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Neonatal anesthesia-induced delay of axon pruning in hippocampus

新生儿麻醉引起的海马轴突修剪延迟

基本信息

批准号：
9911948
负责人：
Omar Hosea Cabrera
金额：
$ 6.74万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9911948
关键词：
Acute Adolescent Adult Anesthesia procedures Anesthesiology Anesthetics Animals Apoptosis Apoptotic Award Axon Binding Biological Availability Brain Brain-Derived Neurotrophic Factor Cell Death Child Clinical Research Cognition Cognitive deficits Colorado Data Dendrites Development Dose Elderly Electrodes Electrophysiology (science)Exposure to Fetus Freezing Frequencies Functional disorder Glutamates Goals Growth Factor Health Hippocampus (Brain)Histology Human Impairment Infant Ketamine Knowledge Lead Length Life Link Measures Memory Memory impairment Methods Microscopic Molecular Morphology Mus NGFR Protein Neonatal Neurodevelopmental Impairment Neurons Neuroprotective Agents Neurosciences Research Neurotrophic Tyrosine Kinase Receptor Type 2 Operative Surgical Procedures Outcome Output Patch-Clamp Techniques Pathology Personal Satisfaction Pharmaceutical Preparations Pharmacology Pliability Presynaptic Terminals Probability Research Research Personnel Rodent Signal Pathway Signal Transduction Slice Stimulus Synapses Techniques Testing Therapeutic Time Training Universities axon growth biophysical properties calbindin career clinically relevant conditioned fear curriculum development dentate gyrus follow-up juvenile animal millisecond mimetics neonatal exposure neonate nerve supply neural circuit neurobehavioral neurobiotin neuromechanism neuron apoptosis neuronal circuitry neurotransmission neurotransmitter release neurotrophic factor nonhuman primate novel patch clamp perinatal medicine postnatal postsynaptic preservation presynaptic prevent pup receptor receptor function response sedative small molecule synaptogenesis translational neuroscience

项目摘要

Project Summary Millions of human fetuses and infants are exposed every year to anesthetic drugs in doses that trigger widespread neuroapoptosis in the developing brains of rodents and non-human primates. Alarmingly, several clinical studies now link human infant anesthesia to cognitive deficits in later life. However, the adult mammalian brain has orders of magnitude more neurons that survive the insult than those that are deleted and why a young and pliable brain cannot recover from a brief anesthetic insult is not understood. A plausible hypothesis is that the surviving neurons form dysfunctional neural circuits. Indeed, neonatal exposure to anesthetic drugs deranges nearly every microscopic component of neural circuits, which, we hypothesize, compromises neural circuit function, synaptic morphology, and ultimately, cognition. For Specific Aim 1, we test the hypothesis that anesthetic drug interference with normal developmental axon pruning leads to neural circuit excitability in animals treated with ketamine as neonates. For Specific Aim 2, we test the hypothesis that ketamine-induced deficits in hippocampus-dependent memory and axonal pruning can be prevented through pharmacological enhancement of BDNF signaling pathways. During the tenure of the award, the applicant will benefit from a highly-tailored professional development curriculum that leverages the strengths of the University of Colorado, generally, and its Department of Anesthesiology, specifically. At the conclusion of the award, the applicant will have mastery of patch clamp electrophysiology, neurobehavioral, molecular, and morphological techniques that will help launch his career investigating the anesthesia effects on neural circuits. The applicant’s long-term goal is to identify safe and effective strategies that prevent anesthetic drugs from exerting deleterious effects, which will be a valuable contribution to the health and well-being of millions of infants and children worldwide.

项目摘要每年有数百万的人类胎儿和婴儿暴露在麻醉药物中，其剂量足以引发啮齿类动物和非人类灵长类动物大脑发育中广泛的神经细胞凋亡。令人担忧的是，临床研究现在将人类婴儿麻醉与以后生活中的认知缺陷联系起来。然而，成年哺乳动物大脑中存活下来的神经元数量比那些被删除的神经元数量多，为什么一个年轻的柔韧的大脑无法从短暂的麻醉损伤中恢复的原因还不清楚。一个合理的假设是，存活的神经元形成功能失调的神经回路。事实上，新生儿接触麻醉药物会导致精神错乱，几乎神经回路的每一个微观组成部分，我们假设，功能，突触形态，最终，认知。对于具体目标1，我们检验假设，麻醉药物干扰正常发育轴突修剪导致动物神经回路兴奋性在新生儿时用氯胺酮治疗对于具体目标2，我们检验了氯胺酮诱导的缺陷的假设，通过药理学增强可以防止海马体依赖性记忆和轴突修剪脑源性神经营养因子信号通路。在奖项有效期内，申请人将受益于量身定制的专业发展课程，利用科罗拉多大学的优势，一般，和尤其是麻醉科在奖励结束时，申请人将掌握膜片钳电生理学、神经行为学、分子学和形态学技术，他的职业是研究麻醉对神经回路的影响。申请人的长期目标是确定安全的和有效的预防麻醉药物产生有害作用的策略，这将是一个有价值的这是对全世界数百万婴儿和儿童的健康和福祉的贡献。