Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)
Morphology and function of the dorsolateral prefrontal cortex (dlPFC), and corresponding working memory performance, are affected early in the aging process, but nearly half of aged individuals are spared of working memory deficits. Translationally relevant model systems are critical for determining...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-04-01
|
| Series: | Frontiers in Aging Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1146245/full |
| _version_ | 1827968608034095104 |
|---|---|
| author | Courtney Glavis-Bloom Casey R. Vanderlip Sammy Weiser Novak Masaaki Kuwajima Lyndsey Kirk Kristen M. Harris Uri Manor John H. Reynolds |
| author_facet | Courtney Glavis-Bloom Casey R. Vanderlip Sammy Weiser Novak Masaaki Kuwajima Lyndsey Kirk Kristen M. Harris Uri Manor John H. Reynolds |
| author_sort | Courtney Glavis-Bloom |
| collection | DOAJ |
| description | Morphology and function of the dorsolateral prefrontal cortex (dlPFC), and corresponding working memory performance, are affected early in the aging process, but nearly half of aged individuals are spared of working memory deficits. Translationally relevant model systems are critical for determining the neurobiological drivers of this variability. The common marmoset (Callithrix jacchus) is advantageous as a model for these investigations because, as a non-human primate, marmosets have a clearly defined dlPFC that enables measurement of prefrontal-dependent cognitive functions, and their short (∼10 year) lifespan facilitates longitudinal studies of aging. Previously, we characterized working memory capacity in a cohort of marmosets that collectively covered the lifespan, and found age-related working memory impairment. We also found a remarkable degree of heterogeneity in performance, similar to that found in humans. Here, we tested the hypothesis that changes to synaptic ultrastructure that affect synaptic efficacy stratify marmosets that age with cognitive impairment from those that age without cognitive impairment. We utilized electron microscopy to visualize synapses in the marmoset dlPFC and measured the sizes of boutons, presynaptic mitochondria, and synapses. We found that coordinated scaling of the sizes of synapses and mitochondria with their associated boutons is essential for intact working memory performance in aged marmosets. Further, lack of synaptic scaling, due to a remarkable failure of synaptic mitochondria to scale with presynaptic boutons, selectively underlies age-related working memory impairment. We posit that this decoupling results in mismatched energy supply and demand, leading to impaired synaptic transmission. We also found that aged marmosets have fewer synapses in dlPFC than young, though the severity of synapse loss did not predict whether aging occurred with or without cognitive impairment. This work identifies a novel mechanism of synapse dysfunction that stratifies marmosets that age with cognitive impairment from those that age without cognitive impairment. The process by which synaptic scaling is regulated is yet unknown and warrants future investigation. |
| first_indexed | 2024-04-09T18:24:13Z |
| format | Article |
| id | doaj.art-4fc7a61de3ca4030a6d5f7025f7fc38f |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-04-09T18:24:13Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-4fc7a61de3ca4030a6d5f7025f7fc38f2023-04-12T04:29:58ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652023-04-011510.3389/fnagi.2023.11462451146245Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)Courtney Glavis-Bloom0Casey R. Vanderlip1Sammy Weiser Novak2Masaaki Kuwajima3Lyndsey Kirk4Kristen M. Harris5Uri Manor6John H. Reynolds7Salk Institute for Biological Studies, Systems Neurobiology Laboratory, La Jolla, CA, United StatesSalk Institute for Biological Studies, Systems Neurobiology Laboratory, La Jolla, CA, United StatesSalk Institute for Biological Studies, Waitt Advanced Biophotonics Center, La Jolla, CA, United StatesDepartment of Neuroscience, Center for Learning and Memory, University of Texas at Austin, Austin, TX, United StatesDepartment of Neuroscience, Center for Learning and Memory, University of Texas at Austin, Austin, TX, United StatesDepartment of Neuroscience, Center for Learning and Memory, University of Texas at Austin, Austin, TX, United StatesSalk Institute for Biological Studies, Waitt Advanced Biophotonics Center, La Jolla, CA, United StatesSalk Institute for Biological Studies, Systems Neurobiology Laboratory, La Jolla, CA, United StatesMorphology and function of the dorsolateral prefrontal cortex (dlPFC), and corresponding working memory performance, are affected early in the aging process, but nearly half of aged individuals are spared of working memory deficits. Translationally relevant model systems are critical for determining the neurobiological drivers of this variability. The common marmoset (Callithrix jacchus) is advantageous as a model for these investigations because, as a non-human primate, marmosets have a clearly defined dlPFC that enables measurement of prefrontal-dependent cognitive functions, and their short (∼10 year) lifespan facilitates longitudinal studies of aging. Previously, we characterized working memory capacity in a cohort of marmosets that collectively covered the lifespan, and found age-related working memory impairment. We also found a remarkable degree of heterogeneity in performance, similar to that found in humans. Here, we tested the hypothesis that changes to synaptic ultrastructure that affect synaptic efficacy stratify marmosets that age with cognitive impairment from those that age without cognitive impairment. We utilized electron microscopy to visualize synapses in the marmoset dlPFC and measured the sizes of boutons, presynaptic mitochondria, and synapses. We found that coordinated scaling of the sizes of synapses and mitochondria with their associated boutons is essential for intact working memory performance in aged marmosets. Further, lack of synaptic scaling, due to a remarkable failure of synaptic mitochondria to scale with presynaptic boutons, selectively underlies age-related working memory impairment. We posit that this decoupling results in mismatched energy supply and demand, leading to impaired synaptic transmission. We also found that aged marmosets have fewer synapses in dlPFC than young, though the severity of synapse loss did not predict whether aging occurred with or without cognitive impairment. This work identifies a novel mechanism of synapse dysfunction that stratifies marmosets that age with cognitive impairment from those that age without cognitive impairment. The process by which synaptic scaling is regulated is yet unknown and warrants future investigation.https://www.frontiersin.org/articles/10.3389/fnagi.2023.1146245/fullmarmoset (Callithrix jacchus)working memoryultrastructural size principleagingnon-human primate (NHP)electron microscopy |
| spellingShingle | Courtney Glavis-Bloom Casey R. Vanderlip Sammy Weiser Novak Masaaki Kuwajima Lyndsey Kirk Kristen M. Harris Uri Manor John H. Reynolds Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus) Frontiers in Aging Neuroscience marmoset (Callithrix jacchus) working memory ultrastructural size principle aging non-human primate (NHP) electron microscopy |
| title | Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus) |
| title_full | Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus) |
| title_fullStr | Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus) |
| title_full_unstemmed | Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus) |
| title_short | Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus) |
| title_sort | violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset callithrix jacchus |
| topic | marmoset (Callithrix jacchus) working memory ultrastructural size principle aging non-human primate (NHP) electron microscopy |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1146245/full |
| work_keys_str_mv | AT courtneyglavisbloom violationoftheultrastructuralsizeprincipleinthedorsolateralprefrontalcortexunderliesworkingmemoryimpairmentintheagedcommonmarmosetcallithrixjacchus AT caseyrvanderlip violationoftheultrastructuralsizeprincipleinthedorsolateralprefrontalcortexunderliesworkingmemoryimpairmentintheagedcommonmarmosetcallithrixjacchus AT sammyweisernovak violationoftheultrastructuralsizeprincipleinthedorsolateralprefrontalcortexunderliesworkingmemoryimpairmentintheagedcommonmarmosetcallithrixjacchus AT masaakikuwajima violationoftheultrastructuralsizeprincipleinthedorsolateralprefrontalcortexunderliesworkingmemoryimpairmentintheagedcommonmarmosetcallithrixjacchus AT lyndseykirk violationoftheultrastructuralsizeprincipleinthedorsolateralprefrontalcortexunderliesworkingmemoryimpairmentintheagedcommonmarmosetcallithrixjacchus AT kristenmharris violationoftheultrastructuralsizeprincipleinthedorsolateralprefrontalcortexunderliesworkingmemoryimpairmentintheagedcommonmarmosetcallithrixjacchus AT urimanor violationoftheultrastructuralsizeprincipleinthedorsolateralprefrontalcortexunderliesworkingmemoryimpairmentintheagedcommonmarmosetcallithrixjacchus AT johnhreynolds violationoftheultrastructuralsizeprincipleinthedorsolateralprefrontalcortexunderliesworkingmemoryimpairmentintheagedcommonmarmosetcallithrixjacchus |