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Updated: Nov 23, 2025
Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
Microglial activation in the right amygdala-entorhinal-hippocampal complex is associated with preserved spatial
Gloria Biechele1, Karin Wind1, Tanja Blume2
1Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
Background:
In Alzheimer`s disease (AD), regional heterogeneity of β-amyloid burden and microglial activation of individual patients is a well-known phenomenon. Recently, we described a high incidence of inter-individual regional heterogeneity in terms of asymmetry of plaque burden and microglial activation in β-amyloid mouse models of AD as assessed by positron-emission-tomography (PET). We now investigate the regional associations between amyloid plaque burden, microglial activation, and impaired spatial learning performance in transgenic mice in vivo.
Methods:
In 30 AppNL-G-F mice (15 female, 15 male) we acquired cross-sectional 18 kDa translocator protein (TSPO-PET, 18F-GE-180) and β-amyloid-PET (18F-florbetaben) scans at ten months of age. Control data were obtained from age- and sex-matched C57BI/6 wild-type mice. We assessed spatial learning (i.e. Morris water maze) within two weeks of PET scanning and correlated the principal component of spatial learning performance scores with voxel-wise β-amyloid and TSPO tracer uptake maps in AppNL-G-F mice, controlled for age and sex. In order to assess the effects of hemispheric asymmetry, we also analyzed correlations of spatial learning performance with tracer uptake in bilateral regions of interest for frontal cortex, entorhinal/piriform cortex, amygdala, and hippocampus, using a regression model. We tested the correlation between regional asymmetry of PET biomarkers with individual spatial learning performance.
Results:
Voxel-wise analyses in AppNL-G-F mice revealed that higher TSPO-PET signal in the amygdala, entorhinal and piriform cortices, the hippocampus and the hypothalamus correlated with spatial learning performance. Region-based analysis showed significant correlations between TSPO expression in the right entorhinal/piriform cortex and the right amygdala and spatial learning performance, whereas there were no such correlations in the left hemisphere. Right lateralized TSPO expression in the amygdala predicted better performance in the Morris water maze (β = -0.470, p = 0.013), irrespective of the global microglial activation and amyloid level. Region-based results for amyloid-PET showed no significant associations with spatial learning.
Conclusion:
Elevated microglial activation in the right amygdala-entorhinal-hippocampal complex of AppNL-G-F mice is associated with better spatial learning. Our findings support a protective role of microglia on cognitive function when they highly express TSPO in specific brain regions involved in spatial memory.
Insights
Higher microglial activation in specific brain regions, particularly the right amygdala, correlates with better spatial learning in Alzheimer's disease mouse models. This suggests a protective role for microglia in cognitive function.
Area of Science:
- Neuroscience
- Neuroimaging
- Alzheimer's Disease Research
Background:
- Regional heterogeneity in amyloid-beta plaque burden and microglial activation is characteristic of Alzheimer's disease (AD).
- Previous studies identified inter-individual regional heterogeneity in plaque burden and microglial activation in AD mouse models using PET imaging.
- This study investigates the regional relationship between amyloid plaque burden, microglial activation, and spatial learning deficits in transgenic mice.
Purpose of the Study:
- To examine the regional associations between amyloid plaque burden, microglial activation, and spatial learning performance in AppNL-G-F mice.
- To determine if hemispheric asymmetry in these biomarkers correlates with spatial learning.
- To explore the potential protective role of microglial activation in cognitive function within specific brain regions.
Main Methods:
- 30 AppNL-G-F mice underwent PET scans for beta-amyloid (18F-florbetaben) and TSPO (18F-GE-180) at ten months of age.
- Spatial learning was assessed using the Morris water maze within two weeks of PET scanning.
- Voxel-wise and region-based analyses correlated PET tracer uptake with spatial learning performance, controlling for age and sex, and examined hemispheric asymmetry.
Main Results:
- Increased TSPO-PET signal in the amygdala, entorhinal/piriform cortices, hippocampus, and hypothalamus correlated with spatial learning performance in AppNL-G-F mice.
- Significant correlations were found between TSPO expression in the right entorhinal/piriform cortex and right amygdala and spatial learning.
- Right-lateralized TSPO expression in the amygdala predicted better spatial learning, independent of global amyloid levels or microglial activation; no significant associations were found for amyloid-PET.
Conclusions:
- Elevated microglial activation, indicated by TSPO-PET signal, in the right amygdala-entorhinal-hippocampal complex is linked to enhanced spatial learning in this AD mouse model.
- These findings suggest that microglial activation in specific brain regions involved in spatial memory may exert a protective effect on cognitive function.
- The study highlights the importance of regional and hemispheric asymmetry in understanding the relationship between neuroinflammation and cognitive deficits in Alzheimer's disease.
