New study links intermittent fasting to improved mood via brain’s dopamine system

Intermittent fasting may help alleviate depression symptoms by targeting dopamine receptors in the brain, according to a new study published in Neurobiology of Disease.

Depression is one of the most common mental health disorders. Traditional antidepressants can take weeks to take effect and often come with undesirable side effects. Researchers have been exploring alternative strategies to improve mental health, and one promising avenue is nutrition. Intermittent fasting — a dietary pattern that involves alternating periods of eating and fasting — has gained increasing attention.

Previous studies have suggested that fasting may influence the brain’s neurotransmitter systems, but the precise mechanisms have remained unclear. In this new research, scientists investigated whether intermittent fasting could reduce depression-like symptoms by acting on dopamine D1 receptors, which are known to play a key role in mood regulation.

To test their hypothesis, a research team led by Jingjing Piao from the Second Hospital of Jilin University in China used a well-established mouse model of depression known as Chronic Unpredictable Mild Stress (CUMS).

The mice were exposed to a series of randomly arranged stressors over several weeks — such as foot shocks, water deprivation, and tail pinching — to mimic the effects of chronic stress in humans. After this period, some of the mice were placed on an intermittent fasting schedule that alternated 24-hour periods of food availability with 24-hour fasting. For comparison, other groups of mice received the common antidepressant fluoxetine or underwent a shorter 9-hour fasting period.

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The results were striking. Mice in the intermittent fasting group showed marked improvements in depression-related behaviors. They were more likely to engage in pleasurable activities, such as drinking a sugar solution — a sign of reduced anhedonia, or loss of pleasure. These mice also exhibited decreased immobility in behavioral tests designed to assess despair-like symptoms, suggesting greater resilience to stress.

To understand how intermittent fasting produced these effects, the researchers examined the mice’s brain activity. They found increased neuronal activation in the medial prefrontal cortex (mPFC), a brain region involved in emotional regulation. More specifically, intermittent fasting enhanced activity in the Drd1-cAMP-PKA-DARPP-32-CREB-BDNF signaling pathway — a cascade of molecular events associated with dopamine D1 receptor function.

When researchers administered a drug that blocked dopamine D1 receptors, the antidepressant-like effects of intermittent fasting disappeared. This indicated that the benefits were directly dependent on this dopamine pathway.

Further experiments using optogenetics — a technique that uses light to control the activity of specific neurons — reinforced this conclusion. When the researchers artificially activated dopamine D1 receptor-expressing neurons in the mPFC, the mice exhibited behavioral improvements similar to those seen with fasting. Conversely, inhibiting these neurons reversed the effects of fasting.

While the findings offer promising insights into the biological mechanisms linking intermittent fasting and depression, the researchers acknowledge key limitations. The study was conducted in mice, and more research is needed to determine whether similar effects occur in humans.

The study, “Intermittent fasting produces antidepressant-like effects by modulating dopamine D1 receptors in the medial prefrontal cortex,” was authored by Jingjing Piao, Hongyu Chen, Xinmiao Piao, Ziqian Cheng, Fangyi Zhao, Ranji Cui, and Bingjin Li.