Tuesday, May 14, 2024
5/14/2024
Project Summary Congestive heart failure (CHF) and mood disorders occur as comorbid conditions at an alarmingly high rate. The incidence of depression in patients that have survived a myocardial infarction (MI) has been reported to be as high as 45%, while occurring at a rate of 2-9% in the general population. Post-MI patients that develop depression are at a much greater risk of experiencing an adverse cardiovascular event within one year as compared to non-depressed patients. In spite of the profound clinical relevance, the mechanisms that promote depression in CHF patients are not known. A compelling hypothesis regarding the coincidence of cardiovascular disease and depression is that the etiological mechanisms in both disorders are similar. Among the commonly observed physiological maladaptations, high circulating levels of the adrenal mineralocorticoid hormone aldosterone (ALDO) have been reported in animal models and human clinical cases of major depressive disorder and CHF. The current proposal will explore the role of ALDO in promoting affective and cognitive impairments in a rat model of CHF that recapitulates many of the physiological outcomes observed in human patients. CHF is induced by coronary artery ligation to induce MI, the most frequent cause of CHF in humans. The neurological impact of CHF is then studied using behavioral and electrophysiological methods. Specifically, we will measure anhedonia, a core symptom of major depressive disorder in humans, as well as cognitive function which is frequently impaired in CHF patients and in individuals with major depressive disorder. The ability of central treatments with mineralocorticoid receptor antagonists to prevent depressive- like behavior and learning and memory deficits will be determined. Synaptic function in the hippocampus, a brain region implicated in mood disorders and cognitive function, is assessed in animals with CHF using electrophysiological techniques. Finally, we will investigate the neurotrophin brain-derived neurotrophic factor (BDNF) as a potential downstream mediator of the behavioral effects of high circulating ALDO in CHF. BDNF expression in the hippocampus has been implicated in mood and cognition and neurological responses to physiological and psychological stressors. The efficacy of direct infusion of BDNF into the hippocampus in preventing aberrant behavioral phenotypes in CHF will be tested, as well as the efficacy of exercise, a behavioral manipulation known to have positive effects on mood, cognition, and cardiac function, and robustly enhance BDNF expression. Results generated from this proposal will enhance our understanding of the impact of cardiac disease states on the brain as well as suggest potential therapeutic avenues for reducing the deleterious impact of CHF on quality of life.
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