# Effects of post-stress corticosterone on hippocampal excitability and behavior involving hyperpolarization-activated cation channel 1 function

## TL;DR

This study shows how stress hormones affect brain function and behavior, linking them to PTSD-like symptoms through a specific ion channel.

## Contribution

The study identifies HCN1 channels as a key mediator of stress-induced hippocampal changes and PTSD-like behaviors.

## Key findings

- SPS + CORT mice showed impaired spatial memory and fear extinction resembling PTSD.
- HCN1 overexpression reproduced stress-induced behavioral and physiological effects.
- Genetic deletion of HCN1 rescued behavioral abnormalities in SPS + CORT mice.

## Abstract

Single Prolonged Stress (SPS) is a widely used rodent model for investigating the consequences of acute traumatic stress, but outcomes in mice are often variable across strains and behavioral domains. Because corticosterone (CORT) release is a central feature of the stress response, we combined SPS with post-stress CORT administration (SPS + CORT) to capture this hormonal component and unmask latent phenotypes. Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels are highly expressed in the dorsal CA1 (dCA1) hippocampus, where they regulate neuronal excitability. We previously demonstrated that acute CORT enhances hyperpolarization-activated current (Ih) in vitro; here, we tested its in vivo contribution to stress-related behavioral and physiological outcomes. Male mice (8–9 weeks old) were exposed to SPS followed by vehicle or CORT. Behavioral assays—including the open field, Y-maze, and contextual fear conditioning—revealed that SPS + CORT mice displayed impaired spatial working memory and deficits in contextual recall and fear extinction, resembling core PTSD-like features. Whole-cell recordings from dCA1 neurons showed decreased input resistance, reduced action potential firing, and elevated Ih, which were normalized by the HCN channel blocker ZD7288. Overexpression of HCN1 in SPS mice reproduced both behavioral and physiological phenotypes seen in SPS + CORT mice, whereas genetic deletion of HCN1 in SPS + CORT mice reduced Ih and rescued the behavioral abnormalities. Together, these findings identify HCN1 channels as a critical mediator linking post-stress glucocorticoid signaling to maladaptive hippocampal plasticity and PTSD-like outcomes.