# Gastrin-releasing peptide is essential for generalization of auditory conditioned fear under stress

## TL;DR

This study shows that gastrin-releasing peptide is crucial for fear generalization in stressful situations, which could lead to new treatments for anxiety disorders.

## Contribution

The study identifies a novel role for gastrin-releasing peptide in maladaptive fear generalization under stress.

## Key findings

- GRP is required for enhanced fear responses to both conditioned and non-conditioned stimuli under stress.
- Infusion of GRP into the auditory cortex restores fear generalization in GRP knockout mice.
- GRP in the auditory cortex is essential for generalizing fear memory retrieval to non-threatening stimuli.

## Abstract

Fear generalization, which allows animals to respond adaptively to cues similar to original threatening ones, is generally beneficial for survival. However, an inability to distinguish between threat and safety, leading to the overgeneralization of fear to non-threatening stimuli, is maladaptive and is implicated in anxiety disorders such as post-traumatic stress disorder (PTSD). The neuropeptide gastrin-releasing peptide (GRP) is known to modulate fear memory under stress, yet its role in response to intense aversive stimuli remains less understood. In this study, we used GRP knockout (Grp−/−) mice to examine the role of GRP in enhancing fear responses to conditioned stimulus (10 kHz tone, CS+) and non-conditioned stimulus (2 kHz tone, CS-) in a model of auditory fear conditioning with high-intensity footshocks following single acute restraint stress (RS). Our findings reveal that GRP is required not only for enhanced response to CS+ but also for generalized fear responses to CS-. Furthermore, we observed that infusion of GRP into the auditory cortex (AC) of Grp−/− mice restores freezing behavior in response to CS- and fear generalization. Additionally, GRP in the AC is essential for the generalization of CS+ responsive neurons to respond to CS- during fear memory retrieval. These results highlight a novel role for GRP in the mechanisms underlying maladaptive fear in highly stressful situations, offering potential new targets for treating anxiety-related disorders.

The online version contains supplementary material available at 10.1186/s13041-025-01214-w.