Neuronal and morphological bases of cognitive decline in aged rhesus monkeys

Abstract

Rhesus monkeys provide a valuable model for studying the basis of cognitive aging because they are vulnerable to age-related decline in executive function and memory in a manner similar to humans. Some of the behavioral tasks sensitive to the effects of aging are the delayed response working memory test, recognition memory tests including the delayed nonmatching-to-sample and the delayed recognition span task, and tests of executive function including reversal learning and conceptual set-shifting task. Much effort has been directed toward discovering the neurobiological parameters that are coupled to individual differences in age-related cognitive decline. Area 46 of the dorsolateral prefrontal cortex (dlPFC) has been extensively studied for its critical role in executive function while the hippocampus and related cortical regions have been a major target of research for memory function. Some of the key age-related changes in area 46 include decreases in volume, microcolumn strength, synapse density, and α1-and α2-adrenergic receptor binding densities. All of these measures significantly correlate with cognitive scores. Interestingly, the critical synaptic subtypes associated with cognitive function appear to be different between the dlPFC and the hippocampus. For example, the dendritic spine subtype most critical to task acquisition and vulnerable to aging in area 46 is the thin spine, whereas in the dentate gyrus, the density of AGE (2012) large mushroom spines with perforated synapses correlates with memory performance. This review summarizes age-related changes in anatomical, neuronal, and synaptic parameters within brain areas implicated in cognition and whether these changes are associated with cognitive decline.

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

“…A common characteristic of advancing age is a gradual decline in cognitive functions associated with the progressive reduction of structural and functional plasticity in brain regions such as cerebral cortex and hippocampus that play a key role in cognition (Benice et al 2006;Driscoll et al 2006;Hara et al 2012; Van der Jeugd et al 2013). Studies in rats and non-human primates have demonstrated that aging impairs the functional integrity of prefrontal cortex neurons (Morrison and Baxter 2012) which is associated with decline in structural plasticity and cognitive performance (Dumitriu et al 2010;Bloss et al 2011Bloss et al , 2013.…”

Estrogen Restores Multisynaptic Boutons in the Dorsolateral Prefrontal Cortex while Promoting Working Memory in Aged Rhesus Monkeys

“…Rhesus monkeys (Macaca mulatta; total, n ϭ 29) were housed in colonies of ϳ40 individuals at the California National Primate Research Center at University of California, Davis. Experimental treatments, behavioral data, perfusion protocol, and tissue preparation for monkeys included in this study have been described in detail previously (Rapp et al, 2003;Hao et al, 2007;Dumitriu et al, 2010;Hara et al, 2014). All experiments were conducted in compliance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Care and Use Committee at the University of California, Davis.…”

“…In rhesus monkeys, DR performance is reliant on the integrity of the dorsolateral prefrontal cortex (dlPFC) area 46 (Funahashi et al, 1989;Goldman-Rakic, 1995), a brain region that shares striking anatomical and functional homology to the human area 46 (McCarthy et al, 1994;Petrides and Pandya, 1999). Rhesus monkeys are valuable models of human aging and menopause, because their neuronal gene expression, reproductive physiology, and patterns of endocrine senescence closely resemble those of humans (Matt et al, 1998;Gill et al, 2002;Woller et al, 2002;Nichols et al, 2005;Loerch et al, 2008;Walker and Herndon, 2008;Hara et al, 2012a).…”

“…In particular, multisynaptic boutons (MSBs) may act as a morphological substrate to enhance coupling between presynaptic and postsynaptic neurons (Harris, 1995;Toni et al, 1999;Geinisman et al, 2001;Yankova et al, 2001). In rats and monkeys, hippocampal MSBs are associated with memory functions and are responsive to hormonal status (Geinisman et al, 2001;Hara et al, 2011). However, little is known about the roles of MSBs in the PFC, particularly in primates.…”

Presynaptic mitochondrial morphology in monkey prefrontal cortex correlates with working memory and is improved with estrogen treatment

“…This complex function is highly vulnerable to age-and menopause-related decline in humans and nonhuman primates and can be assessed in rhesus monkeys using the wellcharacterized delayed response (DR) test of visuospatial working memory (3)(4)(5)(6). Rhesus monkeys are exceptionally valuable models of human aging, menopause, and related cognitive decline, because their brain anatomy, neuronal gene expression, reproductive physiology, and patterns of endocrine senescence closely resemble those of humans (4,(7)(8)(9)(10). Importantly, they fail to develop the histopathological features of Alzheimer's disease (11)(12)(13).…”