Myocardial infarction (MI) induced heart failure (HF) is a leading cause of morbidity and mortality over the world. Regular exercise improves quality of life and decreases hospitalization and mortality of patients with HF. In animals, exercise post MI attenuates progressive cardiac remodeling and cardiac dysfunction, and decreases neuronal activity in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM), which are key brain nuclei contributing to sympathetic hyperactivity post MI. The peripheral and central molecular mechanisms underlying these beneficial effects of exercise are not well understood. We studied one possible mechanism, brain-derived neurotrophic factor (BDNF), an exercise-induced factor, which via binding to its receptor tropomyosin-related kinase B (TrkB) may contribute to improvement of cardiac function post MI. In the brain, the ratio between two isoforms of the TrkB receptor, full-length and truncated forms (TrkB.FL/TrkB.T1) determines the extent of intracellular responses to mature BDNF (mBDNF; an active form of BDNF) and a decrease in this ratio may reflect down-regulation of BDNF-TrkB.FL signaling. Ca2+/calmodulin-dependent kinase II (CaMKII) and protein kinase B (Akt) are intracellular factors of BDNF-TrkB signaling in hippocampal/cortical neurons. Activation of cardiac BDNF-TrkB signaling may increase cardiomyocyte survival and myocardial contractility. In hypertensive rats, the role of BDNF-TrkB signaling in the PVN and RVLM appears opposite with activation of this axis in the PVN increasing, but in the RVLM decreasing sympathetic nerve activity (SNA). However, activation of CaMKII and Akt in the PVN and RVLM both mediate increase in SNA. The specific role of BDNF-TrkB signaling in the PVN and RVLM of rats with HF post MI has not yet been studied. We hypothesized that exercise training post MI enhances BDNF-TrkB signaling pathways in the left ventricle (LV) and RVLM, but inhibits in the PVN, and thereby preserves cardiac structure and function post MI. We evaluated changes in BDNF-TrkB axis and intracellular factors CaMKII and Akt in the non-infarct area of the LV, PVN and RVLM in sedentary and exercising rats with MI. The impact of systemic blockade of BDNF-TrkB signaling was assessed with ANA-12, a selective non-competitive antagonist of TrkB receptors. In the infarct area of the LV, mBDNF protein decreased and TrkB.T1 protein increased. In the non-infarct area, mBDNF tended to be decreased without change in TrkB.T1 expression. The activities of CaMKII and Akt were decreased in the non-infarct area of the LV. In the PVN and RVLM, the TrkB.FL/TrkB.T1 ratio was decreased but without changes in mBDNF and downstream factors except for decrease in Akt activity in the RVLM. Exercise training improved ejection fraction (EF), cardiac index and LV end-diastolic pressure, but only the exercise-induced improvement of EF was blocked by ANA-12. In the non-infarct area of the LV, exercise prevented decreases in mBDNF, CaMKII and Akt, and these effects were prevented by ANA-12. In the PVN, exercise increased mBDNF and decreased Akt activity, whereas in the RVLM, exercise had no effect on mBDNF but decreased CaMKII activity. The exercise-induced increase mBDNF in the PVN and decrease in p-CaMKIIβ expression in the RVLM were prevented by ANA-12. Our findings suggest that down-regulation of BDNF-TrkB signaling post MI is prominent in the LV with decreases in mBDNF protein in the infarct area and intracellular factors CaMKII and Akt in the non-infarct area. Increases in mBDNF, CaMKII and Akt in the LV by exercise may contribute to improvement of EF. In the PVN and RVLM, despite a decrease in the ratio of TrkB.FL/TrkB.T1 in both brain nuclei, only Akt activity decreased in the RVLM post MI. Exercise-induced decreases in activities of CaMKII in the RVLM and Akt in the PVN may both contribute to reduction in sympathetic hyperactivity post MI.