Network Models Predict That Pyramidal Neuron Hyperexcitability and Synapse Loss in the dlPFC Lead to Age-Related Spatial Working Memory Impairment in Rhesus Monkeys.

Sara Ibañez,Wayne Chang,Danel Draguljić,Jennifer I Luebke,Christina M Weaver

doi:10.3389/fncom.2019.00089

Sara Ibañez, Wayne Chang + Show 3 more

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https://doi.org/10.3389/fncom.2019.00089

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Abstract

Behavioral studies have shown spatial working memory impairment with aging in several animal species, including humans. Persistent activity of layer 3 pyramidal dorsolateral prefrontal cortex (dlPFC) neurons during delay periods of working memory tasks is important for encoding memory of the stimulus. In vitro studies have shown that these neurons undergo significant age-related structural and functional changes, but the extent to which these changes affect neural mechanisms underlying spatial working memory is not understood fully. Here, we confirm previous studies showing impairment on the Delayed Recognition Span Task in the spatial condition (DRSTsp), and increased in vitro action potential firing rates (hyperexcitability), across the adult life span of the rhesus monkey. We use a bump attractor model to predict how empirically observed changes in the aging dlPFC affect performance on the Delayed Response Task (DRT), and introduce a model of memory retention in the DRSTsp. Persistent activity—and, in turn, cognitive performance—in both models was affected much more by hyperexcitability of pyramidal neurons than by a loss of synapses. Our DRT simulations predict that additional changes to the network, such as increased firing of inhibitory interneurons, are needed to account for lower firing rates during the DRT with aging reported in vivo. Synaptic facilitation was an essential feature of the DRSTsp model, but it did not compensate fully for the effects of the other age-related changes on DRT performance. Modeling pyramidal neuron hyperexcitability and synapse loss simultaneously led to a partial recovery of function in both tasks, with the simulated level of DRSTsp impairment similar to that observed in aging monkeys. This modeling work integrates empirical data across multiple scales, from synapse counts to cognitive testing, to further our understanding of aging in non-human primates.

Highlights

Spatial working memory in rhesus monkeys, as in humans, is mediated by the action potential firing activity of neurons in the dorsolateral prefrontal cortex
For impaired subjects, impairment typically begins fairly early in the aging process, during early middle age (Moore et al, 2005, 2006, 2017). This distribution of impaired and spared monkeys across the lifespan enables assessment of brain changes associated not with aging, but with cognitive performance per se in this model of normal human aging. This approach has been taken in studies of normal aging by our group and others, in which monkeys were assessed on working memory tasks such as the Delayed Response Task (DRT) and the Delayed Recognition Span Task in the spatial condition (DRSTsp), and their brains subsequently examined for a wide variety of parameters
This study used computational modeling to explore how single pyramidal neuron hyperexcitability and excitatory and inhibitory synapse loss observed with aging in layer 3 of the rhesus monkey dorsolateral prefrontal cortex (dlPFC) might contribute to spatial working memory impairment

Summary

Introduction

Spatial working memory in rhesus monkeys, as in humans, is mediated by the action potential firing activity of neurons in the dorsolateral prefrontal cortex (dlPFC) (reviews: Funahashi, 2017; Constantinidis and Qi, 2018; Miller et al, 2018). For impaired subjects, impairment typically begins fairly early in the aging process, during early middle age (Moore et al, 2005, 2006, 2017) This distribution of impaired and spared monkeys across the lifespan enables assessment of brain changes associated not with aging, but with cognitive performance per se in this model of normal human aging. This approach has been taken in studies of normal aging by our group and others (reviews: Peters, 2007; Luebke et al, 2010, 2015; Wang et al, 2011; Peters and Kemper, 2012), in which monkeys were assessed on working memory tasks such as the Delayed Response Task (DRT) and the Delayed Recognition Span Task in the spatial condition (DRSTsp), and their brains subsequently examined for a wide variety of parameters. Reductions in synapses and increased dystrophy of white matter pathways begin in early middle age; for example, Peters et al (2008) showed a continuous decrease in the number of excitatory and inhibitory synapses, detectable even in middle age in the monkey dlPFC

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