Effects of anesthetics on thalamic excitability

麻醉药对丘脑兴奋性的影响

基本信息

批准号：
9200392
负责人：
Slobodan M. Todorovic
金额：
$ 30.71万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9200392
关键词：
Acids Acute Age Anesthesia procedures Anesthetics Animal Model Animals Brain Brain region Calcium Channel Cell Nucleus Cells Child Childhood Chronic Clinical Cognition Cognitive deficits Data Development Disease Epilepsy Exhibits Exposure to Future Gel General Anesthesia General anesthetic drugs Goals Health Homeostasis Human In Vitro Intravenous Anesthetics Ion Channel Isoflurane Ketamine Laboratory Finding Lead Learning Disabilities Life Mission N-Methyl-D-Aspartate Receptors N-Methylaspartate National Institute of General Medical Sciences Nerve Degeneration Neuronal Plasticity Neurons Outcome Pain Patients Pattern Pharmaceutical Preparations Property Propofol Psyche structure Public Health Rattus Research Risk Rodent Role Sensory Sleep Synapses Synaptic Transmission Synaptic plasticity Testing Thalamic Nuclei Thalamic structure Tinnitus Toxic effect Unconscious State Up-Regulation Wakefulness Work animal data channel blockers clinical practice clinically relevant hypnotic in vivo innovation neuronal excitability neurosteroids neurotoxic nonhuman primate novel nucleus reticularis patch clamp patient population population based postsynaptic pup receptor transmission process voltage

项目摘要

DESCRIPTION (provided by applicant): The ability of the anesthetics to induce safe and reversible loss of consciousness is of paramount importance, yet new animal data suggest that general anesthetics that activate GABAA receptors and/or inhibit NMDA channels are neurotoxic for the developing mammalian brain and have implicated them in causing cognitive deficits later in life. Thus, further research into cellular mechanisms of currently available anesthetics and development of novel anesthetics, particularly for pediatric anesthesia, is warranted. Over the past decade, several studies have shown widespread neurodegeneration in various brain regions, including thalamic nuclei, in young rodents exposed to general anesthetics. However, the possible role of general anesthetics in causing lasting alterations of thalamocortical functioning is not well studied. Our data indicate that immature rats exposed to commonly used general anesthetics at age P7 exhibit lasting reduction in inhibitory synaptic transmission and concomitant plasticity of intrinsic ion channels in the nucleus reticular is thalami (nRT). We hypothesize that exposure to general anesthetics during early development causes reduction of inhibitory GABAergic transmission and up-regulation of T-channels in nRT, leading to chronic hyperexcitability of thalamocortical networks. To test this hypothesis, we will use in vitro patch-clamp recordings from native nRT and thalamocortical (TC) relay neurons and in vivo electroencephalographic (EEG) recordings to pursue the following specific aims: Aim 1: To determine whether rats exposed at P7 to the common volatile anesthetic isoflurane or the commonly used intravenous anesthetics propofol and ketamine will exhibit reduction in inhibitory GABAergic transmission of nRT neurons. Aim 2: To determine whether rats exposed at P7 to isoflurane exhibit up-regulation of T-channels in nRT neurons and whether such up-regulation, in turn, leads to an enhanced burst firing pattern in these cells. Aim 3: To determine whether lasting alterations in synaptic transmission and intrinsic ion channels in the thalamus caused by general anesthetics may lead to hyperexcitability of thalamocortical networks as assessed using EEG recordings in freely moving animals. Aim 4: To determine whether thalamic T-current inhibition contributes to the hypnotic effects of the neuroactive steroid 3�OH, which is a T-channel blocker devoid of any effects on postsynaptic GABAA or NMDA receptors. We also will test the hypothesis that exposure of rat pups to 3�OH will have minimal impact on synaptic homeostasis and, thus, will not trigger neuronal hyperexcitability in the thalamus. The proposed work is innovative in that new mechanisms of anesthetic-induced synaptic and intrinsic neuronal plasticity will be characterized. It is medically significant because it documents important develop- mental alterations induced by short exposures to widely used clinical drugs and is expected to help identify new targets for the development of safer anesthetics and practices in clinical anesthesia.

描述（由申请人提供）：麻醉剂诱导安全且可逆的意识丧失的能力至关重要，但新的动物数据表明，激活 GABAA 受体和/或抑制 NMDA 通道发育的全身麻醉剂对哺乳动物大脑具有神经毒性。因此，有必要对现有麻醉剂的细胞机制进行进一步研究，并开发新型麻醉剂，特别是儿科麻醉剂。几十年来，多项研究表明，接触全身麻醉的年轻啮齿类动物的各个大脑区域（包括丘脑核）出现了广泛的神经退行性变。然而，全身麻醉药在导致丘脑皮质功能持久改变中的可能作用尚未得到充分研究。在 P7 龄暴露于常用全身麻醉剂的大鼠表现出抑制性突触传递的持久减少以及随之而来的网状核丘脑 (nRT) 中固有离子通道的可塑性。在早期发育过程中接触全身麻醉剂会导致抑制性 GABA 能传递减少和 nRT 中 T 通道上调，导致丘脑皮质网络慢性过度兴奋。为了检验这一假设，我们将使用来自天然 nRT 的体外膜片钳记录。和丘脑皮质 (TC) 中继神经元和体内脑电图 (EEG) 记录，以实现以下具体目标：目标 1：确定大鼠是否在 P7 时暴露于常见挥发物麻醉剂异氟烷或常用的静脉麻醉剂异丙酚和氯胺酮会减少 nRT 神经元的抑制性 GABA 能传递。目标 2：确定在 P7 暴露于异氟烷的大鼠是否表现出 nRT 神经元中 T 通道的上调。反过来，调节会导致这些细胞中的突发放电模式增强。目标 3：确定突触传递和内在离子通道是否发生持久改变。使用自由活动动物的脑电图记录评估，全身麻醉药引起的丘脑可能导致丘脑皮质网络过度兴奋。目标 4：确定丘脑 T 电流抑制是否有助于神经活性类固醇 3�OH（一种 T）的催眠作用。 -通道阻滞剂对突触后 GABAA 或 NMDA 受体没有任何影响我们还将测试大鼠幼崽暴露于 3�OH 会产生影响的假设。对突触稳态的影响最小，因此不会引发丘脑神经元过度兴奋。这项工作具有创新性，因为麻醉剂诱导的突触和内在神经元可塑性的新机制将得到表征，这具有医学意义，因为它记录了其重要的发展。短期接触广泛使用的临床药物引起的精神改变，预计将有助于确定开发更安全的麻醉剂和临床麻醉实践的新目标。