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Biol Psychiatry. 2019 Feb 1;85(3):257-267. doi: 10.1016/j.biopsych.2018.09.019. Epub 2018 Oct 5.

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

Author information

1
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
2
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada.
3
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.
4
Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Canada.
5
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.
6
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. Electronic address: Etienne.Sibille@camh.ca.

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:

Aging; Anxiety; Canonical microcircuit; Cognitive deficit; Neuronal vulnerability; Ontology; Single cell–type RNAseq

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