Neuroinflammation and Microglial Activation in The Central Amygdala in Rats with Heart Failure

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Cardiovascular diseases (CVDs), such as heart failure (HF) are the most common cause of death globally. Moreover, clinical studies support a high degree of comorbidity between CVDs cognitive impairment, and emotional distress, with 20–40% of all HF patients displaying depression and anxiety levels significantly higher than the healthy population. Still, the precise underlying mechanisms causing those cognitive and emotional impairments remain elusive. The paraventricular nucleus of the hypothalamus (PVN) is a key brain structure involved in emotional control and directly communicates with the central lateral part of the amygdala (CeA), which actively participates in the regulation of emotion and fear memories. While markers of neuroinflammation (NI) have been previously described in the PVN of HF rats, it is at present unknown whether the CeA is also affected. To address this question, we used an ischemic HF rat model (ejection fraction <35%). We developed a comprehensive quantitative microglial profiler using the IMARIS software along with immunohistochemical staining with the microglial marker IBA‐1 to assess changes in various microglial parameters indicative of different microglia activity stages. At early stages of the established HF (8wks post‐surgery), we found elevated indexes of microglial activation in the PVN compared to sham controls (15.4% decrease in surface area, 29.9% decrease in cell volume, 15.5% decrease in filament length and 35.1% increase in IBA‐1 immunoreactivity intensity, p<0.001 in all cases). These changes became more pronounced at later (14wks) stages of the disease. While no changes were observed in the CeA at the early stage, significant changes were observed at 14wks after HF compared to sham controls (21.2% increase in cell volume, 9.7% decrease in filament length and 12.3% increase in IBA‐1 immunoreactivity intensity, p<0.05 in all cases). These morphometric changes are indicative of de‐ramification and somatic swelling of microglial cells. These findings were corroborated by elevated mRNA levels of IBA‐1, TNF‐a, IL‐1β and IL‐6 measured via qPCR in PVN and CeA punches from HF rats. Importantly, no microglial changes were observed in cortical areas suggesting that HF‐induced NI was not a diffuse phenomenon affecting the entire brain. To the best of our knowledge, our results highlight for the first time that in addition to the PVN, HF also results in a robust microglial cell activation in the CeA, a critical forebrain region involved in emotion and cognition. NI‐related changes in the CeA occurred at a later stage of the disease, and could potentially contribute to cognitive impairment and mood disorders in HF patients.Support or Funding InformationNational Institutes of Health grants R01NS094640 and R01HL090948 to JES