Age-Related Decrease in Stress Responsiveness and Proactive Coping in Male Mice

Abstract

Coping is a strategic approach to dealing with stressful situations. Those who use proactive coping strategies tend to accept changes and act before changes are expected. In contrast, those who use reactive coping are less flexible and more likely to act in response to changes. However, little research has assessed how coping style changes with age. This study investigated age-related changes in coping strategies and stress responsiveness and the influence of age on the processing of conditioned fear memory in 2-, 12- and 23-month-old male mice. Coping strategy was measured by comparing the escape latency in an active avoidance test and by comparing responses to a shock prod. The results showed that proactivity in coping response gradually decreased with age. Stress responsiveness, measured by stress-induced concentration of corticosterone, was also highest in 2-month-old mice and decreased with age. Consolidation of fear memory was highest in 12-month-old mice and was negatively correlated with the degree of stress responsiveness and proactivity in coping. Fear extinction did not differ among age groups and was not correlated with stress responsiveness or the proactivity of coping. However, the maintenance of extinct fear memory, which was best in 2-month-old mice and worst in 12-month-old mice, was negatively correlated with stress responsiveness but not with coping style. Age-dependent changes in the expression of glucocorticoid receptor (GR) and its regulatory co-chaperones, which are accepted mechanisms for stress hormone stimulation, were measured in the hippocampus. The expression of GR was increased at 12 months compared to other age groups. There were no differences in Hsp70 and BAG1 expression by age. These results can be summarized as follows: (1) stress responsiveness and proactivity in coping decreased with age class; (2) consolidation of fear memory was negatively correlated with both stress responsiveness and proactivity; however, maintenance of extinct fear memory was negatively correlated with stress responsiveness only; and (3) consolidation and maintenance of extinct fear memory appeared to be more influenced by factors other than stress reactivity and proactivity in coping, such as the amount of hippocampal glucocorticoid expression.

Evidence for an apathy phenotype in aged mice

“…The findings relating to stress reactivity add to previously published work (Oh et al, 2018) suggesting an age-related decline in active coping including the hormonal response to acute stress. This raises an important issue when considering data obtained from stress-driven cognitive tasks such as the commonly used Morris Water Maze (Morris, 1981).…”

“…However, it has been previously suggested that changes to the functional gating of limbic information by local PVN projections may explain age-related changes to the HPA axis (Herman et al, 2002). Stress reactivity and active coping in response to aversive experiences has previously been shown to reduce with age in mice (Oh et al, 2018) and extend beyond mice to rat and human studies (Brugnera et al, 2017;Buechel et al, 2014). There is some variability in findings possibly due to a lack of standardisation across studies including the nature and intensity of the stressor (Novais et al, 2017;Segar et al, 2009).…”

The HPA Axis under Stress and Aging: Individual Vulnerability is Associated with Behavioral Patterns and Exposure Time

“…[ 56,57 ] There is particularly considerable data on the relationship of behavior to HPA axis function. [ 3,7,9,12,16–19 ]…”

“…[ 2,3,7,12,16 ] A greater response of the HPA axis to stress exposure has also been noted in healthy animals with anxiety and depression‐like behavior. [ 2,9,17,18 ] Part of such research, however, has focused on stress in early life and did not address changes associated with aging. [ 12,13,19 ]…”

Constitutive differences in glucocorticoid responsiveness are related to divergent spatial information processing abilities

“…When probed after the forced-swim test at 18 months of age, CORT responses across lines were lower than following stressful challenges CORT concentrations observed following stressor exposure during earlier life periods. In fact, an age-related decline in the adrenal stimulated secretion of corticosterone has been earlier documented (Cizza et al, 1994; Hauger et al, 1994; Oh et al, 2018). Moreover, it is important to note that the High CORT line shows normal CORT baseline and recovery levels following stress activation, while it displays higher peak CORT levels following stress exposure and lower habituation to repeated stress (Walker et al, 2017).…”