Chronic psychological stressors, including work-related stress, poor socioeconomic status and social isolation —
all heightened by recent Covid-19 lockdowns — are major risk factors for hypertension and cardiovascular
disease. Stress-activated regulatory mechanisms that stimulate the sympathetic nervous system to elevate blood
pressure and redistribute blood flow to vital organs have evolved as life-protecting measures. From an
evolutionary perspective, enhancing cardiovascular responses through long-term sensitization of these
mechanisms is advantageous to organisms subjected to repeated stressors. However, in modern society, where
coping with stressful situations rarely requires marked elevations in blood pressure, these actions become
detrimental, as repeated unnecessary overload of the cardiovascular system exerts irreversible cardiac, vascular,
and renal damage. Accordingly, augmented cardiovascular sensitivity to stressors in young, normotensive
individuals is strongly correlated with the risk of becoming hypertensive later in life. Our long-term goal is to
investigate the central mechanisms that determine the magnitude of blood pressure elevations elicited by stress
in order to identify novel anti-hypertensive therapeutic targets. Here, we propose to investigate a novel signaling
cascade mediated by brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) in
the paraventricular nucleus of the hypothalamus (PVN), a brain region that plays a key role in orchestrating
neuroendocrine and cardiovascular stress responses. BDNF expression is upregulated in the PVN during stress
in response to increased excitatory input and neuronal activity. We have previously shown that BDNF elicits
important adaptive changes within the PVN to elevate sympathetic activity and blood pressure. Our preliminary
data suggest that BDNF stimulates mTOR, as part of mTOR complex-1 (mTORC1) in PVN neurons, and mTORC1
can fundamentally change neuronal morphology and synaptic connectivity, resulting in elevated neuronal
excitability to augment cardiovascular stress responses and promote hypertension. To test our hypothesis, we
employ a comprehensive array of in vitro patch-clamp studies, neuronal morphology analysis, as well as in vivo
experiments using viral vector-mediated genetic manipulation of BDNF and mTORC1 and telemetric monitoring
of cardiovascular parameters in rats. In Aim 1, we test whether mTORC1 activation in the PVN elevates blood
pressure, augments cardiovascular stress responses, and mediates hypertensive actions of BDNF. In Aim 2, we
determine whether BDNF–mTORC1 signaling regulates structural and functional characteristics of PVN pre-
sympathetic neurons, resulting in enhanced excitability. In Aim 3, we test whether inhibition of BDNF–mTORC1
prevents chronic stress-induced hypertension in borderline hypertensive rats. These studies have the potential
to significantly advance the field by establishing the BDNF–mTORC1 axis as a highly important regulator of
autonomic and cardiovascular function that determines the amplitude of blood pressure elevations during stress
and elicits long-term adaptive mechanisms in the PVN that promote the development of hypertension.
