Sukhotinsky I, Zalkind V, Lu J, Hopkins D A, Saper C B, Devor M
Department of Cell and Animal Biology, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Eur J Neurosci. 2007 Mar;25(5):1417-36. doi: 10.1111/j.1460-9568.2007.05399.x.
Anesthesia, slow-wave sleep, syncope, concussion and reversible coma are behavioral states characterized by loss of consciousness, slow-wave cortical electroencephalogram, and motor and sensory suppression. We identified a focal area in the rat brainstem, the mesopontine tegmental anesthesia area (MPTA), at which microinjection of pentobarbital and other GABA(A) receptor (GABA(A)-R) agonists reversibly induced an anesthesia-like state. This effect was attenuated by local pre-treatment with the GABA(A)-R antagonist bicuculline. Using neuroanatomical tracing we identified four pathways ascending from the MPTA that are positioned to mediate electroencephalographic synchronization and loss of consciousness: (i) projections to the intralaminar thalamic nuclei that, in turn, project to the cortex; (ii) projections to several pontomesencephalic, diencephalic and basal forebrain nuclei that project cortically and are considered parts of an ascending "arousal system"; (iii) a projection to other parts of the subcortical forebrain, including the septal area, hypothalamus, zona incerta and striato-pallidal system, that may indirectly affect cortical arousal and hippocampal theta rhythm; and (iv) modest projections directly to the frontal cortex. Several of these areas have prominent reciprocal projections back to the MPTA, notably the zona incerta, lateral hypothalamus and frontal cortex. We hypothesize that barbiturate anesthetics and related agents microinjected into the MPTA enhance the inhibitory response of local GABA(A)-R-bearing neurons to endogenous GABA released at baseline during wakefulness. This modulates activity in one or more of the identified ascending neural pathways, ultimately leading to loss of consciousness.
麻醉、慢波睡眠、昏厥、脑震荡和可逆性昏迷是行为状态，其特征为意识丧失、皮层慢波脑电图以及运动和感觉抑制。我们在大鼠脑干中确定了一个局部区域，即中脑桥被盖麻醉区（MPTA），向该区域微量注射戊巴比妥和其他γ-氨基丁酸A型受体（GABA(A)-R）激动剂可可逆地诱导出类似麻醉的状态。局部预先使用GABA(A)-R拮抗剂荷包牡丹碱可减弱这种效应。通过神经解剖学追踪，我们确定了从MPTA上行的四条通路，这些通路可能介导脑电图同步化和意识丧失：（i）投射至丘脑板内核，而丘脑板内核又投射至皮层；（ii）投射至几个脑桥中脑、间脑和基底前脑核，这些核向皮层投射，被认为是上行“觉醒系统”的一部分；（iii）投射至皮层下前脑的其他部分，包括隔区、下丘脑、未定带和纹状体苍白球系统，这可能间接影响皮层觉醒和海马θ节律；（iv）适度地直接投射至额叶皮层。其中几个区域有明显的反向投射回到MPTA，特别是未定带、外侧下丘脑和额叶皮层。我们推测，微量注射到MPTA的巴比妥类麻醉剂及相关药物增强了局部含GABA(A)-R神经元对清醒时基线释放的内源性GABA的抑制反应。这调节了一条或多条已确定的上行神经通路的活动，最终导致意识丧失。
