Physical inactivity is a major independent risk factor for cardiovascular disease (CVD) and is now considered
the leading cause of premature death (Blair, 2009). Rates of physical inactivity continue to increase along with
health care costs to treat CVD. Despite these disturbing trends, the mechanisms by which a sedentary lifestyle
leads to CVD are not fully known. CVD is associated with increased sympathetic nervous system activity and
overactivity of a brainstem region known as the rostral ventrolateral medulla (RVLM) (Sved et al.,
2003;Guyenet, 2006). Sympathoexcitatory responses to direct activation of the RVLM are enhanced in
sedentary versus physically active animals (Mischel and Mueller, 2011) and are associated with changes in
dendritic branching (Mischel et al., 2014). These data suggest that a sedentary lifestyle may contribute to the
development of CVD by increased sensitivity of RVLM neurons. Our long term goal is to understand the central
sympathetic mechanisms by which physical inactivity contributes to the development of CVD. This is an
important clinical, economic and public health care problem. The overall objective of this application is to define
the mechanisms by which physical inactivity increases, and physical activity prevents over-activation of
presympathetic neurons in the RVLM. Our central hypothesis is that sedentary and hypertensive conditions
each enhance glutamatergic signaling, initiate BDNF-dependent mechanisms and further propagate enhanced
glutamatergic signaling; such that in combination, produce clinically relevant increases in sympathetic outflow
and blood pressure. This project is expected to shift current paradigms regarding the mechanisms by which
physical inactivity and pro-hypertensive stimuli combine to increase sympathetic activity and exaggerate the
hypertensive phenotype. We will test our central hypothesis in distinct but interrelated aims using our well-
established models of sedentary or active conditions and 2K-1C hypertension with sham-operated rats as
controls. Aim 1: Utilize in vivo gene targeting to determine the contribution of BDNF-TrkB signaling in sedentary
and 2K1C mediated neuroplasticity in the RVLM. Aim 2: Establish relationships between BDNF and synaptic
plasticity-associated mRNA and protein expression in the RVLM of sedentary versus active, normotensive and
2K1C rats using laser capture microdissection of presympathetic RVLM neurons and tract-tracing, triple-
immunofluorescent labeling. Aim 3: Quantify glutamatergic tone and neuronal activity in the RVLM of sedentary
versus active, normotensive or 2K1C rats using magnetic resonance spectroscopy (MRS) and magnetic
resonance imaging (MRI) of the RVLM. Our studies combine state-of-the art techniques with conceptually
innovative hypotheses to fill significant knowledge gaps towards understanding two fundamentally important
and intertwined, yet unresolved health problems, i.e. physical inactivity and hypertension.