50%), and compared with controls had reduced room air ventilation and body temperatures at specific postnatal ages. In adult rats, breathing at rest and hypoxic and hypercapnic chemoreflexes were unaltered in adult male and female DA(Tph2-/-) rats. Body temperature was also maintained in adult DA(Tph2-/-) rats exposed to 4°C, indicating unaltered ventilatory and/or thermoregulatory control mechanisms. Finally, DA(Tph2-/-) rats treated with the 5-HT precursor 5-hydroxytryptophan (5-HTP) partially restored CNS 5-HT and showed increased ventilation (P < 0.05) at a developmental age when it was otherwise attenuated in the mutants. We conclude that constitutive CNS production of 5-HT is critically important to fundamental homeostatic control systems for breathing and temperature during postnatal development in the rat.
小鼠脑内血清素（5-羟色胺，5-HT）神经元的基因缺失会导致发育过程中的通气功能缺陷和新生儿死亡率增加。然而，尚不清楚是5-HT神经元的缺失还是神经化学物质5-HT的缺失导致了观察到的生理缺陷。在此，我们通过对深色刺鼠（DA(Tph2-/-)）大鼠的色氨酸羟化酶2（Tph2）基因进行突变，构建了一种中枢神经系统（CNS）5-HT组成性缺失的突变大鼠模型。DA(Tph2-/-)大鼠缺乏TPH免疫反应性和脑内5-HT，但保留了表达多巴脱羧酶的中缝神经元。突变大鼠体型也较小，死亡率相对较高（约50%），与对照组相比，在特定的出生后年龄，其室内空气通气量和体温降低。在成年大鼠中，成年雄性和雌性DA(Tph2-/-)大鼠静息时的呼吸以及低氧和高碳酸化学反射均未改变。暴露于4°C环境下的成年DA(Tph2-/-)大鼠体温也能维持，表明通气和/或体温调节控制机制未改变。最后，用5-HT前体5-羟色氨酸（5-HTP）治疗的DA(Tph2-/-)大鼠，其CNS 5-HT部分恢复，并且在发育年龄阶段，当突变体通气量减弱时，其通气量增加（P < 0.05）。我们得出结论，在大鼠出生后的发育过程中，CNS组成性产生5-HT对于呼吸和体温的基本稳态控制系统至关重要。
