Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats
Abstract 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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-07-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01892-4 |
| _version_ | 1818515425342783488 |
|---|---|
| author | Ferdinand Althammer Hildebrando Candido Ferreira-Neto Myurajan Rubaharan Ranjan K. Roy Atit A. Patel Daniel N. Cox Javier E. Stern |
| author_facet | Ferdinand Althammer Hildebrando Candido Ferreira-Neto Myurajan Rubaharan Ranjan K. Roy Atit A. Patel Daniel N. Cox Javier E. Stern |
| author_sort | Ferdinand Althammer |
| collection | DOAJ |
| description | Abstract 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 contributes to autonomic and cardiovascular dysregulation in heart failure, mechanisms underlying cognitive and mood disorders in this disease remain elusive. The goal of this study was to quantitatively assess markers of neuroinflammation (glial morphology, cytokines, and A1 astrocyte markers) in the central amygdala, a critical forebrain region involved in emotion and cognition, and to determine its time course and correlation to disease severity 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 pro-inflammatory cytokines and A1/A2 astrocyte markers via qPCR. Results We report structural remodeling of central amygdala microglia and astrocytes during heart failure that affected cell volume, surface area, filament length, and glial branches, resulting overall in somatic swelling and deramification, indicative of a change in glial state. These changes occurred in a time-dependent manner, correlated with the severity of heart failure, and were delayed compared to changes in the hypothalamic paraventricular nucleus. Morphometric changes correlated with elevated mRNA levels of pro-inflammatory cytokines and markers of reactive A1-type 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 pro-inflammatory phenotypes. Thus, our studies suggest that neuroinflammation in the amygdala stands as a novel pathophysiological mechanism and potential therapeutic target that could be associated with emotional and cognitive deficits commonly observed at later stages during the course of heart failure. |
| first_indexed | 2024-12-11T00:28:42Z |
| format | Article |
| id | doaj.art-5dc52cfc25e549bd962955445536ae20 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-11T00:28:42Z |
| publishDate | 2020-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-5dc52cfc25e549bd962955445536ae202022-12-22T01:27:26ZengBMCJournal of Neuroinflammation1742-20942020-07-0117111910.1186/s12974-020-01892-4Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure ratsFerdinand Althammer0Hildebrando Candido Ferreira-Neto1Myurajan Rubaharan2Ranjan K. Roy3Atit A. Patel4Daniel N. Cox5Javier E. Stern6Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State UniversityCenter for Neuroinflammation and Cardiometabolic Diseases, Georgia State UniversityNeuroscience Institute, Georgia State UniversityCenter for Neuroinflammation and Cardiometabolic Diseases, Georgia State UniversityNeuroscience Institute, Georgia State UniversityNeuroscience Institute, Georgia State UniversityCenter for Neuroinflammation and Cardiometabolic Diseases, Georgia State UniversityAbstract 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 contributes to autonomic and cardiovascular dysregulation in heart failure, mechanisms underlying cognitive and mood disorders in this disease remain elusive. The goal of this study was to quantitatively assess markers of neuroinflammation (glial morphology, cytokines, and A1 astrocyte markers) in the central amygdala, a critical forebrain region involved in emotion and cognition, and to determine its time course and correlation to disease severity 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 pro-inflammatory cytokines and A1/A2 astrocyte markers via qPCR. Results We report structural remodeling of central amygdala microglia and astrocytes during heart failure that affected cell volume, surface area, filament length, and glial branches, resulting overall in somatic swelling and deramification, indicative of a change in glial state. These changes occurred in a time-dependent manner, correlated with the severity of heart failure, and were delayed compared to changes in the hypothalamic paraventricular nucleus. Morphometric changes correlated with elevated mRNA levels of pro-inflammatory cytokines and markers of reactive A1-type 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 pro-inflammatory phenotypes. Thus, our studies suggest that neuroinflammation in the amygdala stands as a novel pathophysiological mechanism and potential therapeutic target that could be associated with emotional and cognitive deficits commonly observed at later stages during the course of heart failure.http://link.springer.com/article/10.1186/s12974-020-01892-4HypothalamusAmygdalaMicrogliaAstrocytesA1Behavior |
| spellingShingle | Ferdinand Althammer Hildebrando Candido Ferreira-Neto Myurajan Rubaharan Ranjan K. Roy Atit A. Patel Daniel N. Cox Javier E. Stern Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats Journal of Neuroinflammation Hypothalamus Amygdala Microglia Astrocytes A1 Behavior |
| title | Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats |
| title_full | Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats |
| title_fullStr | Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats |
| title_full_unstemmed | Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats |
| title_short | Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats |
| title_sort | three dimensional morphometric analysis reveals time dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats |
| topic | Hypothalamus Amygdala Microglia Astrocytes A1 Behavior |
| url | http://link.springer.com/article/10.1186/s12974-020-01892-4 |
| work_keys_str_mv | AT ferdinandalthammer threedimensionalmorphometricanalysisrevealstimedependentstructuralchangesinmicrogliaandastrocytesinthecentralamygdalaandhypothalamicparaventricularnucleusofheartfailurerats AT hildebrandocandidoferreiraneto threedimensionalmorphometricanalysisrevealstimedependentstructuralchangesinmicrogliaandastrocytesinthecentralamygdalaandhypothalamicparaventricularnucleusofheartfailurerats AT myurajanrubaharan threedimensionalmorphometricanalysisrevealstimedependentstructuralchangesinmicrogliaandastrocytesinthecentralamygdalaandhypothalamicparaventricularnucleusofheartfailurerats AT ranjankroy threedimensionalmorphometricanalysisrevealstimedependentstructuralchangesinmicrogliaandastrocytesinthecentralamygdalaandhypothalamicparaventricularnucleusofheartfailurerats AT atitapatel threedimensionalmorphometricanalysisrevealstimedependentstructuralchangesinmicrogliaandastrocytesinthecentralamygdalaandhypothalamicparaventricularnucleusofheartfailurerats AT danielncox threedimensionalmorphometricanalysisrevealstimedependentstructuralchangesinmicrogliaandastrocytesinthecentralamygdalaandhypothalamicparaventricularnucleusofheartfailurerats AT javierestern threedimensionalmorphometricanalysisrevealstimedependentstructuralchangesinmicrogliaandastrocytesinthecentralamygdalaandhypothalamicparaventricularnucleusofheartfailurerats |