# Homocysteine Mediates Cognitive Inflexibility Induced by Stress via Targeting PIN1

## TL;DR

This study shows that homocysteine (HCY) contributes to stress-induced cognitive inflexibility in mice, and reducing HCY with VitB can help improve cognitive flexibility.

## Contribution

The study identifies HCY as a mediator of stress-induced cognitive inflexibility and suggests VitB as a potential therapeutic strategy.

## Key findings

- Stress increases PIN1 expression and impairs cognitive flexibility in mice.
- Homocysteine induces PIN1 expression in neurons in vitro.
- VitB reduces HCY levels and improves cognitive flexibility in stressed mice.

## Abstract

Background: Increasing evidence shows that HCY plays an important role in stress-induced cognitive dysfunction, and HCY significantly promotes the decline of cognitive function. Stress has been reported to cause elevated HCY in the hippocampus of mice. Cognitive flexibility refers to the ability of individuals to quickly adjust their neurobehavioral strategies to different situations or to solve different tasks. Aims: This study aims to explore the role of HCY in the impairment of cognitive flexibility induced by stress and its possible regulatory mechanism. Methods and Results: First, we examined changes in the protein and mRNA levels of the cognitive flexibility effector molecule, PIN1, during stress in mice. The results show that stress can cause a decline in cognitive flexibility in mice and lead to an increase in PIN1. Moreover, through the use of in vitro experiments, we found that HCY could induce an increase in PIN1 expression in neurons. Further in vivo experiments were used to investigate the effect of VitB on HCY and PIN1 and evaluated the therapeutic effect of VitB on stress-induced impairment of cognitive flexibility. The results show that VitB decreased the levels of HCY in plasma and the hippocampus, alleviated the stress-induced impairment of cognitive flexibility, and reduced the expression of PIN1. Conclusions: These results suggest that the impairment of cognitive flexibility induced by stress can be inhibited by regulating the content of HCY. Collectively, our findings highlight therapeutic strategies aimed at improving HCY treatment for impairments in cognitive flexibility.