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.”
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Reference
DOI: 10.1007/s12035-025-05024-y
About Fujita Health University
Fujita Health University (FHU) is a private medical university located in Aichi, Japan. Established in 1964, it houses one of the largest university hospitals in Japan. Its 900-member faculty provides diverse learning and research opportunities to medical students worldwide. Guided by its founding philosophy of "Our creativity for the people," Fujita Health University believes that its students can shape the future through creativity and innovation. FHU has earned global recognition, ranking eighth among all universities and second among private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. The university ranked fourth worldwide in the 2024 THE University Impact Rankings for contributions to the "Good Health and Well-being" SDG (Sustainable Development Goals) of the United Nations (UN). In June 2021, the university made history as the first Japanese institution to host the THE Asia Universities Summit. In 2024, Fujita Health University was awarded the Forming Japan’s Peak Research Universities (J-PEAKS) Program by the Japanese government to establish an innovative academic drug discovery ecosystem and hub of a multi-university consortium for research and education.
Website: https://www.fujita-hu.ac.jp/en/index.html
About Professor Yoshihisa Sugimura from Fujita Health University
Yoshihisa Sugimura is a professor in the Department of Endocrinology, Diabetes and Metabolism at Fujita Health University, School of Medicine. Prof. Sugimura's research focuses on the interplay between electrolyte imbalances and neurological function. He has published extensively in areas such as hyponatremia, central diabetes insipidus, autoimmune hypophysitis, and osmotic demyelination syndrome. Prof. Sugimura has over 85 peer-reviewed publications and more than 20 authored books. His recent research has uncovered how low sodium levels can disrupt neurotransmitter signaling and contribute to anxiety-like behaviors, highlighting the neurological consequences of common metabolic disorders and informing future therapeutic approaches.
Funding information
This work was supported by JSPS KAKENHI (Grant Number 20 K08919 to Yoshihisa Sugimura, 22 K16229 to Haruki Fujisawa), The Salt Science Research Foundation No. 22 C2, YOKOYAMA Foundation for Clinical Pharmacology, The Hori Science and Arts Foundation, The Nitto Foundation, and MEXT Promotion of Distinctive Joint Research Center Program (Grant Number FY2018-2020 JPMXP0618217663, FY2021-2023 JPMXP0621467949).
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