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

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.

Cognitive Reserve in Model Systems for Mechanistic Discovery: The Importance of Longitudinal Studies

“…As noted above, increasing the number of arms from 8 to 12 may increase the demand for spatial working memory (Sabolek et al, 2004). Longitudinal studies in monkeys indicate that the decline in working memory capacity, is highly variable and in some cases, the influence of practice effects cannot be ruled out (Moss, 1993;Koo et al, 2018;Ibanez et al, 2019).…”

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

“…These data are consistent with our previous finding that DRST performance, which reflects working memory capacity, declines with age. 57,68 Based on this analysis and our previous studies, we next grouped the monkeys into categorical age groups (young: 5-12 years, middle-aged: 13-20 years, and aged: >20 years) to better assess when declines in working memory begin and whether there is a significant difference between middle-aged and aged monkeys on the DRST. A one-way ANOVA revealed a significant effect of age group on the total DRST spatial span (Fig.…”

“…Our previous work has shown significant correlations between LPFC neuronal properties and DRST task performance. 57 Here we build on these findings to assess whether LPFC neuron biophysical properties are related to DRSTsp performance in this group of monkeys and whether they similarly are associated with task performance on the CSST. Thus, we employed linear regression and correlation analyses of electrophysiological and cognitive measures.…”

Comparative neuropathology in aging primates: A perspective

“…Computational models have considered these unique features of pyramidal neurons and other key determinants of area-specific network behavior in NHP to make predictions about the consequences of these empirically observed age-related changes at both the single neuron and circuit level (Coskren et al, 2015;Ibañez et al, 2019;Rumbell et al, 2016).…”

“…The results demonstrate that dlPFC but not V1 neurons show action potential hyperexcitability that is associated with cognitive decline as well as reduced excitatory and increased inhibitory synaptic activity (Amatrudo et al, 2012; Kabaso et al, 2009; Luebke et al, 2015; Peters et al, 2001). Computational models have considered these unique features of pyramidal neurons and other key determinants of area‐specific network behavior in NHP to make predictions about the consequences of these empirically observed age‐related changes at both the single neuron and circuit level (Coskren et al, 2015; Ibañez et al, 2019; Rumbell et al, 2016).…”