Chronic nicotine and synaptic transmission in brainstem respiratory neurons

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Despite a growing body of evidence showing that in utero nicotine exposure leads to aberrant development of brainstem neurons involved in the maintenance of key homeostatic functions such as breathing, the consumption of nicotine via smokeless nicotine delivery devices (e.g., e-cigarettes, water pipes, nicotine patches or gum) more than doubled between 2008-2012. A particular concern is raised by recent studies showing that 30% of pregnant smokers were advised to use nicotine patches or gum by their physician. To date, the majority of the data on nicotine exposure and development of brainstem neurons has focused on how in utero exposure alters the brains of very young neonatal animals. As a result, we do not know if the changes observed with in utero exposure resolve or persist with maturation, or worsen if exposure continues after birth. The specific objective of this application is to test the hypothesis that prenatal and/or postnatal exposure to nicotine alters the structure and function of brainstem neurons that control the muscles of the tongue (hypoglossal motor neurons, XIIMNs), using an in vitro approach, as well as the breathing-related control of the tongue muscles, using an in vivo approach. The tongue muscles participate in breathing, swallowing, suckling and mastication, and therefore are critical for organismal homeostasis. A key focus is whether abnormal development of the tongue muscle motor system is worsened if nicotine exposure continues after birth, or if the alterations persist or are attenuated if exposure ends at weaning. Animals (rats) will be studied at key developmental time points, including the early neonatal period (postnatal day 1 (P1) - P5); the putative critical period for development of brainstem neurons (P10 - P12); the end of adolescence when brain maturation is largely complete (P50 – P60); and after sexual and social maturity (4 – 6 months). Specific Aims: We will use neuroanatomy, immunohistochemistry, patch clamp electrophysiology and in vivo plethysmography and EMG recordings to examine how prenatal and/or postnatal nicotine exposure alters: 1) the dendrite branching pattern and the expression of inhibitory (GABA, glycine) and excitatory (glutamate) neurotransmitter receptors on XIIMNs; 2) development of important neuron membrane properties (resting potential, voltage threshold for spike initiation, etc.), the cell's response to excitatory and inhibitory neurotransmitters; 3) development of the breathing pattern and the function of tongue muscles during normal, quiet breathing and when breathing is increased in response to an acute nicotine challenge or by increasing inspired carbon dioxide. The proposed experiments will result in a comprehensive understanding of how in utero and life-long nicotine exposure alters development of brainstem motoneurons that are critical for survival.