Date of Award
Doctor of Philosophy (PhD)
The paraventricular nucleus of the hypothalamus (PVN) is an important cardiovascular and autonomic regulatory center. Activation of PVN neurons projecting to the brainstem and spinal cord elevates sympathetic activity and blood pressure. Brain derived neurotrophic factor (BDNF) plays a key role in stress-induced cardiovascular responses within the PVN and is also known to be upregulated in the PVN in response to stress and hyperosmolality. PVN overexpression or acute injection of BDNF also elevates blood pressure chronically. However, the mechanism behind BDNF-mediated cardiovascular regulation is not fully understood. BDNF is known to modulate excitatory/inhibitory signaling by altering the expression and membrane trafficking of neurotransmitter receptors. Further, changes in the excitatory/inhibitory signaling in the PVN have been shown to elevate blood pressure and sympathetic activity chronically in various hypertensive models. Thus, we set out to examine the long‐term effects of BDNF overexpression within the PVN on NMDA‐, GABAA‐ and catecholaminergic receptor‐mediated blood pressure mechanisms. We tested the hypothesis that BDNF increases blood pressure, in part by diminishing catecholaminergic inhibitory input from the nucleus of the solitary tract (NTS) to the PVN, while also enhancing NMDA and diminishing GABAA-signaling in the PVN. Sprague-Dawley (SD) rats received bilateral PVN injections of viral vectors expressing either green fluorescent protein (GFP) or BDNF and bilateral NTS injections of vehicle or anti-dopamine-β-hydroxylase-conjugated saporin (DSAP), which selectively lesions catecholaminergic neurons. BDNF overexpression in the PVN without NTS lesioning significantly increased mean arterial pressure in awake animals (p < 0.001). DSAP treatment also increased blood pressure in the GFP group but failed to affect blood pressure in the BDNF group. In addition, hypotensive responses to PVN injections of a β-adrenergic agonist were significantly attenuated by BDNF overexpression, while BDNF treatment also significantly reduced β1-adrenergic receptor mRNA expression in the PVN (p < 0.01). Cardiovascular responses to PVN injections of NMDA and GABAA agonists and antagonists were also recorded in GFP and BDNF rats. NMDA inhibition led to greater decreases in blood pressure in the BDNF group (p<0.05), while NMDA activation did not significantly alter blood pressure in the two groups (p=0.31, n.s.). NMDA-signaling is elevated in the PVN in response to BDNF, which may be due to an increase in presynaptic release of glutamate or an increase in glutamatergic innervation. Meanwhile, GABAA inhibition led to greater increases in blood pressure in the GFP group, while GABAA activation led to a greater decrease in blood pressure in the GFP group. GABAergic signaling is reduced in the PVN in response to BDNF, potentially due to a decrease in both presynaptic and postsynaptic GABAA signaling mechanisms. Protein expression of NMDAR1 in the PVN was also significantly elevated in the BDNF group (p<0.05) while GABAA-alpha1 expression in the PVN was diminished in the BDNF group (p<0.01). In summary, increased BDNF expression in the PVN elevates blood pressure, in part by downregulating β-receptor signaling and diminishing hypotensive catecholaminergic input from the NTS to the PVN, while also promoting NMDA-mediated excitatory activity and diminishing GABAA-mediated inhibitory activity in the PVN.
Number of Pages
Thorsdottir, Daniella Johanna, "The Role Of Bdnf-Mediated Neuroplasticity In Cardiovascular Regulation Within The Hypothalamus And Brainstem" (2021). Graduate College Dissertations and Theses. 1387.
Available for download on Wednesday, April 13, 2022