# Fluoxetine Reduces Hyperglycemia‐Induced Facilitation of Fear Memory in Mice

## TL;DR

Fluoxetine reduces fear memory enhancement caused by high blood sugar in mice, suggesting it may help with emotional changes linked to diabetes.

## Contribution

Fluoxetine reverses hyperglycemia-induced fear memory without affecting hippocampal Tnf expression.

## Key findings

- Hyperglycemia increases freezing behavior in fear conditioning tests in mice.
- Fluoxetine treatment reversed the enhanced fear memory caused by hyperglycemia.
- The effect of fluoxetine was independent of hippocampal Tnf expression changes.

## Abstract

Although it is well established that people with diabetes are at an increased risk of developing neuropsychiatric disorders, including depression and anxiety, the mechanisms that mediate this relationship are not fully understood. The use of preclinical models can be helpful in the investigation of mechanisms. For example, studies have shown that chronic hyperglycemia (HG), induced by administration of streptozotocin (STZ) to mice, induces neuroinflammation and depressive‐like behaviors in classic tests of antidepressant efficacy (e.g., forced swim test, splash test). However, there is a need to establish more specific assessments of affective dysfunction, including assessment of changes within the negative valeence systems. It has been previously reported that HG rodents show increased susceptibility to fear conditioning, potentially through increased salience of negative stimuli. Based on this, we sought to determine whether this enhanced fear memory is sensitive to fluoxetine (FLX), a commonly used antidepressant.

Male C57BL/6J mice were administered 50 mg/kg STZ per day for five consecutive days or an equal volume of citrate buffer to induce HG. Four weeks after HG induction, a time at which behavioral changes are well established, mice started daily treatment with 10 mg/kg FLX or saline vehicle. After approximately 2 weeks of treatment, mice were evaluated for activity (i.e., marble burying and open field) and memory within the fear conditioning paradigm.

As previously reported, mice with HG showed reduced marble burying, reduced open field activity, and increased freezing in the conditioning context. Although FLX treatment did not reverse HG‐induced burying or activity effects, it did reverse HG‐facilitated freezing. This effect was independent of changes in HG‐induced hippocampal Tnf expression.

This provides support for the utilization of the fear conditioning task to understand HG‐associated changes in the negative valence systems. It also provides additional confirmatory data indicating that the basal lateral amygdala is sensitive to HG‐induced dysfunction.

Hyperglycemia (HG) enhances fear memory in mice, potentially reflecting negative valence bias rather than cognitive enhancement. Fluoxetine (FLX) prevented HG‐induced facilitation of fear conditioning independent of locomotor activity or hippocampal Tnf expression changes. These findings support using fear conditioning to assess HG‐associated affective alterations in negative valence systems.