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）患者患有特定的认知缺陷和抑郁症状，但是这些异常的神经系统依据尚不清楚。最近在OSA患者和严重抑郁症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。成人神经发生，海马中新细胞的扩散及其分化为功能性神经元，是在成年动物中获得复杂的空间和时间结构的学习任务所必需的。在OSA患者中发现了这种类型的认知缺陷。我们建议OSA患者的海马神经发生受损。我们将使用大鼠OSA的慢性间歇性缺氧（CIH）模型来评估CIH抑制神经发生的假设，而与CIH相关的睡眠剥夺（SD）进一步抑制了神经发生。我们将表明，神经发生的抑制作用可以预测海马依赖性空间学习范式Barnes Maze中的认知性能。细胞增殖和神经发生的测量将基于5-溴-2-脱氧尿苷5-单磷酸盐（BRDU）免疫染色，并结合神经元和神经胶质标记物，并将使用立体技术评估细胞数。在缺氧和睡眠期间，脑温度（TBR）通常下调，但是CIH和CIH偶然睡眠期间的变化尚不清楚。 TBR是局灶性或全球缺血性脑损伤程度的主要决定因素，但 尚未检查CIH后病理变化中的作用。我们建议的第二个目标是确定CIH和SD如何影响TBR，以及TBR是否调节了SD和CIH对神经发生的抑制。血清素能神经传递在CIH期间得到了强烈的调节，也已知可以控制神经发生。我们建议的第三个目标是确定血清素能神经传递的增强是否会降低IH对神经发生的抑制作用。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解释了IH对神经发生的抑制。这些研究将提供有关OSA认知缺陷的基础的证据，包括1）CIH中神经发生的调节 OSA的模型，2）睡眠剥夺，温度和其他变量的调节作用，以及3）干预措施，以帮助从缺陷中恢复。