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.

Public Health Relevance

. The proposed experiments will result in a comprehensive understanding of how in utero and/or lifelong nicotine exposure alters the structure and function of brainstem neurons involved in the control of the tongue muscles; tongue muscles are required for normal breathing, swallowing, suckling and chewing. The 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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD071302-06A1
Application #
9457632
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Krotoski, Danuta
Project Start
2012-07-10
Project End
2023-04-30
Budget Start
2018-07-12
Budget End
2019-04-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Arizona
Department
Physiology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Wollman, Lila Buls; Levine, Richard B; Fregosi, Ralph F (2018) Developmental nicotine exposure alters glycinergic neurotransmission to hypoglossal motoneurons in neonatal rats. J Neurophysiol 120:1135-1142
Wollman, Lila Buls; Levine, Richard B; Fregosi, Ralph F (2018) Developmental plasticity of GABAergic neurotransmission to brainstem motoneurons. J Physiol 596:5993-6008
Cholanian, Marina; Powell, Gregory L; Levine, Richard B et al. (2017) Influence of developmental nicotine exposure on glutamatergic neurotransmission in rhythmically active hypoglossal motoneurons. Exp Neurol 287:254-260
Cholanian, Marina; Wealing, Jesse; Levine, Richard B et al. (2017) Developmental nicotine exposure alters potassium currents in hypoglossal motoneurons of neonatal rat. J Neurophysiol 117:1544-1552
Powell, Gregory L; Gaddy, Joshua; Xu, Fei et al. (2016) Developmental nicotine exposure disrupts dendritic arborization patterns of hypoglossal motoneurons in the neonatal rat. Dev Neurobiol 76:1125-37
Jaiswal, Stuti J; Wollman, Lila Buls; Harrison, Caitlyn M et al. (2016) Developmental nicotine exposure enhances inhibitory synaptic transmission in motor neurons and interneurons critical for normal breathing. Dev Neurobiol 76:337-54
Wakefield, Hilary E; Fregosi, Ralph F; Fuglevand, Andrew J (2016) Current injection and receptor-mediated excitation produce similar maximal firing rates in hypoglossal motoneurons. J Neurophysiol 115:1307-13
Wollman, Lila B; Haggerty, Jarl; Pilarski, Jason Q et al. (2016) Developmental nicotine exposure alters cholinergic control of respiratory frequency in neonatal rats. Dev Neurobiol 76:1138-49
Powell, Gregory L; Levine, Richard B; Frazier, Amanda M et al. (2015) Influence of developmental nicotine exposure on spike-timing precision and reliability in hypoglossal motoneurons. J Neurophysiol 113:1862-72
Ferng, Jonathan; Fregosi, Ralph F (2015) Influence of developmental nicotine exposure on the ventilatory and metabolic response to hyperthermia. J Physiol 593:5201-13

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