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Preparation of Acute Hippocampal Slices from Rats and Transgenic Mice for the Study of Synaptic Alterations during Aging and Amyloid Pathology
Published on: March 23, 2011
Retrosplenial cortex microglia and perineuronal net densities are associated with memory impairment in aged rhesus
Daniel T Gray1, Salma Khattab1, Jeri Meltzer1
1Evelyn F. McKnight Brain Institute, University of Arizona, Tucson, AZ 85721, United States.
Abstract:
Synapse loss and altered plasticity are significant contributors to memory loss in aged individuals. Microglia, the innate immune cells of the brain, play critical roles in maintaining synapse function, including through a recently identified role in regulating the brain extracellular matrix. This study sought to determine the relationship between age, microglia, and extracellular matrix structure densities in the macaque retrosplenial cortex. Twenty-nine macaques ranging in age from young adult to aged were behaviorally characterized on 3 distinct memory tasks. Microglia, parvalbumin (PV)-expressing interneurons and extracellular matrix structures, known as perineuronal nets (PNNs), were immuno- and histochemically labeled. Our results indicate that microglia densities increase in the retrosplenial cortex of aged monkeys, while the proportion of PV neurons surrounded by PNNs decreases. Aged monkeys with more microglia had fewer PNN-associated PV neurons and displayed slower learning and poorer performance on an object recognition task. Stepwise regression models using age and the total density of aggrecan, a chondroitin sulfate proteoglycan of PNNs, better predicted memory performance than did age alone. Together, these findings indicate that elevated microglial activity in aged brains negatively impacts cognition in part through mechanisms that alter PNN assembly in memory-associated brain regions.
Insights
Increased microglia in aged brains impair memory by altering brain extracellular matrix structures called perineuronal nets (PNNs), affecting neuron function and cognitive performance.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Synapse loss and impaired plasticity contribute to age-related memory decline.
- Microglia, the brain's immune cells, are crucial for synaptic function and extracellular matrix regulation.
- The retrosplenial cortex is vital for memory processing.
Purpose of the Study:
- To investigate the relationship between aging, microglial density, and extracellular matrix structures (perineuronal nets) in the macaque retrosplenial cortex.
- To correlate these factors with cognitive performance on memory tasks.
Main Methods:
- Behavioral characterization of 29 macaques (young adult to aged) on memory tasks.
- Immunohistochemical labeling for microglia, parvalbumin (PV)-expressing interneurons, and perineuronal nets (PNNs).
- Analysis of microglia density, PV neurons associated with PNNs, and aggrecan density.
Main Results:
- Microglia density increased in the retrosplenial cortex of aged macaques.
- The proportion of PV neurons ensheathed by PNNs decreased with age.
- Higher microglia density correlated with fewer PNN-associated PV neurons and poorer memory performance.
- Aggrecan density improved prediction of memory performance compared to age alone.
Conclusions:
- Elevated microglial activity in aged brains negatively impacts cognition.
- This cognitive decline is partly mediated by alterations in PNN assembly in memory-related brain regions.
- Microglia-driven changes in the extracellular matrix represent a potential therapeutic target for age-related memory loss.
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