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Age-Induced Spatial Memory Deficits in Rats Are Correlated with Specific Brain Region Alterations in Microglial
Shai Shoham1, Michal Linial2, Marta Weinstock3
1The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
Abstract:
Effect of age and ladostigil treatment (1 mg/kg/day), given for 6 months to 16 month old rats, was investigated on microglial morphology in brain regions associated with control of spatial learning. This was assessed in the Morris water maze (MWM). Microglial morphology was assessed with diaminobenzidine and fluorescent staining with Iba1 and CD11b in these brain regions. Aging did not change the number of microglia in the parietal cortex (PC) or hippocampal CA1 region (CA1-HC), but decreased microglial process tips in the CA1-HC, increased the area fraction stained by CD11b and number of bulbs on processes in PC and CA1-HC and thickness of microglial processes in corpus callosum (CC) and fornix (Fx). Performance in MWM (distance swam to escape platform) was negatively correlated with number of bulbs in PC and thickness of process in CC, and positively correlated with number of process tips in CA1-HC. Aging increased expression of MHC class II genes and others associated with motility and membrane adhesion in the PC and hippocampus, but Adora2a (Adenosine A2a receptor), only in hippocampus. Age-related increase in the number of bulbs and expression of inflammatory genes was prevented by ladostigil in PC. In the CA1-HC, ladostigil increased the number of process tips and prevented the increase in expression of Adora2a and genes regulating ion channels. Ladostigil also decreased thickening of the processes in CC and Fx. The data show brain region-specific relations induced by age in spatial learning, microglial morphology and associated genes and their response to ladostigil treatment. Graphical Abstract.
Insights
Ladostigil treatment improved microglial morphology and reversed age-related changes in spatial learning and inflammatory gene expression in specific brain regions of aging rats.
Area of Science:
- Neuroscience
- Aging Research
- Pharmacology
Background:
- Aging alters microglial morphology and function, impacting cognitive processes like spatial learning.
- Specific brain regions exhibit distinct age-related changes in microglia and gene expression.
- Ladostigil is a potential therapeutic agent for age-related cognitive decline.
Purpose of the Study:
- To investigate the effects of aging and ladostigil treatment on microglial morphology in brain regions critical for spatial learning.
- To correlate microglial changes with spatial learning performance in aging rats.
- To examine the impact of ladostigil on age-related gene expression changes.
Main Methods:
- 16-month-old rats were treated with ladostigil (1 mg/kg/day) for 6 months.
- Microglial morphology was assessed using diaminobenzidine and Iba1/CD11b staining.
- Spatial learning was evaluated using the Morris water maze (MWM).
- Gene expression analysis focused on MHC class II, motility, membrane adhesion, Adora2a, and ion channel genes.
Main Results:
- Aging decreased microglial process tips in CA1-HC and increased process thickness in CC/Fx.
- Aging increased CD11b staining and bulb formation in PC/CA1-HC, correlating negatively with MWM performance.
- Ladostigil prevented age-related increases in inflammatory genes and microglial bulb formation in PC.
- Ladostigil increased process tips in CA1-HC and normalized Adora2a expression and ion channel gene regulation.
Conclusions:
- Aging induces region-specific alterations in microglial morphology and gene expression, affecting spatial learning.
- Ladostigil treatment mitigates these age-related changes, improving microglial morphology and cognitive function.
- Ladostigil demonstrates therapeutic potential for age-related neuroinflammation and cognitive impairment.
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