Effects of chronic nicotinic excitation on central glutamatergic control of breat

描述（由申请方提供）：尼古丁是一种神经致畸剂，可穿过血脑屏障，与神经元烟碱乙酰胆碱受体（nAChR）结合，并改变人类和非人类动物的大脑发育。在中枢呼吸神经元中，有证据表明子宫内暴露于尼古丁会增加快速兴奋性和抑制性神经传递，但这种神经可塑性的解剖学和功能细节尚不清楚。这些数据似乎自相矛盾，但越来越多的证据表明，许多类型的中枢神经元和神经网络通过调节其兴奋性来响应不适当的突触输入（例如尼古丁），以实现抑制性和兴奋性神经传递的适当平衡。因此，本建议的目的是研究中枢呼吸控制区的神经可塑性机制，调节呼吸模式，导致慢性尼古丁暴露在发展过程中。指导这一建议的假设是，产前尼古丁暴露（PNE）导致延髓呼吸区的多巴胺能快速兴奋性神经传递增加，产生呼吸节律并控制运动输出的频率和幅度。我们将使用一个“分裂浴”脑干脊髓准备，有和没有压力显微注射谷氨酸受体激动剂和拮抗剂（具体目标1），以及全细胞膜片钳电生理检查突触的变化，可能是由PNE（具体目标2）诱导。我们认为，PNE诱导的兴奋性神经传递的增加可能是持续兴奋的nAChRs和体内呼吸控制异常之间的关键环节，特别是当面临呼吸的挑战。 公共卫生相关性：研究控制中枢呼吸行为的孤立神经网络对于了解更完整的哺乳动物呼吸系统以及影响产前和产后发育期间人类呼吸控制的病理生理条件至关重要。在这里，我们使用两个不同的和高度听话的体外模型，是类似于在体内的呼吸行为，研究如何髓呼吸网络被产前尼古丁暴露改变。这一知识是理解子宫内暴露于尼古丁（即，吸烟）和呼吸调节改变的危及生命的状况。

DESCRIPTION (provided by applicant): Nicotine is a neuroteratogen that crosses the blood brain barrier, binds to neuronal nicotinic acetylcholine receptors (nAChRs), and alters brain development in human and non-human animals. In central respiratory neurons, there is evidence that in utero exposure to nicotine increases both fast excitatory and inhibitory neurotransmission, but the anatomical and functional details of this neuroplasticity are unclear. These data seem paradoxical, but there is growing evidence that many types of central neurons and neural networks respond to inappropriate synaptic input (e.g. nicotine) by adjusting their excitability to achieve the appropriate balance of inhibitory and excitatory neurotransmission. Consequently, the present proposal aims to investigate mechanisms of neural plasticity in central respiratory control regions that regulate breathing pattern resulting from chronic nicotine exposure during development. The hypothesis guiding this proposal is that prenatal nicotine exposure (PNE) leads to an increase in glutamatergic fast excitatory neurotransmission in medullary respiratory regions that generate respiratory rhythm and control the frequency and amplitude of motor output. We will use a "split-bath" brainstem spinal cord preparation with and without pressure microinjections of glutamate receptors agonists and antagonists (Specific aim 1), as well as whole-cell patch clamp electrophysiology to examine synaptic changes that may be induced by PNE (Specific aim 2). We suggest that the PNE-induced increase in excitatory neurotransmission may be a critical link between the persistent excitation of nAChRs and in vivo respiratory control abnormalities, especially when faced with respiratory challenges. PUBLIC HEALTH RELEVANCE: Studying isolated neural networks that control central breathing behavior is fundamental to understanding the more integrated mammalian respiratory system, as well as pathophysiological conditions that effect human respiratory control during prenatal and postnatal development. Here we use two distinct and highly tractable in vitro models that are similar to in vivo breathing behavior to investigate how medullary respiratory networks are altered by prenatal nicotine exposure. This knowledge is key in understanding the numerous links between the in utero exposure to nicotine (i.e., cigarette smoking) and life threatening conditions in which breathing regulation is altered.