Tuesday, April 16, 2024
4/16/2024
Brain-immune crosstalk in myocardial infarction Project Summary Myocardial infarction (MI) remains a leading cause of death worldwide and even survivors suffer from reduced quality of life, increased hospitalization rates, high health care costs, and lower life expectancy. Decades of research have improved primary prevention as well as interventional and drug therapies, but the clinical problem for MI patients remains huge, particularly regarding aspects of post-MI healing. While some patients develop a stable scar with adaptive remodeling of the surviving myocardium and a compensated cardiac function for many years, other patients with comparable extent of initial damage rapidly develop ischemic heart failure with extremely poor prognosis. Furthermore, an MI triggers a vicious inflammatory cycle of further atherosclerosis acceleration, increasing the risk for subsequent ischemic events. Various studies have shown that the immune system plays a critical role in these processes. An MI activates multiple sensory systems of the brain, including pain, stress, and autonomic centers, as well as hypothalamic and brainstem sensors of inflammation and hemodynamics. It was recently described that distinct brain regions control large scale leukocyte shifts and functional alterations during episodes of acute stress (Poller et al., Nature 2022). How different brain centers orchestrate the immune response to an MI and whether such neuro-immune axes can be therapeutically harnessed to optimize post-MI inflammation and healing via targeted non-invasive brain interventions is unknown. This project combines state-of-the-art tools of neuroscience, cardiology, and immunology to comprehensively explore how an MI alters regional brain activity and how different brain centers in turn shape the course of MI healing. Aim 1 combines interruption of different sensory input branches with iDISCO cFos ClearMap histology, fiber photometry, and retrograde tracing to map MI-induced alterations in neuronal circuit activity. Preliminary data show strongly altered neuronal firing after an MI. Aim 2 elucidates the effects of MI-activated brain centers on the peripheral immune response after an MI. Preliminary data show that ablation of stress centers in the brain increases post-MI leukocytosis in bone marrow and heart, whereas chemogenetic stimulation of hypothalamic CRH neurons after an MI strongly reduces myocardial inflammation, which is known to correlate with better functional outcomes. Aim 2 combines different MI models with an established set of gain and loss-of-function interventions, including chemogenetics, optogenetics, viral tracing, brain-region specific KO mice, and cell-type specific stress hormone receptor KO mice to investigate how different brain regions contribute to post MI inflammation and healing. Finally, Aim 3 integrates gained insights and focuses on blocking detrimental while enhancing beneficial aspects of neuro-immune signaling, e.g. by dynamically manipulating CRH neuron activity during defined phases after an MI, to therapeutically tailor brain- immune crosstalk toward better MI healing. Aim 3 will provide the scientific basis for translational approaches such as transcranial magnetic stimulation of specific brain regions to improve MI patients’ outcomes.
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