Abstract
Brain aging proceeds with cellular and molecular changes in the limbic system. Aging-dependent changes might affect emotion and stress coping, yet the underlying mechanisms remain unclear. Here, we show aged (18-month-old) mice exhibit upregulation of NADPH oxidase and oxidative stress in the hippocampus, which mirrors the changes in young (2-month-old) mice subjected to chronic stress. Aged mice that lack p47phox, a key subunit of NADPH oxidase, do not show increased oxidative stress. Aged mice exhibit depression-like behavior following weak stress that does not produce depressive behavior in young mice. Aged mice have reduced expression of the epigenetic factor SUV39H1 and its upstream regulator p-AMPK, and increased expression of Ppp2ca in the hippocampus—changes that occur in young mice exposed to chronic stress. SUV39H1 mediates stress- and aging-induced sustained upregulation of p47phox and oxidative stress. These results suggest that aging increases susceptibility to stress by upregulating NADPH oxidase in the hippocampus.
Highlights
Brain aging proceeds with cellular and molecular changes in the limbic system
The hypophysiotrophic factors corticotrophin-releasing hormone (CRH) and vasopressin (AVP) in the paraventricular nucleus of the hypothalamus (PVN) in aged mice were upregulated compared with young mice (Fig. 1d, e)
Given that aging brains exhibited increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and oxidative stress in the hippocampus (Fig. 1f–i), similar to changes induced by chronic stress (Fig. 1o–t), we examined whether aged mice are sensitive to stress-induced depression or exhibit depressive behaviors
Summary
Brain aging proceeds with cellular and molecular changes in the limbic system. Agingdependent changes might affect emotion and stress coping, yet the underlying mechanisms remain unclear. We show aged (18-month-old) mice exhibit upregulation of NADPH oxidase and oxidative stress in the hippocampus, which mirrors the changes in young (2month-old) mice subjected to chronic stress. SUV39H1 mediates stress- and aging-induced sustained upregulation of p47phox and oxidative stress These results suggest that aging increases susceptibility to stress by upregulating NADPH oxidase in the hippocampus. Depression patients exhibit increased basal serum GC levels[12,13,14] These reports suggest that the stress-regulating neuroendocrine system is dysfunctional in aged people and patients with depression. AMPK activation increases phospho-CREB expression[31,32], and improves impaired depressive behaviors[33] These results suggest that AMPK and factors centered on AMPK have a role in stress-induced pathophysiology in aged brains. Epigenetic modifications of histone proteins play a role in development of psychiatric disorders including depression[34,35]
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