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

Abstract

Humans and nonhuman primates are vulnerable to age-and menopause-related decline in working memory, a cognitive function reliant on the energy-demanding recurrent excitation of neurons within Brodmann's Area 46 of the dorsolateral prefrontal cortex (dlPFC). Here, we tested the hypothesis that the number and morphology (straight, curved, or donut-shaped) of mitochondria in dlPFC presynaptic boutons are altered with aging and menopause in rhesus monkeys (Macaca mulatta) and that these metrics correlate with delayed response (DR) accuracy, a well-characterized measure of dlPFC-dependent working memory. Although presynaptic bouton density or size was not significantly different across groups distinguished by age or menses status, DR accuracy correlated positively with the number of total and straight mitochondria per dlPFC bouton. In contrast, DR accuracy correlated inversely with the frequency of boutons containing donut-shaped mitochondria, which exhibited smaller active zone areas and fewer docked synaptic vesicles than those with straight or curved mitochondria. We then examined the effects of estrogen administration to test whether a treatment known to improve working memory influences mitochondrial morphology. Aged ovariectomized monkeys treated with vehicle displayed significant working memory impairment and a concomitant 44% increase in presynaptic donutshaped mitochondria, both of which were reversed with cyclic estradiol treatment. Together, our data suggest that hormone replacement therapy may benefit cognitive aging, in part by promoting mitochondrial and synaptic health in the dlPFC.toroidal mitochondria | axonal bouton | cognition W orking memory is a type of executive function that involves the storage, organization, and update of information which together guide decision making and goal-directed behavior (1, 2). 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 (3-6). 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, 7-10). Importantly, they fail to develop the histopathological features of Alzheimer's disease (11-13). Thus, we can investigate the neurobiological parameters that are coupled to age-and menopause-related cognitive dysfunction in the absence of confounding factors inherent to pathology.Performance on DR is mediated in part by layer III neurons of the dorsolateral prefrontal cortex (dlPFC) Brodmann's Area 46, which exhibit persistent spatially tuned firing during the delay period of the DR when the spatial position is held in working memory (1,14). A recent electrophysiological study showed that firing of these "delay cells" in Brodmann's Area 46 is markedly decreased in aged monkeys (15, 16). This...

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