Chronic heart failure (CHF) is one of the leading causes of death in the U.S. A primary characteristic of this disease is elevated sympatho-excitation and exercise intolerance during physical activity. During exercise in heart failure patients, extreme activation of the sympathetic nervous system is often seen and evokes an exaggerated pressor response accompanied by hyperventilation. These abnormalities potentially increase cardiovascular risk during physical activity in these patients. Experimental evidence suggests that 1) the exaggerated sympatho-excitation during exercise is directly related to an increased sensitivity of the exercise pressor reflex (EPR); 2) the enhanced mechanically sensitive afferent component of this reflex (i.e. mechanoreflex) primarily contributes to the exaggerated EPR in CHF and 3) muscle metaboreflex activated by femoral intra-arterial injection of capsaicin is blunted in CHF rats, which is associated with downregulated Transient Receptor Potential Vanilloid Type 1 (TRPV1) protein expression in lumbar dorsal root ganglia (DRGs). The molecular and cellular mechanisms underlying altered mechano- and metabo-sensitive afferent limb in CHF have not been fully understood. Our preliminary data showed that myocardial infarct (MI) triggered time-dependent macrophage infiltration into lumbar DRGs, suggesting that a neural inflammatory cascade occurs in muscle afferent ganglia post MI. We hypothesize that macrophage activation in lumbar DRGs plays a critical role in muscle afferent sensitization as well as the exaggerated EPR via regulating Kv channels and glutamatergic signaling in CHF. We also hypothesize that macrophage activation in lumbar DRGs also serves as an upstream mechanism to cause the TRPV1 channel dysfunction in muscle metabo-sensitive neurons in CHF. In Aim 1, we propose to determine the time-dependent macrophage infiltration/activation in lumbar (L4-L6) DRGs in post-MI male and female rats as well as post-MI CX3CR1CreER-tdTomato reporter mice. We will also plan to identify the pro-inflammatory (M1)/anti-inflammatory (M2) phenotypes of macrophages in lumbar DRGs post MI. Finally we will determine if pharmacological macrophage inhibition in lumbar DRGs can restore the exaggerated EPR as well as muscle afferent sensitization in CHF male and female rats. Aim 2 is designed to address how macrophages influence muscle afferent neuronal excitability post MI. We will determine if local pharmacological macrophage inhibition in lumbar DRGs can restore altered Kv channels, TRPV1 channel and glutamatergic dysfunction in CHF male and female rats. We will use highly integrative techniques including molecular (real-time PCR, western blot, immunofluorescence and tissue clearance), cellular (patch clamp) and whole animal experiments (measuring EPR function, single afferent recording) to test our hypotheses in this project. We believe that this proposed research will address important functional and mechanistic issues that direct...