Network Models Predict That Pyramidal Neuron Hyperexcitability and Synapse Loss in the dlPFC Lead to Age-Related...

Area of Science:

• Neuroscience
• Cognitive Aging
• Computational Modeling

Background:

• Spatial working memory declines with age across species.
• Persistent neural activity in the dorsolateral prefrontal cortex (dlPFC) is crucial for working memory.
• Age-related changes in dlPFC neurons are known, but their impact on spatial working memory mechanisms is unclear.

Purpose of the Study:

• To investigate how age-related changes in dlPFC neurons affect spatial working memory performance.
• To model the neural mechanisms underlying age-related spatial working memory impairment in rhesus monkeys.

Main Methods:

• Empirical testing of spatial working memory using the Delayed Recognition Span Task (DRSTsp).
• In vitro assessment of dlPFC neuronal excitability across the adult lifespan.
• Computational modeling (bump attractor model) to simulate the effects of neuronal changes on working memory tasks (DRT and DRSTsp).

Main Results:

• Aging rhesus monkeys showed impaired DRSTsp performance and increased dlPFC neuronal hyperexcitability.
• Computational models indicated that pyramidal neuron hyperexcitability, rather than synapse loss, significantly impacted persistent activity and cognitive performance.
• Simulations predicted that increased inhibitory interneuron activity is necessary to explain reduced in vivo firing rates in aging dlPFC.

Conclusions:

• Pyramidal neuron hyperexcitability is a key factor in age-related spatial working memory deficits in rhesus monkeys.
• Simultaneous modeling of hyperexcitability and synapse loss partially restored function, aligning with observed impairment levels.
• This integrated modeling approach advances understanding of aging neural mechanisms from synaptic to cognitive scales.