Stress ends while brain changes continue to unfold. A study published on March 13, 2025 in Communications Biology finds that shortly after repeated restraint stress, male mice show no clear reduction in open-arm exploration, although activity markers in prefrontal PrL cells increase. Six days later, those cells are less active and avoidance-related behavior is stronger. GHS-R1a, a receptor usually associated with ghrelin signaling, also increases in this region after a delay. Altering receptor expression connects this later molecular change to excitatory input and post-stress vulnerability.

01 / Delayed changes

Cells activate first, behavior changes later

Shortly after repeated stress ends, open-arm time remains similar to baseline. Six days later, open-arm exploration and social interaction decrease while tail-suspension and swimming immobility increase. An observable delay separates the stress event from later behavioral changes.

Activity markers in PrL αCaMKII-positive excitatory cells rise early but fall later. In neighboring IL, markers rise at both time points. Even within prefrontal cortex, stress-related time courses differ, directing the study toward PrL.

Original figure 1Post-stress behavior and cellular activity over time

02 / Entering exposed areas

A response to entering open arms weakens after stress

At baseline, entering an open arm increases PrL calcium signals. After repeated stress, that clear entry-associated increase is absent. Entering a closed arm lowers calcium in both states, while overall recorded activity is lower after stress.

Electrical recordings show lower frequency and amplitude of miniature excitatory events at the later stage, while inhibitory events remain broadly unchanged. The weaker response has an input-level counterpart: reduced excitatory drive accompanies altered dynamics during environmental events.

Original figure 3Calcium responses during open- and closed-arm exploration

03 / Effects of increasing activity

Increasing PrL activity after stress increases exploration

Directly increasing activity in these PrL cells raises open-arm time and reduces tail-suspension immobility in stressed mice. In unstressed mice, open-arm exploration does not clearly change, although immobility decreases. Effects depend on both task and state.

This gives functional meaning to the early activation and later low activity: increasing these cells’ activity changes some post-stress measures. The study next searches for a delayed cellular change that could contribute to weakened inputs and responses.

Original figure 4Behavioral effects of increasing cellular activity

04 / Delayed receptor expression

More cells carry GHS-R1a transcripts

GHS-R1a is usually studied as a ghrelin receptor. Here, its PrL transcripts increase six days after stress without a clear early change; the basolateral amygdala lacks the same alteration. The expression time course accompanies behavioral and cellular-activity changes.

In situ detection shows a larger fraction of αCaMKII-positive cells carrying receptor transcripts, without a clear increase in average signal intensity within each positive cell. A broader receptor-positive population and uniform upregulation in every cell represent different observational scales.

Original figure 5Regional and cellular distribution of receptor transcripts

05 / Reducing expression

Behavioral improvement differs by task

Reducing GHS-R1a in these PrL cells increases open-arm exploration and reduces immobility before stress. After stress, immobility remains lower but open-arm time does not clearly differ. The effects on different stress-associated measures are therefore not identical.

In receptor-reduced mice, excitatory-event frequency rises after stress, while amplitude and inhibitory events remain broadly unchanged. This differs from the declining excitatory input observed in ordinary stressed mice, supporting a contribution of receptor expression to stress-related synaptic responses.

Original figure 6Behavior and synaptic changes with reduced GHS-R1a

06 / Increasing expression

Little baseline change, greater avoidance after stress

Increasing GHS-R1a expression does not clearly alter tested behavior before stress. After repeated stress, open-arm exploration falls and swimming immobility increases. Higher expression thus changes vulnerability in a stressful context rather than producing an identical effect in every condition.

After stress, receptor-overexpressing cells show lower excitatory-event frequency and amplitude and higher spontaneous inhibitory-event frequency. The input changes jointly shift toward reduced excitatory drive, accompanying stronger avoidance.

Original figure 7Stress vulnerability under increased expression