Nicotine Modulation of Parasympathetic Cardiac Neurons

胎儿接触尼古丁是婴儿猝死综合症(SID)的最高风险因素，但尽管有大量的负面宣传，几乎每四名孕妇中就有一人吸烟。死于婴儿猝死综合征的婴儿有严重的中枢调节的心脏减慢。在每个呼吸周期中，心脏通常在吸气时跳动更快，在吸气后减慢，这在很大程度上(如果不是完全的话)是通过副交感神经心脏迷走神经活动的呼吸调节来调节的。死于婴儿呼吸窘迫综合征的婴儿被认为具有异常的或可能被夸大的中枢性心肺相互作用，据推测，长时间的吸气后伴随着严重的 心率减慢，可能与此有关。然而，令人惊讶的是，尽管具有重要的生理和临床意义，但人们对介导延髓副交感心脏迷走神经元呼吸调节的通路、递质和受体以及这些相互作用如何随着胎儿尼古丁暴露而改变知之甚少。 该项目将直接测试尼古丁受体负责心脏迷走神经呼吸调节的统一假设。我们还将检验这样一种假设，即胎儿长期接触尼古丁会夸大这些心肺反应。为了实现这些目标，我们将利用一种新的脑干制备方法，使我们能够测量心脏迷走神经中自发的节律性呼吸活动和诱发的突触反应。我们的初步结果表明，心脏迷走神经在吸气时被增加的抑制性GABA和甘氨酸能输入抑制，GABA和甘氨酸能频率的增加是通过激活烟碱受体介导的。除了吸气时的抑制性输入，我们的初步结果显示心脏迷走神经在吸气时兴奋。 通过尼古丁可能调节的谷氨酸能途径进行后吸入。这项工作不仅解决了理解起源于延髓的新生大鼠心肺节律的基础和机制的基本假设，还将表明胎儿暴露于尼古丁会改变哪些受体和过程，从而增加患上SID等心肺疾病的风险。

Fetal nicotine exposure is the highest risk factor for Sudden Infant Death Syndrome (SIDS) and yet despite substantial adverse publicity nearly one out of every four pregnant women smoke tobacco. Infants that succumb to SIDS have a severe centrally mediated slowing of the heart. During each respiratory cycle the heart normally beats more rapidly in inspiration and slows during post-inspiration, which is mediated largely, if not entirely, via respiratory modulation of parasympathetic cardiac vagal activity. Infants that succumb to SIDS are thought to have abnormal and perhaps exaggerated central cardiorespiratory interactions, and it has been speculated that a prolonged period of post-inspiration accompanied by a severe maintained decrease in heart rate, may be involved. Surprisingly, however, despite the physiological and clinical importance little is known about the pathways, transmitters and receptors that mediate respiratory modulation of parasympathetic cardiac vagal neurons in the medulla and how these interactions may change with fetal nicotine exposure. This project will directly test the unifying hypothesis that nicotinic receptors are responsible for the respiratory modulation of cardiac vagal neurons. We will also test the hypothesis that chronic fetal nicotine exposure exaggerates these cardiorespiratory responses. To accomplish these aims we will utilize a novel brainstem preparation that allows us to measure spontaneous rhythmic respiratory activity and evoked synaptic responses in cardiac vagal neurons. Our preliminary results show cardiac vagal neurons are inhibited during inspiration by increased inhibitory GABAergic and glycinergic inputs, and that the increases in GABA and glycinergic frequencies are mediated by activation of nicotinic receptors. In addition to the inhibitory inputs during inspiration, our preliminary results show cardiac vagal neurons are excited during post-inspiration by a glutamatergic pathway which may be modulated by nicotine. This work will not only address hypotheses fundamental to understanding the basis and mechanisms of cardiorespiratory rhythms in the neonatal rat that originate in the medulla, but will also suggest which receptors and processes could be altered by fetal exposure to nicotine which increases the risk of cardiorespiratory diseases such as SIDS.