Nicotine induced neuroplasticity in the carotid body

描述：(根据申请者的描述扫描)：尼古丁，一种主要的 烟草烟雾的成分，是一种与尼古丁结合的神经致畸原 儿茶酚胺能神经元上的胆碱能受体及其诱导 神经可塑性。儿茶酚胺能系统易受 产前暴露于尼古丁，因为这些系统在个体发育早期和 对多个神经元网络的发育有营养影响。 大鼠脑内多巴胺能和去甲肾上腺素能神经元的神经传递紊乱 尼古丁暴露诱导的中枢神经系统与 出生后的疾病，包括，认知功能受损，注意力 运动中的缺陷障碍和异常。产前尼古丁暴露 也会影响肾上腺嗜铬细胞的成熟，导致应激改变 回应。我们提供了产前尼古丁暴露增加的数据 外周动脉化学感受器中儿茶酚胺能特性 参与心肺控制。抑制性的增加 外周动脉化学感受器的儿茶酚胺能特性可能是部分原因 解释了产前接触尘埃的显著流行病学关联 烟草烟雾与婴儿猝死综合症(小岛屿发展中国家)。因吸烟而生的婴儿 母亲们抑制了缺氧性唤醒反应，降低了呼吸动力， 以及对低氧的呼吸反应迟钝。同样，动物暴露在 产前对尼古丁的低氧呼吸有异常，延迟 自我复苏和暴露在低氧环境下的死亡率增加。可比 至黑质纹状体神经元和肾上腺嗜铬细胞，外周动脉 化学感受器富含儿茶酚胺，并表达尼古丁受体。 尼古丁诱导的中枢神经系统神经元可塑性 暴露涉及对儿茶酚胺能特性的调节，通过 CAMP/钙与神经营养因子、碱性成纤维细胞生长因子和 脑源性神经生长因子(BDNF)。我们的初步数据显示， 产前尼古丁增加酪氨酸羟基酶(TH)mRNA的表达， 外周动脉中儿茶酚胺合成的限速酶 化学感受器。然而，这种效应的机制尚不清楚。然而，它确实是 已知外周动脉中儿茶酚胺能特性的表达 发育过程中的化学感受器依赖于神经营养素。在当前 提案中，我们假设在发育过程中尼古丁暴露会上调 外周动脉化学感受器中儿茶酚胺能系统 CAMP/钙机制与神经营养因子的诱导。因此，使用in 外周动脉化学感受器的体外大鼠模型 建议1)测定外周动脉的可塑性 胎儿晚期和出生后早期尼古丁暴露诱导的化学感受器和 2)，阐明了细胞和分子机制。 可塑性。

DESCRIPTION: (Scanned from the applicant's description): Nicotine, a major component of tobacco smoke, is a neuroteratogen that binds to nicotinic cholinergic receptors on catecholamine-containing neurons and induces neuroplasticity. Catecholaminergic systems are vulnerable to the effects of prenatal exposure to nicotine since these systems develop early in ontogeny and have trophic influences on the development of multiple neuronal networks. Perturbations in neurotransmission in dopaminergic and noradrenergic neurons in the central nervous system induced by nicotine exposure are associated with postnatal morbidities which include, impaired cognitive function, attention deficit disorders and abnormalities in locomotion. Prenatal nicotine exposure also affects maturation of adrenal chromaffin cells resulting in altered stress responses. We present data that prenatal nicotine exposure increases catecholaminergic traits in peripheral arterial chemoreceptors that are involved in cardiorespiratory control. An increase in inhibitory catecholaminergic traits in peripheral arterial chemoreceptors may in part account for the striking epidemologic association between prenatal exposure to tobacco smoke and sudden infant death syndrome (SIDS). Infants born to smoking mothers have depressed hypoxic arousal responses, reduced respiratory drive, and blunted ventilatory responses to hypoxia. Similarly, animals exposed prenatally to nicotine have abnormalities in hypoxic ventilation, delayed autoresuscitation and increased mortality with exposure to hypoxia. Comparable to nigrostriatal neurons and adrenal chromaffin cells, peripheral arterial chemoreceptors are rich in catecholamines and express nicotinic receptors. Plasticity of neurons in the central nervous system induced by nicotine exposure involves regulation of catecholaminergic traits mediated by cAMP/calcium and the neurotrophins, basic fibroblast growth factor (bFGF) and brain-derived nerve growth factor (BDNF). Our preliminary data show that prenatal nicotine increases tyrosine hydroxylase (TH) mRNA expression, the rate-limiting enzyme for catecholamine synthesis, in peripheral arterial chemoreceptors. However, the mechanism for this effect is unknown. Yet, it is known that the expression of catecholaminergic traits in peripheral arterial chemoreceptors during development is neurotrophin dependent. In the current proposal, we hypothesize that nicotine exposure during development up-regulates catecholaminergic systems in peripheral arterial chemoreceptors via cAMP/calcium mechanisms and the induction of neurotrophins. Thus, using an in vitro rat model of peripheral arterial chemoreceptors, the goals of this proposal are to 1) determine the plasticity of peripheral arterial chemoreceptors induced by late fetal and early postnatal nicotine exposure and 2), elucidate the cellular and molecular mechanisms involved in this plasticity.