Chronic Hyponatremia Causes Anxiety-Like Behavior by Disrupting Monoamine Signaling in the Amygdala — Mouse Study
Summary: New research from Fujita Health University shows that chronic hyponatremia — persistently low blood sodium — alters brain chemistry and produces anxiety-like behaviors in mice. The study identifies reductions in serotonin and dopamine in the amygdala, a brain region central to emotion and fear processing, and demonstrates that these changes and behavioral effects are reversible when sodium balance is restored.
Chronic hyponatremia (CHN) has long been considered largely asymptomatic because the brain adapts to low-sodium conditions. This adaptation involves cellular mechanisms that protect neurons but also deplete organic osmolytes and neurotransmitter precursors. The new findings reveal that this compensation has neurochemical consequences that can manifest as anxiety-like symptoms.
Key findings
- Neurochemical disruption: CHN produced significant decreases in serotonin and dopamine levels in the amygdala of affected mice.
- Measurable anxiety-like behavior: Mice with sustained low serum sodium displayed increased anxiety-related responses in the light/dark transition and open field behavioral tests.
- Reversibility: Correcting serum sodium normalized both the animals’ behavior and the amygdala’s monoamine levels, as well as associated molecular signaling.
Study background and purpose
Researchers led by Professor Yoshihisa Sugimura at Fujita Health University, with collaborators including Dr. Haruki Fujisawa, Professor Atsushi Suzuki, Professor Tsuyoshi Miyakawa, and Professor Akihiro Mouri, designed this study to determine whether chronic sodium deficiency can directly cause psychological or behavioral changes through effects on monoaminergic neurotransmission. Prior clinical observations had suggested cognitive impairment and subtle neurological symptoms in patients with CHN, but the precise psychological manifestations, underlying mechanisms, and potential for recovery were not well defined.
Methods
The team developed a mouse model to reproduce CHN associated with the syndrome of inappropriate antidiuresis (SIAD). Mice received a sustained infusion of desmopressin (a vasopressin analog) while being fed a controlled liquid diet to maintain chronically low serum sodium concentrations. The researchers monitored serum sodium over time and evaluated behavior using standard assays for innate anxiety: the light/dark transition test and the open field test. Biochemical analyses focused on monoamine neurotransmitters and downstream signaling molecules in the amygdala.
Results
Mice with experimentally induced CHN showed persistently reduced serum sodium and developed consistent anxiety-like behavior across tests. Biochemical measurements revealed significantly lower levels of serotonin and dopamine in the amygdala compared with control animals. The study also measured phosphorylation of extracellular signal-regulated kinase (ERK), a molecular marker linked to emotional regulation, and found ERK phosphorylation was decreased in the CHN group.
Importantly, when investigators halted desmopressin infusion and returned mice to a standard solid diet, serum sodium concentrations recovered. Corresponding behavioral measures improved: anxiety-like behaviors subsided. At the same time, serotonin and dopamine levels and ERK phosphorylation in the amygdala returned toward baseline, demonstrating that the neurochemical and behavioral consequences of CHN were reversible under these experimental conditions.
Implications
Although this study was conducted in mice, the parallels with human CHN are significant: chronic low sodium is common in elderly and chronically ill patients, particularly those with SIAD, heart failure, or liver disease. The results suggest that CHN may contribute directly to mood and anxiety symptoms through disruption of monoaminergic systems in the amygdala. Clinicians should be aware that correcting chronic sodium imbalance may not only prevent metabolic complications but also improve neuropsychiatric symptoms and patients’ quality of life.
According to the authors, these findings strengthen the view that chronic hyponatremia is not merely a biochemical abnormality but a condition with clear neurological and psychological consequences. Early identification and appropriate correction of sodium imbalance could therefore have tangible benefits for mental well-being in vulnerable populations.
Funding and support
This work was supported by JSPS KAKENHI (Grant Number 20 K08919 to Yoshihisa Sugimura and 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 Numbers FY2018-2020 JPMXP0618217663 and FY2021-2023 JPMXP0621467949).
About this research news
Author: Hisatsugu Koshimizu
Source: Fujita Health University
Contact: Hisatsugu Koshimizu – Fujita Health University
Image credit: Neuroscience News
Abstract
Hyponatremia is the most common clinical electrolyte disorder. Although adaptation by the brain was previously thought to render chronic hyponatremia asymptomatic, accumulating evidence indicates the condition can cause neurological and psychological manifestations. Using a mouse model of SIAD-related chronic hyponatremia, this study demonstrates that sustained low serum sodium potentiates innate anxiety-like behaviors in standard behavioral assays and reduces serotonin and dopamine concentrations in the amygdala. ERK phosphorylation in the amygdala was also diminished. Correction of serum sodium restored monoamine levels, ERK phosphorylation, and normal behavior. These results highlight the importance of recognizing and treating chronic hyponatremia to prevent or reverse neuropsychiatric consequences and improve patient quality of life.
Original research citation: “Chronic Hyponatremia Potentiates Innate Anxiety‑Like Behaviors Through the Dysfunction of Monoaminergic Neurons in Mice” by Yoshihisa Sugimura et al., Molecular Neurobiology (closed access), DOI: 10.1007/s12035-025-05024-y.