Network Models Predict That Pyramidal Neuron Hyperexcitability and Synapse Loss in the dlPFC Lead to Age-Related Spatial Working Memory Impairment in Rhesus Monkeys.
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TL;DR: 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.
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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.
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Citations
Cognitive Reserve in Model Systems for Mechanistic Discovery: The Importance of Longitudinal Studies.
Joseph A. McQuail,Amy R. Dunn,Yaakov Stern,Carol A. Barnes,Gerd Kempermann,Peter R. Rapp,Catherine C. Kaczorowski,Thomas C. Foster +7 more
TL;DR: In this article, the authors provide a resource for longitudinal studies, using animal models, directed at understanding and modifying the relationship between cognition and brain structure and function throughout life, and propose that forthcoming longitudinal studies will build upon a wealth of knowledge gleaned from prior cross-sectional designs to identify early predictors of variability in cognitive function during aging, and characterize fundamental neurobiological mechanisms that underlie the vulnerability to, and the trajectory of cognitive decline.
Comparative neuropathology in aging primates: A perspective
Carmen Freire-Cobo,Melissa K. Edler,Merina Varghese,Emily L. Munger,Jessie Laffey,Sophia Raia,Selena S In,Bridget Wicinski,Maria Medalla,Sylvia E. Perez,Elliott J. Mufson,Joseph M. Erwin,Elaine E. Guevara,Elaine E. Guevara,Chet C. Sherwood,Jennifer I. Luebke,Agnès Lacreuse,M. A. Raghanti,Patrick R. Hof +18 more
TL;DR: A comparative overview of existing neuropathologic observations across the primate order, including classic age-related changes such as cell loss, amyloid deposition and tau accumulation, is presented in this article.
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Neuronal properties of pyramidal cells in lateral prefrontal cortex of the aging rhesus monkey brain are associated with performance deficits on spatial working memory but not executive function
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TL;DR: In this paper , the authors show that performance on EF and WM tasks exhibited significant changes with age, and these impairments correlate with changes in biophysical properties of layer 3 pyramidal neurons in lateral LPFC (LPFC).
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Age-related alterations to working memory and to pyramidal neurons in the prefrontal cortex of rhesus monkeys begin in early middle-age and are partially ameliorated by dietary curcumin.
01 Jan 2022
TL;DR: This paper found that the appropriate time frame for intervention for age-related cognitive changes is early middle age, and points to the efficacy of curcumin in delaying WM decline in rhesus monkeys.
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Network Models Predict That Pyramidal Neuron Hyperexcitability and Synapse Loss in the dlPFC Lead to Age-Related Spatial Working Memory Impairment in Rhesus Monkeys.
TL;DR: 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.
12
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