Effects of different chronic restraint stress periods on anxiety- and depression-like behaviors and tryptophan-kynurenine metabolism along the brain-gut axis in C57BL/6N mice

by Selleckchem | Feb 10 2024

Chronic restraint stress (CRS) is a widely used stimulus to induce anxiety- and depression-like behaviors, linked to alterations in tryptophan-kynurenine (TRP-KYN) metabolism in animals. This study assessed the effects of different CRS periods on anxiety- or depression-like behaviors and TRP-KYN metabolism along brain-gut axis in C57BL/6N mice. Results showed that one-week CRS decreased the open arm entries of mice in elevated plus maze and delayed latency of feeding in novelty suppressed feeding test. Four-week CRS reduced sucrose preference, increases forced swimming immobility time, and also induced anxiety-like behaviors of mice. UPLC-MS/MS analysis revealed decreased levels of the neurotoxic 3-hydroxykynurenine (3-HK) and quinolinic acid (QA), and an increase in the neuroprotective kynurenic acid (KA) in the hippocampus of one-week CRS mice; meanwhile, four-week CRS mice displayed a reduction in KA and increases in 3-HK and QA. In the colon, both one-week and four-week CRS mice exhibited significant reductions in 3-HK and QA, with a marked increase of KA exclusively in four-week CRS mice. Briefly, one-week CRS only induced anxiety-like behaviors with hippocampal neuroprotection in TRP-KYN metabolism, whereas four-week CRS caused anxiety- and depression-like behaviors with neurotoxicity. In the colon, during both CRS periods, KYN was metabolized in the direction of NAD+ production. However, four-week CRS triggered intestinal inflammation risk with increased KA. Summarily, slightly short-term stress has beneficial effects on mice, while prolonged chronic stress can lead to pathological changes. This study offers valuable insights into stress-induced emotional disturbances.

Comments:

This study you've described presents intriguing findings about the impact of chronic restraint stress (CRS) on behavior and the tryptophan-kynurenine (TRP-KYN) metabolism in mice, especially in relation to anxiety and depression-like behaviors.

The key takeaways seem to be:

1. **Behavioral Effects**:
- One-week CRS resulted in anxiety-like behaviors (elevated plus maze, novelty suppressed feeding test).
- Four-week CRS induced both anxiety and depression-like behaviors (reduced sucrose preference, increased immobility in forced swimming test).

2. **TRP-KYN Metabolism**:
    - In the hippocampus, one-week CRS showed neuroprotection by decreasing neurotoxic metabolites (3-HK, QA) and increasing the neuroprotective KA.
    - Four-week CRS exhibited a shift towards neurotoxicity with reduced KA and increased levels of 3-HK and QA in the hippocampus.
    - In the colon, both CRS durations reduced neurotoxic metabolites (3-HK, QA) and increased KA, particularly prominently during four-week CRS.

3. **Implications**:
    - Short-term stress might have some beneficial effects on behavior and hippocampal neuroprotection.
    - Prolonged stress can lead to both anxiety and depression-like behaviors, along with neurotoxic changes in the hippocampus.
    - Despite the positive increase in neuroprotective KA in the colon, the prolonged stress duration showed an increased risk of intestinal inflammation.

Overall, this research suggests that the duration of stress significantly influences its impact on behavior and the intricate TRP-KYN pathway. Short-term stress might have protective effects, while prolonged stress can lead to pathological changes, impacting both behavior and the neurochemical balance in the brain and gut.

These findings provide valuable insights into stress-related emotional disturbances and shed light on potential therapeutic targets within the TRP-KYN pathway for stress-related disorders.