Testosterone's role in sex-specific outcomes after early anesthesia

睾酮在早期麻醉后性别特异性结果中的作用

• 批准号: 9215684
• 负责人: Jeffrey W Sall
• 金额: $ 29.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215684
• 关键词: Aftercare; Age; Anesthesia procedures; Anesthetics; Animal Experiments; Animals; Basic Science; Brain; Cell Death; Child; Cognitive; Cognitive deficits; Data; Decision Making; Dendrites; Dendritic Spines; Development; Electroporation; Exposure to; Female; Future; General Anesthesia; Goals; Hippocampus (Brain); Human; Impaired cognition; Intervention; Isoflurane; Laboratories; Lead; Life; Light; Measures; Mediating; Memory; Memory impairment; Mission; Morphology; Neonatal; Neurons; Outcome; Patients; Play; Predisposition; Prevention; Procedures; Prospective Studies; Protein Family; Public Health; Publishing; Rattus; Reporting; Research; Risk Assessment; Risk Factors; Risk stratification; Rodent; Role; Safety; Sex Characteristics; Signal Transduction; Stem cells; Strategic Planning; Synapses; Testing; Testosterone; United States; United States National Institutes of Health; Vertebral column; Women' s Health; base; brain cell; clinical risk; cognitive function; density; differential expression; early childhood; experimental study; hippocampal pyramidal neuron; improved; in utero; innovation; male; memory recognition; neuron loss; neurotransmission; postnatal; prevent; public health relevance; sex; sodium-potassium-chloride cotransporter 1 protein; solute; synaptogenesis

DESCRIPTION (provided by applicant): Sex differences in cognitive outcome after early childhood anesthesia have been poorly studied and no mechanism for such differences is known. The long-term goal of this laboratory is to improve the safety of anesthesia delivered to children by eliminating lasting cognitive effects from anesthetic-induced changes in the developing brain. The objective of this proposal is to identify specific sex related factors that lead to divergent cognitive outcomes in male and female rodents. The central hypothesis is that sex-specific cognitive outcomes after early anesthesia are due to testosterone-mediated delay of KCC2 expression which slows the transition from excitatory to inhibitory GABAergic signaling in the hippocampus of male rats leading to loss of neuronal spines and eventual cognitive dysfunction. This hypothesis will be tested in two specific aims: 1) Establish the role of testosterone in dendritic spinogenesis and cognitive outcome after neonatal anesthesia in rats. 2) Establish the role of testosterone in KCC2 expression and determine whether excitatory GABAergic neurotransmission is necessary for anesthetic-mediated spine loss and cognitive deficits. The first aim will compare dendritic spine densities of hippocampal pyramidal neurons and cognitive function following anesthesia exposure in male and female rats after gonadectomy and/or treatment with exogenous testosterone. Under the second aim, section 2.1, will define the role of testosterone in sex-specific temporal expression of KCC2 in control, male and female rats after gonadectomy or treatment with exogenous testosterone. And section 2.2, will use in utero electroporation, to genetically manipulate hippocampal excitatory signaling by early expression of KCC2 or the inward rectifying Kir2.1 (two mechanisms that inhibit GABAergic depolarization) then assess dendritic spine morphology and density as well as cognitive function after early anesthesia exposure. The approach is innovative because cellular level mechanistic studies are guided by and interpreted in light of cognitive function testing, the most relevant outcome that can be measured in animals. The expected contribution from these studies is a detailed understanding of the sex-specific factors leading to deficits of recognition memory in males' vs females after early anesthesia exposure. The proposed research is significant because 1)~ T of children anesthetized in the first three years of life are male, and 2)few other studies have investigated the role of sex in cognitive outcome after early anesthesia, and 3)there is no known mechanism for sex-specific cognitive outcomes after early childhood anesthesia exposure. The results obtained from the proposed research will lead to eventual trials to improve risk stratification and guide decision making around the youngest patients that must be exposed to anesthesia.

描述（由申请人提供）：儿童早期麻醉后认知结果的性别差异的研究很少，并且尚无这种差异的机制。该实验室的长期目标是通过消除麻醉诱导的发育中大脑变化的持久认知作用来提高麻醉的安全性。该建议的目的是确定特定的性别相关因素，从而导致男性和雌性啮齿动物的认知结果不同。中心假设是，早期麻醉后性别特异性的认知结果是由于睾丸激素介导的KCC2表达延迟引起的，这减慢了雄性大鼠海马导致神经元棘的海马中从兴奋性到抑制性GABAergic信号的过渡，导致神经元棘的丧失和最终的认知功能障碍。该假设将以两个具体的目的进行检验：1）确定睾丸激素在大鼠新生儿麻醉后树突状旋转生成和认知结果中的作用。 2）确定睾丸激素在KCC2表达中的作用，并确定兴奋性GABA能神经传递是否对于麻醉介导的脊柱丧失和认知缺陷是必不可少的。第一个目的将比较男性和雌性大鼠在性腺切除术和/或用外源睾丸激素治疗后，在男性和雌性大鼠麻醉后，海马锥体神经元的树突密度和认知功能。在第二个目标下，第2.1节将定义睾丸激素在KCC2在性别特异性时间表中的作用，在促性腺切除术后雄性和雌性大鼠或外源睾丸激素治疗后的雄性和雌性大鼠。和第2.2节将用于子宫电穿孔，通过KCC2的早期表达或向内纠正Kir2.1（两种抑制GABAGAGAGAGAGAGAGAGIC ETALLALILAIGY的机制）在遗传上操纵海马兴奋性信号，然后评估树突状的棘突形态和密度，并在早期的Antesthia eartsiia eartsisia eartsia eartsia earthia eartsia eartsia eartsia eartsia eartsia。这种方法具有创新性，因为细胞水平的机械研究是根据认知功能测试的指导和解释的 可以在动物中测量的大多数相关结果。这些研究的预期贡献是对性别特异性因素的详细理解，导致早期麻醉后男性与女性的识别记忆不足。拟议的研究很重要，因为在生命的头三年中，1）〜T是男性的，而2）其他研究很少研究性行为早期麻醉后的性别在认知结果中的作用，3）3）没有已知的性别特异性认知能力机制，这些机制是儿童早期麻醉后的性别特异性认知结果。从拟议的研究中获得的结果将导致最终的试验，以改善风险分层，并指导必须暴露于麻醉的最年轻患者的决策。