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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Article info
Publication history
Published online: October 04, 2018
Accepted:
September 11,
2018
Received in revised form:
August 30,
2018
Received:
June 14,
2018
Identification
Copyright
© 2018 Society of Biological Psychiatry.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Biological Signatures of Brain Aging and Accelerated Aging by Early Life ThreatBiological PsychiatryVol. 85Issue 3
- PreviewUnderstanding 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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