title: Estrogen Restores Multisynaptic Boutons in the Dorsolateral Prefrontal Cortex while Promoting Working Memory in Aged Rhesus Monkeys.
abstract: Humans and nonhuman primates are vulnerable to age- and menopause- related decline in working memory, a cognitive function reliant on area 46 of the dorsolateral prefrontal cortex (dlPFC). We showed previously that presynaptic mitochondrial number and morphology in monkey dlPFC neurons correlate with working memory performance. The current study tested the hypothesis that the types of synaptic connections these boutons form are altered with aging and menopause in rhesus monkeys and that these metrics may be coupled with mitochondrial measures and working memory. Using serial section electron microscopy, we examined the frequencies and characteristics of nonsynaptic, single-synaptic, and multisynaptic boutons (MSBs) in the dlPFC. In contrast to our previous observations in the monkey hippocampal dentate gyrus, where MSBs comprised ∼40% of boutons, the vast majority of dlPFC boutons were single-synaptic, whereas MSBs constituted a mere 10%. The frequency of MSBs was not altered by normal aging, but decreased by over 50% with surgical menopause induced by ovariectomy in aged monkeys. Cyclic estradiol treatment in aged ovariectomized animals restored MSB frequencies to levels comparable to young and aged premenopausal monkeys. Notably, the frequency of MSBs positively correlated with working memory scores, as measured by the average accuracy on the delayed response (DR) test. Furthermore, MSB incidence positively correlated with the number of healthy straight mitochondria in dlPFC boutons and inversely correlated with the number of pathological donut-shaped mitochondria. Together, our data suggest that MSBs are coupled to cognitive function and mitochondrial health and are sensitive to estrogen. Significance statement: Many aged menopausal individuals experience deficits in working memory, an executive function reliant on recurrent firing of prefrontal cortex (PFC) neurons. However, little is known about the organization of presynaptic inputs to these neurons and how they may be altered with aging and menopause. Multisynaptic boutons (MSBs) were of particular interest, because they form multiple synapses and can enhance coupling between presynaptic and postsynaptic neurons. We found that higher MSB frequency correlated with better working memory performance in rhesus monkeys. Additionally, aged surgically menopausal monkeys experienced a 50% loss of MSBs that was restored with cyclic estradiol treatment. Together, our findings suggest that hormone replacement therapy benefits cognitive aging, in part by retaining complex synaptic organizations in the PFC.
authors.affiliation: Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Friedman Brain Institute.
authors.forename: Yuko
authors.identifier: http://orcid.org/0000-0001-5828-442X
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Friedman Brain Institute.
authors.forename: Frank
authors.initials: F
authors.lastname: Yuk
authors.affiliation: Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Friedman Brain Institute.
authors.forename: Rishi
authors.initials: R
authors.lastname: Puri
authors.affiliation: Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, Friedman Brain Institute.
authors.forename: William G M
authors.initials: WG
authors.lastname: Janssen
authors.affiliation: National Institute on Aging, Laboratory of Behavioral Neuroscience, Baltimore, Maryland 21224.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rapp
authors.affiliation: Fishberg Department of Neuroscience and 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, New York 10029, California National Primate Research Center, Davis, California 95616, and Department of Neurology, School of Medicine, University of California, Davis, California 95616 jhmorrison@ucdavis.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Morrison
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D015914:Estrogen Replacement Therapy / Q000379:methods; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D008253:Macaca mulatta; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D010052:Ovariectomy; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D004967:Estrogens
keywords: MSB; area 46; delayed response; estradiol; menopause; mitochondria