Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Br J Anaesth. 2021 Jun;126(6):1141-1156. doi: 10.1016/j.bja.2021.01.017. Epub 2021 Feb 26.
Both animal and retrospective human studies have linked extended and repeated general anaesthesia during early development with cognitive and behavioural deficits later in life. However, the neuronal circuit mechanisms underlying this anaesthesia-induced behavioural impairment are poorly understood.
Neonatal mice were administered one or three doses of propofol, a commonly used i.v. general anaesthetic, over Postnatal days 7-11. Control mice received Intralipid® vehicle injections. At 4 months of age, the mice were subjected to a series of behavioural tests, including motor learning. During the process of motor learning, calcium activity of pyramidal neurones and three classes of inhibitory interneurones in the primary motor cortex were examined in vivo using two-photon microscopy.
Repeated, but not a single, exposure of neonatal mice to propofol i.p. caused motor learning impairment in adulthood, which was accompanied by a reduction of pyramidal neurone number and activity in the motor cortex. The activity of local inhibitory interneurone networks was also altered: somatostatin-expressing and parvalbumin-expressing interneurones were hypoactive, whereas vasoactive intestinal peptide-expressing interneurones were hyperactive when the mice were performing a motor learning task. Administration of low-dose pentylenetetrazol to attenuate γ-aminobutyric acid A receptor-mediated inhibition or CX546 to potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-subtype glutamate receptor function during emergence from anaesthesia ameliorated neuronal dysfunction in the cortex and prevented long-term behavioural deficits.
Repeated exposure of neonatal mice to propofol anaesthesia during early development causes cortical circuit dysfunction and behavioural impairments in later life. Potentiation of neuronal activity during recovery from anaesthesia reduces these adverse effects of early-life anaesthesia.
动物和回顾性人类研究都将早期发育过程中长时间和重复的全身麻醉与生命后期的认知和行为缺陷联系起来。然而，这种麻醉诱导的行为损伤的神经元回路机制尚不清楚。
在出生后第 7-11 天，给新生小鼠单次或三次腹腔注射丙泊酚，一种常用的静脉全身麻醉剂。对照组小鼠接受 Intralipid® 载体注射。在 4 个月大时，对小鼠进行一系列行为测试，包括运动学习。在运动学习过程中，使用双光子显微镜在体内检查初级运动皮层中的锥体神经元和三类抑制性中间神经元的钙活性。
新生小鼠重复但非单次腹腔注射丙泊酚会导致成年后运动学习障碍，同时伴有运动皮层中锥体神经元数量和活性减少。局部抑制性中间神经元网络的活性也发生改变：生长抑素表达和钙蛋白酶表达中间神经元活性降低，而血管活性肠肽表达中间神经元活性升高，当小鼠执行运动学习任务时。在麻醉苏醒期间给予低剂量戊四氮以减弱 γ-氨基丁酸 A 受体介导的抑制作用，或给予 CX546 以增强 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸亚型谷氨酸受体功能，可改善皮层神经元功能障碍并防止长期行为缺陷。
新生小鼠在早期发育过程中反复暴露于丙泊酚麻醉会导致皮质回路功能障碍，并在生命后期出现行为缺陷。麻醉苏醒期间神经元活性的增强可减少早期麻醉的这些不良影响。
