Adrenocortical Status Predicts the Degree of Age-Related Deficits in Prefrontal Structural Plasticity and Working Memory

Abstract

Cognitive decline in aging is marked by considerable variability, with some individuals experiencing significant impairments and others retaining intact functioning. Whereas previous studies have linked elevated hypothalamo-pituitary-adrenal (HPA) axis activity with impaired hippocampal function during aging, the idea has languished regarding whether such differences may underlie the deterioration of other cognitive functions. Here we investigate whether endogenous differences in HPA activity are predictive of age-related impairments in prefrontal structural and behavioral plasticity. Young and aged rats (4 and 21 months, respectively) were partitioned into low or high HPA activity, based upon averaged values of corticosterone release from each animal obtained from repeated sampling across a 24 h period. Pyramidal neurons in the prelimbic area of medial prefrontal cortex were selected for intracellular dye filling, followed by 3D imaging and analysis of dendritic spine morphometry. Aged animals displayed dendritic spine loss and altered geometric characteristics; however, these decrements were largely accounted for by the subgroup bearing elevated corticosterone. Moreover, high adrenocortical activity in aging was associated with downward shifts in frequency distributions for spine head diameter and length, whereas aged animals with low corticosterone showed an upward shift in these indices. Follow-up behavioral experiments revealed that age-related spatial working memory deficits were exacerbated by increased HPA activity. By contrast, variations in HPA activity in young animals failed to impact structural or behavioral plasticity. These data implicate the cumulative exposure to glucocorticoids as a central underlying process in age-related prefrontal impairment and define synaptic features accounting for different trajectories in age-related cognitive function.

Aging, glucocorticoids and developmental programming

“…There is support for the view that glucocorticoids accelerate aging processes (Anderson et al 2014) as well as for development of both glucocorticoid resistance and glucocorticoid enhanced aging in different metabolic pathways (Chen et al 2013). We propose that circulating glucocorticoids follow an age-related trajectory, which can be affected by both the external environment and internal physiological events.…”

Molecular aspects of age-related cognitive decline: the role of GABA signaling

“…For example, emerging evidence suggests that GABAergic interneurons may be particularly vulnerable to the effects of psychogenic stress [117,118]. Because dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis and protracted exposure to glucocorticoids is a well-documented feature of normal aging [8,119–121], normalization of glucocorticoid signaling represents one avenue to explore for the prevention of inhibitory signaling dysfunction across both PFC and hippocampus.…”

Perceived and posttraumatic stress is associated with decreased learning, memory, and fluency in HIV-infected women

“…For example, intracellular trafficking of the glucocorticoid receptor is diminished in the hippocampus of aged rats [40] , especially in those with hippocampal-related memory impairments [41] . Cumulative over-exposure to glucocorticoids is also associated with age-related prefrontal impairments in rats [42] . Thus, glucocorticoid receptor dysfunction and altered cortisol levels combined could predispose HIV+ women to stress-associated psychiatric disorders and memory impairment linked to glucocorticoid resistance.…”