Low Sodium in Blood Triggers Anxiety in Mice by Disrupting Their Brain Chemistry 444i5

Chronic low sodium levels disrupt brain chemistry and trigger anxiety-like behavior in mice through amygdala dysfunction 2w3z1h

Researchers from Fujita Health University have found that chronic hyponatremia (CHN), a condition of prolonged low blood sodium, induces anxiety-like behaviors in mice. CHN disrupts serotonin and dopamine levels and reduces extracellular signal-regulated kinase phosphorylation in the amygdala, a key brain region for emotion. These changes are reversible with sodium level correction. The findings suggest that CHN directly affects brain function and early diagnosis and treatment to improve mental well-being in affected individuals. 

Hyponatremia, or low blood sodium concentration, is typically viewed as a symptomless condition—until recently. A research team led by Professor Yoshihisa Sugimura, including Dr. Haruki Fujisawa, Professor Atsushi Suzuki, Professor Tsuyoshi Miyakawa, and Professor Akihiro Mouri, from Fujita Health University, Japan, has demonstrated that chronic hyponatremia (CHN) can directly cause anxiety-like behaviors in mice by disrupting key neurotransmitters in the brain. Their findings, published online in the journal Molecular Neurobiology on May 14, 2025, reveal that CHN alters monoaminergic signaling in the amygdala, a brain region critical for processing fear and emotion.

“While CHN has been associated with cognitive impairments, our study is among the first to provide evidence that it also leads to innate anxiety-like behaviors through changes in brain chemistry,” explains Dr. Fujisawa.

Hyponatremia is usually caused by conditions like liver cirrhosis, heart failure, or syndrome of inappropriate antidiuresis (SIAD). In chronic cases, the brain adapts to the low-sodium environment by adjusting its cellular content through a compensatory mechanism known as volume regulatory decrease (VRD). But this adaptation, while protective, comes at a physiological cost.

This compensation process involves the loss of organic osmolytes and neurotransmitter precursors that help stabilize brain cell volume under low-sodium conditions. Over time, this may lead to disruption in the production, release, or recycling of key mood-regulating chemicals.

To explore whether CHN could cause neurological manifestations, the researchers developed a mouse model using a sustained infusion of desmopressin (a vasopressin analog) and feeding a liquid diet to mimic SIAD. They found that the mice exhibited significantly lower serum sodium levels, which were maintained over a prolonged period, consistent with chronic hyponatremia (CHN) and exhibited increased anxiety-like behaviors in both the light/dark transition and open field tests—standard behavioral assays in neuroscience.

Further biochemical analyzes revealed that levels of serotonin and dopamine, two key neurotransmitters that regulate mood, were significantly reduced in the amygdala of mice with CHN. These changes were accompanied by a drop in extracellular signal-regulated kinase (ERK) phosphorylation—a molecular signal for emotional regulation.

“Our data suggest that CHN disrupts the balance of monoamines in the amygdala, especially serotonin and dopamine, which in turn modulates innate anxiety,” says Prof. Sugimura. To test whether these effects were reversible, the researchers corrected the mice’s sodium levels by stopping desmopressin infusion and reverting them to a solid diet. As a result, anxiety-like behaviors subsided. Serotonin, dopamine, and ERK phosphorylation levels in the amygdala also returned to normal. “This shows not only that CHN causes anxiety-like symptoms but also that these symptoms can be alleviated with proper correction of sodium imbalance,” says Dr. Fujisawa.

While the study focused on mice, the findings could apply to humans. CHN is fairly common among elderly patients and those with chronic illnesses. Identifying and treating its neurological manifestations can improve their quality of life. “Our findings add to the growing evidence that chronic hyponatremia is not just a metabolic abnormality, but a condition with real neurological and psychological consequences,” Prof. Sugimura concluded. “This underscores the importance of early diagnosis and treatment, not only to protect the brain but also to improve mental well-being.”