ORCID
0009-0004-9142-1544
Date of Award
2025
Document Type
Thesis
Degree Name
Master of Science (MS)
Department
Pharmacology
First Advisor
Anna K. Pace
Abstract
The paraventricular nucleus of the hypothalamus (PVN) orchestrates neuroendocrine and cardiovascular responses to stress. Our lab previously identified the pro-hypertensive role of brain-derived neurotrophic factor (BDNF) in the PVN, where stress-induced BDNF upregulation incites adaptive structural and connective changes in neurons. These changes enhance sensitivity to hypertensive stimuli, augmenting sympathetic activity and raising blood pressure. Additionally, BDNF has been implicated as an activator of the mammalian target of rapamycin (mTOR), a serine/threonine kinase. Together with regulatory-associated protein of mTOR (Raptor), mTOR forms mTOR complex-1 (mTORC1), known to couple various stimuli with energy-demanding cellular functions and modulate neural circuit sensitivity within the central nervous system. We hypothesized that the BDNF-mTOR signaling pathway modulates the integration and transmission of afferent stress signals in the PVN, leading to pro-hypertensive cardiovascular responses. To test this, male Sprague-Dawley (SD) rats received bilateral PVN injections of AAV2 viral vectors expressing myc-tagged BDNF (BDNFmyc), shRNA against TSC1 (an mTORC1 repressor) to stimulate mTORC1, shRNA against Raptor to inhibit mTORC1, or scrambled shRNA/GFP as controls. Blood pressure and heart rate were monitored via telemetry over 4 weeks, with cardiovascular responses to restraint (60 minutes) and water stress (15 minutes, 1 cm deep, 25°C water) recorded 3-4 weeks post-injection. Injections were verified, and neuronal morphology and pS6 levels (a marker of mTOR activity) were assessed using immunofluorescence. TSC1 knockdown, activating mTORC1, significantly increased resting blood pressure compared with controls, whereas Raptor knockdown, inhibiting mTORC1, had no effect. BDNF overexpression also significantly raised blood pressure, consistent with our previous findings, and these increases were completely abolished by Raptor knockdown. Additionally, mTORC1 inhibition via Raptor knockdown significantly reduced stress-induced hypertensive responses. Immunofluorescence analysis showed that both soma size and immunoreactivity of pS6, indicating mTOR activity, were significantly increased by both TSC1 knockdown and BDNF overexpression in the PVN. Raptor knockdown reduced both soma size and pS6 intensity relative to controls and counteracted the effects of BDNF. In conclusion, our study demonstrates that mTOR activation in the PVN significantly elevates blood pressure under both baseline and acute stress conditions and mediates the hypertensive responses and neuronal morphological changes induced by BDNF.
Language
en
Number of Pages
65 p.
Recommended Citation
Pace, Anna Katrin, "Brain-Derived Neurotrophic Factor (BDNF)-Mammalian Target of Rapamycin (mTOR) Signaling in Hypothalamic Blood Pressure Regulation" (2025). Graduate College Dissertations and Theses. 2004.
https://scholarworks.uvm.edu/graddis/2004
