Effects of anesthetics on thalamic excitability

麻醉药对丘脑兴奋性的影响

• 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
• 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

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（由适用提供）：麻醉剂诱导安全和可逆的意识丧失的能力至关重要，但是新的动物数据表明，激活GABAA受体和/或抑制NMDA通道的一般麻醉剂是为发展乳腺的脑毒性而导致乳腺毒性的新动物毒性，并在后期的认可中实现了后期的生命。这是对当前可用麻醉药的细胞机制的进一步研究，并有必要进行新型麻醉药的开发，尤其是针对儿科麻醉药。在过去的十年中，几项研究表明，在暴露于全身麻醉剂的年轻啮齿动物中，包括丘脑核的各个大脑区域的宽度神经变性。然而，全身麻醉药在引起丘脑皮质功能的持久变化中的可能作用不是很好。我们的数据表明，在P7时代，暴露于常规通用麻醉的未成熟大鼠表现出抑制性突触传播的持续降低，并且核网状内固有离子通道的可塑性伴随着thalami（NRT）。我们假设在早期发育过程中暴露于全身麻醉剂会导致NRT中T通道的抑制性GABA能传播和T通道的上调，从而导致丘脑皮质网络的慢性过度过度兴奋。为了检验该假设，我们将使用本地NRT和丘脑皮质（TC）中继神经元和体内脑电图（EEG）记录的体外斑块钳记录来追求以下具体目的：目标1：以确定P7在P7中暴露于P7的常见挥发性挥发性易挥发性的静脉内静脉内静脉内静脉内，并将其提取。 NRT神经元的抑制性GABA能传播的降低。目标2：确定在P7处暴露于NRT神经元中T通道的异氟烷展示上的上调以及这种上调是否会导致这些细胞中增强的爆发模式。目标3：确定由一般麻醉药引起的丘脑中突触传播和内在离子通道的持久变化是否会导致丘脑皮质网络过度兴奋，并使用自由移动动物中的EEG记录进行评估。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的催眠作用，这是对突触后GABAA或NMDA受体的任何影响的T通道阻滞剂。我们还将检验以下假设：大鼠幼崽暴露于3 OH将对合成稳态产生最小的影响，因此不会触发丘脑中神经元的过度兴奋性。拟议的工作是创新的，因为将表征麻醉诱导的突触和内在神经元可塑性的新机制。它具有医学意义，因为它记录了由于短期暴露于广泛使用的临床药物而引起的重要发育改变，并有望帮助确定开发安全麻醉和实践临床麻醉的新目标。