Transient receptor potential canonical 6 (TRPC6) channels are permeable to Na+ and Ca2+ and are widely expressed in the brain. In this study, we investigated the role of TRPC6 following ischemia/reperfusion (I/R) and oxygen-glucose deprivation (OGD). We found that TRPC6 expression was increased in wild type (WT) mice cortical neurons following I/R and in primary neurons with OGD, and that deletion of TRPC6 reduced the I/R-induced brain infarct in mice and the OGD- /neurotoxin-induced neuronal death. Using live-cell imaging to examine intracellular Ca2+ levels ([Ca2+]i), we found that OGD induced a significant higher increase in glutamate-evoked Ca2+ influx compared to untreated control and such an increase was reduced by TRPC6 deletion. Enhancement of TRPC6 expression using AdCMV-TRPC6-GFP infection in WT neurons increased [Ca2+]i in response to glutamate application compared to AdCMV-GFP control. Inhibition of N-methyl-d-aspartic acid receptor (NMDAR) with MK801 decreased TRPC6- dependent increase of [Ca2+]i, indicating that such a Ca2+ influx was NMDAR dependent. Furthermore, TRPC6-dependent Ca2+ influx was blunted by blockade of Na+ entry. Finally, OGD-enhanced Ca2+ influx was reduced, but not completely blocked, in the presence of voltage dependent Na+ channel blocker tetrodotoxin (TTX) and dl‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) blocker CNQX. Altogether, we concluded that I/R-induced brain damage was, in part, due to upregulation of TRPC6 in cortical neurons. We postulate that overexpression of TRPC6 following I/R may induce neuronal death partially through TRPC6-dependent Na+ entry which activated NMDAR, thus leading to a damaging Ca2+ overload. These findings may provide a potential target for future intervention in stroke-induced brain damage. Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that is associated with many cardiovascular complications, such as autonomic dysfunctions, stroke and heart failure. Chronic intermittent hypoxia (CIH) is a prominent feature of OSA. In CIH exposed rodents (a model for OSA), CIH induces the similar cardiovascular complications as seen in OSA patients. In particular, OSA impairs baroreflex control of the heart rate (HR), which is used as an independent indicator for heart failure. Since the baroreflex control arc includes the aortic depressor nerve (ADN), vagal efferent and central components, we hypothesize that CIH induces dysfunctions of all three components. Since mice can be genetically manipulated, an understanding of the effects of CIH on multiple neural components in the baroreflex arc in wild type mice may lead to a future study of treatments. In this study, we have examined the effects of CIH on baroreceptor afferent, central and vagal efferent components of the baroreflex circuitry in normal wild type C57BL/6J mice. Mice (4-5 months) were exposed to room air (RA) or CIH for 35-50 days and were then anesthetized with isoflurane, ventilated and catheterized for measurement of mean arterial blood pressure (MAP) and HR. Baroreceptor function was characterized by measuring percent changes of integrated ADN activity (Int ADNA) relative to the baseline value in response to the vasodilator sodium nitroprusside and the vasoconstrictor phenylephrine-induced changes in MAP. Data were fitted to a sigmoid logistic function curve. HR responses to electrical stimulation of the left ADN and the right vagus nerve were assessed under anesthesia. Compared with RA controls, CIH significantly increased maximum baroreceptor gain or maximum slope, maximum Int ADNA, and Int ADNA range (maximum-minimum Int ADNA). In addition, CIH maintained the maximum amplitude of the bradycardic response to vagal efferent stimulation. In contrast, CIH significantly reduced the maximum amplitude of bradycardic response to left ADN stimulation. Thus, CIH decreased central mediation of the baroreflex, but augmented the baroreceptor afferent function and maintained vagal efferent control of HR in mice. Excessive reactive oxygen species (ROS) (such as the superoxide radical) is commonly associated with cardiac autonomic dysfunctions. Though superoxide dismutase 1 (SOD1) overexpression may protect against ROS damage to the autonomic nervous system, superoxide radical reduction may change normal physiological functions. Previously, we demonstrated that human SOD1 (hSOD1) overexpression did not change baroreflex bradycardia and tachycardia, but increased aortic depressor nerve activity (ADNA) in responses to arterial pressure changes in C57B6SJL-Tg (SOD1)2 Gur/J mice. Since the barorelfex arc includes afferent, central and efferent components, the objective of this study was to determine whether hSOD1 overexpression alters the central and vagal efferent mediation of the heart rate (HR) responses. Our data indicate that SOD1 overexpression decreased HR responses to vagal efferent nerve stimulations but did not change HR responses to aortic nerve stimulation. Along with the previous study, we suggest that SOD1 overexpression preserves the normal baroreflex function but may alter the functions of aortic depressor nerve, vagal efferent and central components differently. While SOD1 overexpression likely enhanced aortic depressor nerve function and central mediation of bradycardia, it decreased vagal efferent control of HR. Currently, we are using the hSOD1 overexpressing mouse model to determine whether hSOD1 overexpression can preserve normal afferent, efferent, and central components of the baroreflex arc in the CIH model of sleep apnea.

Graduation Date





Cheng, Zixi


Doctor of Philosophy (Ph.D.)


College of Medicine


Burnett School of Biomedical Sciences

Degree Program

Biomedical Sciences









Release Date

May 2022

Length of Campus-only Access

5 years

Access Status

Doctoral Dissertation (Campus-only Access)