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The Relative Contributions of Cell-Dependent Cortical Microcircuit Aging to Cognition and Anxiety

  • Rammohan Shukla
    Affiliations
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada

    Department of Psychiatry, University of Toronto, Toronto, Canada
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  • Thomas D. Prevot
    Affiliations
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
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  • Leon French
    Affiliations
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada

    Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, Canada

    Department of Psychiatry, University of Toronto, Toronto, Canada

    Institute of Medical Science, University of Toronto, Toronto, Canada
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  • Ruth Isserlin
    Affiliations
    Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Canada
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  • Brad R. Rocco
    Affiliations
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
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  • Mounira Banasr
    Affiliations
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada

    Department of Psychiatry, University of Toronto, Toronto, Canada

    Departments of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
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  • Gary D. Bader
    Affiliations
    Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Canada
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  • Etienne Sibille
    Correspondence
    Address correspondence to Etienne Sibille, Ph.D., Campbell Family Mental Health Research Institute of CAMH, Department of Psychiatry, 250 College St, Room 134, Toronto, ON M5T 1R8, Canada.
    Affiliations
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada

    Department of Psychiatry, University of Toronto, Toronto, Canada

    Departments of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

    Institute of Medical Science, University of Toronto, Toronto, Canada
    Search for articles by this author

      Abstract

      Background

      Aging is accompanied by altered thinking (cognition) and feeling (mood), functions that depend on information processing by brain cortical cell microcircuits. We hypothesized that age-associated long-term functional and biological changes are mediated by gene transcriptomic changes within neuronal cell types forming cortical microcircuits, namely excitatory pyramidal cells (PYCs) and inhibitory gamma-aminobutyric acidergic neurons expressing vasoactive intestinal peptide (Vip), somatostatin (Sst), and parvalbumin (Pvalb).

      Methods

      To test this hypothesis, we assessed locomotor, anxiety-like, and cognitive behavioral changes between young (2 months of age, n = 9) and old (22 months of age, n = 12) male C57BL/6 mice, and performed frontal cortex cell type–specific molecular profiling, using laser capture microscopy and RNA sequencing. Results were analyzed by neuroinformatics and validated by fluorescent in situ hybridization.

      Results

      Old mice displayed increased anxiety and reduced working memory. The four cell types displayed distinct age-related transcriptomes and biological pathway profiles, affecting metabolic and cell signaling pathways, and selective markers of neuronal vulnerability (Ryr3), resilience (Oxr1), and mitochondrial dynamics (Opa1), suggesting high age-related vulnerability of PYCs, and variable degree of adaptation in gamma-aminobutyric acidergic neurons. Correlations between gene expression and behaviors suggest that changes in cognition and anxiety associated with age are partly mediated by normal age-related cell changes, and that additional age-independent decreases in synaptic and signaling pathways, notably in PYCs and somatostatin neurons, further contribute to behavioral changes.

      Conclusions

      Our study demonstrates cell-dependent differential vulnerability and coordinated cell-specific cortical microcircuit molecular changes with age. Collectively, the results suggest intrinsic molecular links among aging, cognition, and mood-related behaviors, with somatostatin neurons contributing evenly to both behavioral conditions.

      Keywords

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      Linked Article

      • Biological Signatures of Brain Aging and Accelerated Aging by Early Life Threat
        Biological PsychiatryVol. 85Issue 3
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          Understanding aging and the factors that affect its pace is becoming increasingly relevant. Humans live considerably longer than just a few decades ago, and the world’s population is aging at a faster pace than ever. However, this marked increase in longevity has not been paralleled by a suppression of the deterioration processes that are characteristic of old age—the debilitating effects of aging have just been postponed (1). Aging typically encompasses physiological deterioration, worsening the quality of life, and driving chronic diseases and mortality.
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