Nicotine induced neuroplasticity in the carotid body

描述：（从申请人的描述扫描）：尼古丁，主要 烟草烟雾的一种成分，是一种神经致畸剂，与尼古丁结合， 胆碱能受体的儿茶酚胺神经元，并诱导 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发育， 对多种神经元网络的发育有营养影响。 多巴胺能和去甲肾上腺素能神经元的神经传递扰动 尼古丁暴露引起的中枢神经系统与 产后疾病，包括认知功能受损、注意力 运动缺陷障碍和异常。产前尼古丁暴露 也影响肾上腺嗜铬细胞的成熟，导致压力改变 应答我们提供的数据表明，产前尼古丁暴露增加 外周动脉化学感受器中的儿茶酚胺能特性， 参与心肺控制。抑制性增加 外周动脉化学感受器中的儿茶酚胺能特性可能部分 解释了产前暴露于 吸烟与婴儿猝死综合症（SIDS）因吸烟而出生的婴儿 母亲的缺氧性觉醒反应受到抑制，呼吸驱动力降低， 以及对缺氧的反应迟钝。同样， 产前尼古丁有异常缺氧通气，延迟 暴露于缺氧可导致自动复苏和死亡率增加。可比 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烟碱受体。 尼古丁对中枢神经系统神经元可塑性的影响 暴露涉及调节儿茶酚胺能性状介导的 cAMP/钙和神经营养因子，碱性成纤维细胞生长因子（bFGF）和 脑源性神经生长因子（BDNF）。初步数据显示， 产前尼古丁增加酪氨酸羟化酶（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， 已知外周动脉中儿茶酚胺能特征的表达 在发育过程中的化学受体是神经营养因子依赖性的。在当前 建议，我们假设尼古丁暴露在发展过程中上调 外周动脉化学感受器中的儿茶酚胺能系统 cAMP/钙机制和神经营养素的诱导。因此，使用in 外周动脉化学感受器的体外大鼠模型，本研究的目的是 建议1）确定外周动脉的可塑性 晚期胎儿和出生后早期尼古丁暴露诱导的化学感受器， 2）阐明参与这一过程的细胞和分子机制 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.