Abstract
Cognitive processes associated with prefrontal cortex and hippocampus decline with age and are vulnerable to disruption by stress. The stress/stress hormone/allostatic load hypotheses of brain aging posit that brain aging, at least in part, is the manifestation of life-long stress exposure. In addition, as humans age, there is a profound increase in the incidence of new onset stressors, many of which are psychosocial (e.g., loss of job, death of spouse, social isolation), and aged humans are well-understood to be more vulnerable to the negative consequences of such new-onset chronic psychosocial stress events. However, the mechanistic underpinnings of this age-related shift in chronic psychosocial stress response, or the initial acute phase of that chronic response, have been less well-studied. Here, we separated young (3 month) and aged (21 month) male F344 rats into control and acute restraint (an animal model of psychosocial stress) groups (n = 9–12/group). We then assessed hippocampus-associated behavioral, electrophysiological, and transcriptional outcomes, as well as blood glucocorticoid and sleep architecture changes. Aged rats showed characteristic water maze, deep sleep, transcriptome, and synaptic sensitivity changes compared to young. Young and aged rats showed similar levels of distress during the 3 h restraint, as well as highly significant increases in blood glucocorticoid levels 21 h after restraint. However, young, but not aged, animals responded to stress exposure with water maze deficits, loss of deep sleep and hyperthermia. These results demonstrate that aged subjects are hypo-responsive to new-onset acute psychosocial stress, which may have negative consequences for long-term stress adaptation and suggest that age itself may act as a stressor occluding the influence of new onset stressors.
Highlights
Normal aging is a complex process resulting in functional decline and increased susceptibility to a variety of insults across multiple organ systems
Young, but not aged, animals responded to stress exposure with water maze deficits, loss of deep sleep and hyperthermia. These results demonstrate that aged subjects are hypo-responsive to new-onset acute psychosocial stress, which may have negative consequences for long-term stress adaptation and suggest that age itself may act as a stressor occluding the influence of new onset stressors
Synergistic actions of stress and aging are thought to be especially disruptive in the hippocampus, leading to memory impairments and weakened control over stress hormones (Sapolsky et al, 1984; Meaney et al, 1992; Stranahan et al, 2008)
Summary
Normal aging is a complex process resulting in functional decline and increased susceptibility to a variety of insults across multiple organ systems. The hippocampus plays a critical role in cognitive function (Lupien et al, 1998; Yankner et al, 2008) and provides important feedback regulation over the hypothalamic-pituitary-adrenal (HPA) axis (McEwen et al, 1992; Rostene et al, 1995; Ziegler and Herman, 2002; Joels et al, 2013). The convergence of age and stress at the hippocampus is highlighted by evidence of increased cognitive dysfunction in aged humans after exposure to new-onset stress, including jet lag, physical wounding, anesthesia, infection or psychosocial stressors (PS- stressors that do not involve nociceptive input) (Wofford et al, 1996; Bekker and Weeks, 2003; Lupien et al, 2005; Vondras et al, 2005; Barrientos et al, 2012)
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