Date of Award

8-1-2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Steve W. Mifflin

Second Advisor

J. Thomas Cunningham

Third Advisor

Ann M. Schreihofer

Abstract

Chronic intermittent hypoxia (CIH) rodent model is widely utilized to study obstructive sleep apnea (OSA) associated disease such as hypertension. Arterial chemoreceptor is activated by CIH, and leads to increased sympathetic nerve discharge, resulting in elevated arterial pressure. The central neuronal mechanisms of CIH induced hypertension are barely understood. The nucleus of the solitary tract (NTS) receives the first synaptic inputs from arterial chemoreceptor afferents. Transcription factor ΔFosB is increased in the NTS after a 7 day-CIH exposure. We hypothesize that NTS ΔFosB could mediate neuronal plasticity, contribute to CIH induced hypertension.

Three specific aims were addressed. Aim 1: To determine the relationship between NTS ΔFosB and CIH hypertension. Viral constructs were delivered into NTS to functionally block ΔFosB (ΔJunD group). Mean arterial pressure (MAP) was measured in day time when rats were exposed to intermittent hypoxia and night time when they were in normoxia. The increase in MAP observed in ΔJunD and sham groups during day time was dampened in ΔJunD group during night time, indicating the contribution of ΔFosB to the sustained component of CIH associated hypertension. Aim 2: To determine the time-course of induction of ΔFosB immunoreactive NTS neurons during CIH exposure. Rats were separated into normoxia, 1 day, 3, 5, 7 days CIH, and 1 day, 3, 7 days recovery after 7 days CIH groups. ΔFosB immunoreactivity increased within 1 day CIH, and maintained this elevation throughout 7 days of CIH. 1 day recovery was sufficient to reduce ΔFosB immunoreactivity to normoxia level. Therefore, ΔFosB under CIH develops rapidly. Aim 3: To determine the function of ΔFosB in glutamatergic transmission after CIH. Miniature excitatory post-synaptic current (mEPSC) properties of NTS neurons of rats exposed to either different days of CIH or room air were compared. CIH increased mEPSC amplitude but not frequency, suggesting a post-synaptic site of effect. Additionally, functional blockade of NTS ΔFosB with ΔJunD decreased mEPSC amplitude back to normoxia level. Finally, overexpression of NTS ΔFosB increased mEPSC amplitude to similar levels as CIH. These results suggest that ΔFosB in NTS neurons mediates molecular adaptations which might play an important role in CIH associated hypertension.

Comments

Wu, Qiong, Role of ΔFosB in nucleus of the solitary tract (NTS) in cardiovascular adaptations to chronic intermittent hypoxia (CIH) in rats. Doctor of Philosophy (Biomedical Sciences), July 2015, 121 pp., 16 figures, bibliography, 146 references. Available August 2016.