Fast oscillatory neuronal activity is a prominent feature observed in many areas of the central nervous system (CNS), including CNS regions associated with respiratory motor control. In the respiratory neural control system, it has long been recognized that fast oscillatory rhythms are present in inspiratory-related muscles, nerves, and neurons, and that these fast rhythmic oscillations provide an index of short-time scale synchronization within the inspiratory burst. The neuronal mechanisms that underlie fast oscillations in the CNS are poorly understood. It has been hypothesized, however, that interneuronal gap junctions and fast inhibitory synaptic mechanisms play a critical role in the generation of fast network oscillations. Recent observations further indicate that gap junctions, composed of the neuron specific gap junction protein connexin36 (Cx36), among GABAergic inhibitory neurons may participate in the generation of fast oscillations in some areas of the CNS. The experiments proposed in this application will use biochemical and immunohistochemical analyses in conjunction with in vivo and in vitro experiments in wild type and Cx36- deficient mice to further define the roles of brainstem gap junctions (including gap junctions composed of Cx36) and GABAA-mediated synaptic inhibition in the generation of fast oscillations in the inspiratory neural control system.
The specific aims of this research proposal are: (1) investigate the effects of genetic manipulation (deletion) of the neuronal gap junction protein Cx36 on fast oscillatory rhythms in inspiratory motor discharges, (2) investigate the effects of pharmacological blockade of GABAA receptors on fast oscillatory rhythms in inspiratory motor discharges in Cx36-deficient mice, (3) investigate the effects of pharmacological blockade of gap junctions and GABAA receptors in the dorsal respiratory group (DRG), rostral ventral respiratory group (rVRG), and phrenic motor nucleus (PMN) on fast oscillatory rhythms in inspiratory discharges, (4) identify the repertoire of gap junction proteins in GABAergic neurons in respiratory-related medullary regions, and (5) investigate whether the expression levels of other neuronal gap junction proteins in respiratory-related brainstem regions are altered in Cx36-deficient mice.
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