Date of Award

Summer 8-7-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Chun Jiang

Second Advisor

Julia Hilliard

Third Advisor

Hang Shi

Abstract

The autonomic nervous system (ANS) controls several vital functions of the body, especially the autonomic regulation of respiratory and cardiovascular systems. Dysfunction of either can be life-threatening. Some of cellular and molecular mechanisms underlying the respiratory and cardiovascular dysfunction is more critical and general. The demonstration of such general processes not only may help the understanding of etiology and pathophysiology of the diseases, but also suggests potential therapeutic modalities for the diseases. Severe breathing disorders including high apnea rate and breathing irregularity are found in Rett syndrome (RTT). In a novel rat model of RTT, we compared rat physical condition and behaviors with traditional mouse models of RTT. We found that the novel Mecp2−/Y rat model as an alternative RTT model recapitulated numerous RTT-like symptoms. To uncover the neuronal mechanisms underlying the RTT respiratory disorders, we performed in vivo recording from brainstem neurons in ventral respiratory column (VRC). Excessive activity of both inspiratory and expiratory neurons as well as ectopic discharge of phrenic nerve were detected in null rats. Such defects were likely caused by hyperexcitability of respiratory neurons due to inadequate synaptic inhibition necessary for phase switching. Then we took the GABAergic intervention to hyperexcitability of respiratory neurons, and successfully corrected the defects in neuronal firing patterns as well as the RTT breathing phenotypes.

Similarly, change of cellular excitability was also observed in diabetic vascular complications. A critical player for the membrane excitability of vascular smooth muscle cells (VSMCs) is the KATP channel that is strongly suppressed by methylglyoxal (MGO) known to be overly produced with persistent hyperglycemia. The elevated level of microRNA (miR)-9a-3p contributed to the down-regulation of vascular KATP channels. miR-9a-3p inhibition using antisense oligonuecleotides corrected the dysfunction of KATP channels. Since VSMC membrane excitability plays an important role in vascular tone regulation, we generated a new strain of transgenic Tagln-ChR mouse model and demonstrate an alterative to manipulate VSMC membrane excitability and vascular tone using optogenetic approaches. Thus several molecular targets in cardiorespiratory system have been demonstrated underlying membrane excitability and the developments of several disease conditions in this thesis study.

DOI

https://doi.org/10.57709/12426547

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