Fetal Alcohol Exposure and Biological Rhythms

胎儿酒精暴露和生物节律

• 批准号: 6879451
• 负责人: Robert J Handa
• 金额: $ 32.63万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879451
• 关键词: autonomic nervous system; behavioral /social science research tag; biological clocks; circadian rhythms; corticosterone; developmental neurobiology; fetal alcohol syndrome; gastrin releasing peptide; gene expression; immunocytochemistry; laboratory rat; neuroendocrine system; neuropathology; nonvisual photosensitivity; paraventricular nucleus; polymerase chain reaction; radioimmunoassay; suprachiasmatic nucleus; vasoactive intestinal peptide; vasopressins

Prenatal exposure to alcohol has profound effects on the developing nervous system. This can result in neurobehavioral pathology without growth deficits, mental retardation or the dysmorphological characteristics associated with Fetal Alcohol Syndrome (FAS). The effects of fetal alcohol exposure (FAE) are of concern to national health because the FAE population is so much larger that that of FAS. In contrast to FAS, deficits in FAE children can also include changes associated with autonomic and neuroendocrine function. Developmental damage to the suprachiasmatic nucleus (SCN) of the hypothalamus may be a common thread linking many FAE associated neuropathologies. The SCN acts to entrain multiple biological rhythms which normally fluctuate across the 24 hour day. When entrainment is weak or slow to respond to normal entrainment cues such as light, behavioral and physiological disturbances can occur. Preliminary data indicate that fetal alcohol exposure alters adult circadian rhythms in core body temperature and plasma corticosterone. This is accompanied by changes in vasopressin and Per2 expression within the SCN. Vasopressin serves a key effector function of the SCN to modulate amplitude and sensitivity of systems related to the control of rhythms. Per2 is an intrinsic clock gene that is expressed in a circadian fashion within the SCN. Therefore, the experiments described in this application will test the hypothesis that prenatal alcohol exposure disrupts hypothalamic development resulting in a dysregulation of the neural mechanisms involved in the entrainment of autonomic and neuroendocrine rhythms. This application will determine: 1) If FAE causes circadian rhythm dysfunction in adult male and female rats due to an insensitivity of the SCN to photic entrainment. 2) If FAE disrupts the function of local circuits within the SCN that regulate diurnal rhythms of neuropeptides and intrinsic clock genes. 3) If FAE disrupts the functional outputs of the SCN to the paraventricular nucleus of the hypothalamus, a brain region that regulates autonomic and neuroendocrine function. The long term goals of these studies are to establish the extent of rhythm dysregulation caused by FAE and the mechanisms underlying such a dysregulation. This will lay the foundation for future neurodevelopmental studies which will help determine intervention strategies useful in counteracting the effects of FAE on SCN function

产前暴露于酒精会对发展中的神经系统产生深远影响。这可以导致神经行为病理，而没有生长缺陷，智力低下或与胎儿酒精综合征相关的畸形特征（FAS）。胎儿酒精暴露（FAE）的影响引起了国家健康的关注，因为FAE人群较大，以至于FAS的人口更大。与FAS相反，FAE儿童的缺陷还可以包括与自主神经和神经内分泌功能相关的变化。下丘脑上核核（SCN）的发育损害可能是连接许多相关神经病理学的共同线。 SCN的作用是夹带多种生物节奏，这些节奏通常在整个24小时内波动。当夹带较弱或缓慢以应对正常的夹带线索（例如光，行为和生理障碍）时。初步数据表明，胎儿酒精暴露会改变核心体温和血浆皮质酮的成年昼夜节律。这伴随着SCN中加压素和PER2表达的变化。加压素具有SCN的关键效应函数，以调节与节奏控制相关的系统的振幅和灵敏度。 PER2是一个内在的时钟基因，在SCN中以昼夜节律的方式表达。因此，本申请中描述的实验将检验以下假设：产前酒精暴露会破坏下丘脑的发育，从而导致涉及自主神经和神经内分泌节奏的神经机制失调。该应用将确定：1）如果FAE导致成年男性和雌性大鼠的昼夜节律功能障碍，因为SCN对光学夹带不敏感。 2）如果FAE破坏了SCN内局部电路的功能，以调节神经肽和固有时钟基因的昼夜节奏。 3）如果FAE破坏了SCN的功能输出对下丘脑的室室核的功能输出，该核核是调节自主神经和神经内分泌功能的大脑区域。这些研究的长期目标是确定由FAE引起的节奏失调的程度以及这种失调的机制。这将为未来的神经发育研究奠定基础，这将有助于确定有助于抵消FAE对SCN功能的影响的干预策略