Regulation of Adult Neurogenesis During Intermittent Hypoxia

间歇性缺氧期间成人神经发生的调节

• 批准号: 6741108
• 负责人: DENNIS J MCGINTY
• 金额: $ 12.99万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6741108
• 关键词: behavior test; brain injury; cell proliferation; cognition; electroencephalography; electromyography; glucocorticoids; hippocampus; hypoxia; ischemia; laboratory rat; neural transmission; neurogenesis; respiratory airflow disorder; serotonin; sleep apnea

Obstructive sleep apnea (OSA) patients have specific cognitive deficits and symptoms of depression, but the neurological basis of these abnormalities is unknown. Reduced hippocampal gray matter volume was recently detected in OSA patients and in major depression. Suppression of neurogenesis could account for a critical part of these hippocampal volume changes. Adult neurogenesis, the proliferation of new cells in the hippocampus and their differentiation into functional neurons, was found to be required for acquisition of complex spatially- and temporally-structured learning tasks in adult animals. Cognitive deficits of this type are found in OSA patients. We propose that OSA patients have impaired hippocampal neurogenesis. We will use the chronic intermittent hypoxia (CIH) model of OSA in rats to assess the hypotheses that CIH inhibits neurogenesis, and that sleep deprivation (SD) associated with CIH further inhibits neurogenesis. We will show that the inhibition of neurogenesis predicts cognitive performance in a hippocampal-dependent spatial learning paradigm, the Barnes maze. Measurement of cell proliferation and neurogenesis will be based on 5-bromo-2-deoxyuridine-5-monophosphate (BrdU) immunostaining, combined with neuronal and glial markers and will use stereological technique to assess cell counts. Brain temperature (Tbr) is normally down-regulated during hypoxia as well as during sleep, but changes during CIH and CIH-coincident sleep are unknown. Tbr is a primary determinant of the extent of focal or global ischemic brain damage, but its role in the pathological changes following CIH has not been examined. A second objective of our proposal is to determine how CIH and SD affect Tbr and if Tbr modulates the inhibition of neurogenesis by SD and CIH. Serotonergic neurotransmission is strongly modulated during CIH and is also known to control neurogenesis. A third goal of our proposal is to determine if augmentation of serotonergic neurotransmission reduces the inhibition of neurogenesis by IH. Glucocorticoids and stress inhibit neurogenesis. We will determine if changes in glucocorticoid secretion account for inhibition of neurogenesis by IH. These studies will provide evidence about the basis of cognitive deficits in OSA, including 1) regulation of neurogenesis in the CIH model of OSA, 2) the modulating effects of sleep deprivation, temperature, and other variables, and 3) interventions to aid in recovery from deficits.

阻塞性睡眠呼吸暂停（OSA）患者有特定的认知缺陷和抑郁症状，但这些异常的神经学基础尚不清楚。最近在OSA患者和重度抑郁症患者中检测到海马灰质体积减少。神经发生的抑制可以解释这些海马体积变化的关键部分。成年神经发生，海马中新细胞的增殖及其分化为功能性神经元，被认为是成年动物获得复杂的空间和时间结构的学习任务所必需的。这种类型的认知缺陷在OSA患者中发现。我们认为OSA患者海马神经发生受损。我们将使用慢性间歇性缺氧（CIH）的OSA大鼠模型，以评估CIH抑制神经发生的假设，以及与CIH相关的睡眠剥夺（SD）进一步抑制神经发生。我们将表明，神经发生的抑制预测认知表现在一个营地依赖的空间学习范式，巴恩斯迷宫。细胞增殖和神经发生的测量将基于5-溴-2-脱氧尿苷-5-单磷酸（BrdU）免疫染色，结合神经元和神经胶质标志物，并将使用体视学技术评估细胞计数。脑温度（Tbr）通常在缺氧和睡眠期间下调，但CIH和CIH同步睡眠期间的变化尚不清楚。TBR是局灶性或全脑缺血性脑损伤程度的主要决定因素， 在CIH后病理变化中的作用尚未研究。我们建议的第二个目标是确定CIH和SD如何影响Tbr以及Tbr是否调节SD和CIH对神经发生的抑制。5-羟色胺能神经传递在CIH期间受到强烈调节，并且也已知其控制神经发生。我们建议的第三个目标是，以确定是否增强的肾上腺素能神经传递减少抑制神经发生的IH。糖皮质激素和应激抑制神经发生。我们将确定糖皮质激素分泌的变化是否是IH抑制神经发生的原因。这些研究将为OSA认知功能障碍的基础提供证据，包括1）CIH中神经发生的调节 OSA模型，2）睡眠剥夺、温度和其他变量的调节作用，以及3）帮助从缺陷中恢复的干预措施。