# Repeated treatment with short-term mild stress reverses aging- and stress-induced emotional and social behavioral deficits

## TL;DR

Repeated mild stress can reverse age-related and stress-induced emotional and social problems in mice by targeting brain regions like the ventral subiculum.

## Contribution

The study reveals that repeated mild stress reverses stress-induced impairments in aged and young mice by normalizing Fkbp5-dependent signaling in the ventral subiculum.

## Key findings

- Aged mice show elevated stress hormones but not depressive-like behavior, but subthreshold stress induces impairments.
- Repeated mild stress reverses stress-induced behavioral and physiological impairments in both young and aged mice.
- Targeted Fkbp5 knockdown in the ventral subiculum mitigates stress effects and rescues behavior.

## 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.

As we age, our brains undergo changes that make us more vulnerable to stress. This study explores how enhanced sensitivity to stress in aging brains can be overcome. Researchers have demonstrated that aging is accompanied by the accumulation of stress hormone-dependent changes in the brain, which can be reversed by a method known as ‘repeated mild stress’, involving short daily sessions of gentle restraint or rocking. Researchers measured changes in behavior and brain chemistry, focusing on specific brain areas such as the ventral subiculum, which are functionally downregulated in aged brains as in young mice under chronic stress. The study found that repeated mild stress helped reverse stress-induced behavioral problems and the reduced neural activity changes in both young and aged mice. This suggests that mild stress could be a potential therapy for stress-related issues in aging brains.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.