Differentially Expressed Genes in the Brain of Aging Mice With Cognitive Alteration and Depression- and Anxiety-Like Behaviors

Abstract

Despite the great increase in human lifespan with improved medical care, the physiological and pathological changes such as memory and cognitive disorders and associated anxiety and depression are major concern with aging. Molecular mechanisms underlying these changes are little known. The present study examined the differentially expressed genes (DEGs) and the genes with differentially expressed isoforms in three brain regions, anterior cingulate cortex (ACC), amygdala and hippocampus, throughout the lifespan of mice. Compared to 2-month old mice, both 12-and 24-month old mice displayed memory and cognitive impairments in the Morris water maze, Y-maze, and novel object recognition tests and depression-and anxiety-like behaviors in the tail suspension, forced swimming, open field, and elevated plus maze tests. RNA sequencing analysis identified 634 and 1078 DEGs in ACC, 453 and 1015 DEGs in the amygdala and 884 and 1054 DEGs in hippocampus in the 12-and 24-month old mice, respectively. Similarly, many genes with differentially expressed isoforms were also identified in these three brain regions in the 12-and 24-month old mice. Further functional analysis revealed that many DEGs and the genes with differentially expressed isoforms in the ACC and amygdala were mapped to depression-and anxiety-related genes, respectively and that a lot of DEGs and the genes with differentially expressed isoforms in hippocampus were mapped to cognitive dysfunction-related genes from both 12-and 24-month old mice. All of these mapped DEGs and the genes with differentially expressed isoforms were closely related to neuroinflammation. Our findings indicate that these neuroinflammation-related DEGs and the genes with differentially expressed isoforms are likely new targets in the management of memory/cognitive impairment and emotional disorders during the aging.

Vitamin K2 (Menaquinone-7) Reverses Age-Related Structural and Cognitive Deterioration in Naturally Aging Rats

“…The aging brain is characterized by various pathological and physiological changes in memory and cognitive functions associated with anxiety, mood disruption, and depression [33]. An animal model of human behavior represents a complex of cognitive and/or emotional processes, which are translated from animals to humans.…”

Gene Transcript Alterations in the Spinal Cord, Anterior Cingulate Cortex, and Amygdala in Mice Following Peripheral Nerve Injury

“…Interestingly, among the anxiety- and depression-related DEGs, we found the upregulation of Bcl3, C3, Gpat3, and Tnf in the AMY as well as the increased expression of Crhr2, Nant, Sar1a, and Tgif1 and the decreased expression of Ier2, Il12a, Nrep, and Tnfrsf25 in the ACC. These alternations were in step with the sequencing results in 12- and 24-month-old mice ( Li M. et al, 2020 ), suggesting some common gene expression alterations in different pathological processes, at least for anxiety- and depression-related genes.…”

“…For the function analysis, about 2,230, 1,689, and 1,812 DE mRNAs ( P < 0.05, fold change ≥ 1.74), respectively, from the SC, ACC, and AMY were categorized using the Kyoto Encyclopedia of Genes and Genomes (KEGG pathway analysis) and Gene ontology analysis by the database for Annotation, Visualization and Integrated Discovery (DAVID 5 ) ( Li M. et al, 2020 ). Likewise, GO Annotations and KEGG Pathways Analysis were applied to predict the role of DE lncRNAs through their target mRNAs.…”

Increased Endogenous GDNF in Mice Protects Against Age-Related Decline in Neuronal Cholinergic Markers

“…Aging induces a gradual decline in cognitive function. Decline in Y-maze performance has been previously reported upon normal aging ( Li et al, 2020 ) and in several mouse models of AD ( Webster et al, 2014 ). Similarly, we observed a decline in Y-maze performance in old Gdnf wt/wt animals but interestingly not in old Gdnf wt/hyper mice.…”