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Research
Javier E Stern
Georgia State University
Corresponding Author
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Background
Cardiovascular diseases, including heart failure are the most common cause of death globally. Recent studies support a high degree of comorbidity between heart failure and cognitive and mood disorders resulting in memory loss, depression and anxiety. While neuroinflammation in the hypothalamic paraventricular nucleus has been shown to contribute to autonomic/cardiovascular dysregulation in heart failure, mechanisms underlying cognitive and mood disorders in this disease remain elusive. The goal of this study was to quantitatively asses several markers of neuroinflammation in the central amygdala, a critical forebrain region involved in emotion and cognition, and to compare the time course of neuroinflammation between the central amygdala and paraventricular nucleus during the progression of heart failure.
Methods
We developed and implemented a comprehensive microglial/astrocyte profiler for precise three-dimensional morphometric analysis of individual microglia and astrocytes in specific brain nuclei at different time points during the progression of heart failure. To this end, we used a well-established ischemic heart failure rat model. Morphometric studies were complemented with quantification of various proinflammatory cytokines and A1/A2 astrocyte markers via qPCR.
Results
We report a drastic structural remodeling of central amygdala microglia and astrocytes during heart failure that affected cell volume, surface area, filament length, dendritic branches, resulting overall in somatic swelling and deramification, indicative of an activated microglial state. These changes occurred in a time-dependent manner and were delayed compared to changes in the hypothalamic paraventricular nucleus. Morphometric changes correlated with elevated mRNA levels of proinflammatory cytokines and markers of reactive neurotoxic astrocytes in the paraventricular nucleus and central amygdala during heart failure.
Conclusion
We provide evidence that in addition to the previously described hypothalamic neuroinflammation implicated in sympathohumoral activation during heart failure, microglia and astrocytes within the central amygdala also undergo structural remodeling indicative of glial shifts towards an activated and neurotoxic phenotype, respectively. Thus, our studies suggest that neuroinflammation in the amygdala stands as a novel pathophysiological mechanism and therapeutic target for alleviating comorbid emotional and cognitive deficits commonly observed at later stages during the course of heart failure.
Keywords
hypothalamus, amygdala, microglia, astrocytes, A1, behavior, cytokines, heart failure, neuroinflammation, autonomic
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A new preprint design is coming!
We have improved readability, clarity, accessibility, and opportunities for engagement.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Javier E Stern
Georgia State University
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 28 Jan, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Cardiovascular diseases, including heart failure are the most common cause of death globally. Recent studies support a high degree of comorbidity between heart failure and cognitive and mood disorders resulting in memory loss, depression and anxiety. While neuroinflammation in the hypothalamic paraventricular nucleus has been shown to contribute to autonomic/cardiovascular dysregulation in heart failure, mechanisms underlying cognitive and mood disorders in this disease remain elusive. The goal of this study was to quantitatively asses several markers of neuroinflammation in the central amygdala, a critical forebrain region involved in emotion and cognition, and to compare the time course of neuroinflammation between the central amygdala and paraventricular nucleus during the progression of heart failure.
Methods
We developed and implemented a comprehensive microglial/astrocyte profiler for precise three-dimensional morphometric analysis of individual microglia and astrocytes in specific brain nuclei at different time points during the progression of heart failure. To this end, we used a well-established ischemic heart failure rat model. Morphometric studies were complemented with quantification of various proinflammatory cytokines and A1/A2 astrocyte markers via qPCR.
Results
We report a drastic structural remodeling of central amygdala microglia and astrocytes during heart failure that affected cell volume, surface area, filament length, dendritic branches, resulting overall in somatic swelling and deramification, indicative of an activated microglial state. These changes occurred in a time-dependent manner and were delayed compared to changes in the hypothalamic paraventricular nucleus. Morphometric changes correlated with elevated mRNA levels of proinflammatory cytokines and markers of reactive neurotoxic astrocytes in the paraventricular nucleus and central amygdala during heart failure.
Conclusion
We provide evidence that in addition to the previously described hypothalamic neuroinflammation implicated in sympathohumoral activation during heart failure, microglia and astrocytes within the central amygdala also undergo structural remodeling indicative of glial shifts towards an activated and neurotoxic phenotype, respectively. Thus, our studies suggest that neuroinflammation in the amygdala stands as a novel pathophysiological mechanism and therapeutic target for alleviating comorbid emotional and cognitive deficits commonly observed at later stages during the course of heart failure.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
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