title: 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 donut-shaped 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.
authors.affiliation: Fishberg Department of Neuroscience, Kastor Neurobiology of Aging Laboratories, Friedman Brain Institute, Department of Geriatrics and Palliative Medicine, and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hara
authors.forename: Frank
authors.initials: F
authors.lastname: Yuk
authors.forename: Rishi
authors.initials: R
authors.lastname: Puri
authors.forename: William G M
authors.initials: WG
authors.lastname: Janssen
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rapp
authors.forename: John H
authors.initials: JH
authors.lastname: Morrison
mesh_terms: D000375:Aging; D000818:Animals; D001522:Behavior, Animal; D001931:Brain Mapping / Q000379:methods; D003071:Cognition; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D000882:Haplorhini; D021621:Imaging, Three-Dimensional; D008253:Macaca mulatta; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D008597:Menstrual Cycle; D008928:Mitochondria / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D015203:Reproducibility of Results; D009435:Synaptic Transmission; D013997:Time Factors
chemical_list: D004967:Estrogens; D004958:Estradiol
keywords: axonal bouton; cognition; toroidal mitochondria