Respiratory control is multifaceted and complex. In mammals, a network of brain stem nuclei is essential for rhythm generation, pattern formation, and respiratory modulation. The mediators of respiratory neural processing are diverse sets of excitatory and inhibitory neurotransmitters, neuromodulators, and their receptors. Respiratory control differs between different stages of development. The assumption is that growth is progressive and the maturation of respiratory control follows a straight path. This may prove not to be the case, as the incidence of Sudden Infant Death Syndrome suggests that the peak of susceptibility is not at birth, but between the 2nd and 4th months after birth. Physiological studies of responses to hypoxia, hypercapnia, and other insults also suggest critical periods of postnatal development in animals. If such periods exist, the neurochemical bases underlying them need to be explored. When the development of several key neurochemicals in the rat brain stem was analyzed daily from postnatal day (P) 0 to 21, we found that, despite general trends of increasing or decreasing expressions with age, there is a distinct fall in the expression of excitatory neurotransmitters and receptors and a prominent rise in the expression of inhibitory neurotransmitters and receptors at P12. These events suggest a transient period of neurochemical imbalance, during which the system is under stronger inhibitory than excitatory drive, concomitant with a sudden drop in metabolic enzyme activity at P12. Remarkably, an apparent switch in subunit dominance of GABAA receptors from oc3 to a1 also occurs around P12 in the rat pre-Botzinger complex, suggesting that the same neurotransmitter may have different physiological effects before and after the subunit switch. The goal of the present proposal is to test our hypothesis that receptor subunit switching is a common theme for a number of neurotransmitter receptors during the presumed critical period of development in rats. Specifically, we will investigate in several key brain stem nuclei by quantitative immunohistochemical assays the developmental expressions of: 1) GABAA receptor subunits a1, a2, and a3;2) glutamate receptors, including NMDA receptor subunits 2A and 2B, and AMPA receptor subunits GluR1 and GluR2;and 3) serotonin receptors 5-HT1A, 1B, 2A, 2C, and 3, tryptophan hydroxylase (TPH) and serotonin transporter (SERT). Finally, 4) the possibility that switches occur at the mRNA level will be explored using isolated cDNA fragments and in situ hybridization of subunit-specific riboprobes for GABA, NMDA, and 5-HT receptors. These studies will provide a solid anatomical and neurochemical foundation regarding the temporal events during postnatal development of brain stem respiratory nuclei, so that future physiological and behavioral studies may extend such knowledge toward a more complete understanding of respiratory control in neonatal and early postnatal animals.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Willinger, Marian
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Medical College of Wisconsin
Anatomy/Cell Biology
Schools of Medicine
United States
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Gao, Xiu-Ping; Liu, Qiuli; Nair, Bindu et al. (2014) Reduced levels of brain-derived neurotrophic factor contribute to synaptic imbalance during the critical period of respiratory development in rats. Eur J Neurosci 40:2183-95
Liu, Qiuli; Wong-Riley, Margaret T T (2013) Postnatal development of brain-derived neurotrophic factor (BDNF) and tyrosine protein kinase B (TrkB) receptor immunoreactivity in multiple brain stem respiratory-related nuclei of the rat. J Comp Neurol 521:109-29
Wong-Riley, Margaret T T; Liu, Qiuli; Gao, Xiu-ping (2013) Peripheral-central chemoreceptor interaction and the significance of a critical period in the development of respiratory control. Respir Physiol Neurobiol 185:156-69
Liu, Qiuli; Wong-Riley, Margaret T T (2013) Postnatal development of glycine receptor subunits *1, *2, *3, and * immunoreactivity in multiple brain stem respiratory-related nuclear groups of the rat. Brain Res 1538:1-16
Liu, Qiuli; Wong-Riley, Margaret T T (2013) Gender considerations in ventilatory and metabolic development in rats: special emphasis on the critical period. Respir Physiol Neurobiol 188:200-7
Liu, Q; Wong-Riley, M T T (2012) Postnatal development of Na(+)-K(+)-2Cl(-) co-transporter 1 and K(+)-Cl(-) co-transporter 2 immunoreactivity in multiple brain stem respiratory nuclei of the rat. Neuroscience 210:1-20
Gao, Xiu-ping; Liu, Qing-song; Liu, Qiuli et al. (2011) Excitatory-inhibitory imbalance in hypoglossal neurons during the critical period of postnatal development in the rat. J Physiol 589:1991-2006
Liu, Q; Wong-Riley, M T T (2010) Postnatal changes in the expressions of serotonin 1A, 1B, and 2A receptors in ten brain stem nuclei of the rat: implication for a sensitive period. Neuroscience 165:61-78
Liu, Q; Wong-Riley, M T T (2010) Postnatal development of N-methyl-D-aspartate receptor subunits 2A, 2B, 2C, 2D, and 3B immunoreactivity in brain stem respiratory nuclei of the rat. Neuroscience 171:637-54
Liu, Qiuli; Wong-Riley, Margaret T T (2010) Postnatal changes in tryptophan hydroxylase and serotonin transporter immunoreactivity in multiple brainstem nuclei of the rat: implications for a sensitive period. J Comp Neurol 518:1082-97

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