Abstract
Aging increases vulnerability to stress-induced neuronal dysfunction, yet the underlying mechanisms remain unclear. Here, in young mice (2 months), chronic stress elevates basal serum glucocorticoid (GC) levels and induces despair-like behavior, as well as impaired sociability. By contrast, aged mice (14.5 months) naturally exhibit elevated basal GC levels, but do not display depressive-like behavior or sociability deficits, although further analysis reveals a social memory impairment. However, exposure to subthreshold stress in aged mice further elevates basal GC levels and induces both emotional and sociability impairments. Notably, repeated mild stress reverses these stress-induced physiological and behavioral impairments in young and aged mice. Neural activity-dependent c-Fos expression mapping identifies the ventral subiculum (vSub) as a potential upstream neural hub that regulates both serum GC responses and emotional and social behaviors. Chemogenetic activation of the vSub, particularly the vSub-to-dorsal bed nucleus of the stria terminalis circuitry, reverses stress-induced increases in basal GC levels and the associated behavioral deficits. Transcriptomic analysis reveals that the vSub gene expression profile in aged mice significantly overlaps with that of young mice exposed to chronic stress, notably characterized by Fkbp5 upregulation. Targeted knockdown of Fkbp5 within the vSub mitigates stress-induced increases in GC levels and rescues behavioral deficits. Moreover, repeated short-term mild stress or low-dose GC treatment ameliorates stress-induced physiological and behavioral impairments, accompanied by downregulation of Fkbp5 in the vSub. Collectively, these results suggest that the aged brain acquires chronic stress-like signatures, heightening its vulnerability to maladaptive outcomes, and that repeated short-term mild stress can restore emotional and social function by normalizing vSub Fkbp5-dependent signaling.