["Acta Physiologica, Volume 231, Issue 4, April 2021. ", "\nAbstract\n\nAim\nImpairments in cerebral structure and cognitive performance in chronic heart failure (CHF) are critical components of its comorbidity spectrum. Autonomic afferents that arise from cardiac sensory fibres show enhanced activity with CHF. Desensitization of these fibres by local application of resiniferatoxin (RTX) during myocardial infarction (MI) is known to prevent cardiac hypertrophy, sympathetic hyperactivity and CHF. Whether these afferents mediate cerebral allostasis is unknown.\n\n\nMethods\nCHF was induced by myocardial infarction. To evaluate if cardiac afferents contribute to cerebral allostasis, RTX was acutely applied to the pericardial space in controls (RTX) and in MI treated animals (MI/RTX). Subjects were then evaluated in a series of behavioural tests recapitulating different symptoms of depressive disorders. Proteomics of the frontal cortices (FC) was performed to identify contributing proteins and pathways responsible for behavioural allostasis.\n\n\nResults\nDesensitization of cardiac afferents relieves hallmarks of an anxio/depressive‐like state in mice. Unique protein signatures and regulatory pathways in FCs isolated from each treatment reveal the degree of complexity inherent in the FC response to stresses originating in the heart. While cortices from the combined treatment (MI/RTX) did not retain protein signatures from the individual treatment groups, all three groups suffer dysregulation in circadian entrainment.\n\n\nConclusion\nCHF is comorbid with an anxio/depressive‐like state and ablation of cardiac afferents relieves the despair phenotype. The strikingly different proteomic profiles observed in FCs suggest that MI and RTX lead to unique brain‐signalling patterns and that the combined treatment, potentially through destructive interference mechanisms, most closely resembles controls.\n\n"]