Serotonin neurons are necessary for tonic sodium intake inhibition.

Sodium appetite is a motivated behavior that occurs in response to sodium deprivation. Various neurotransmitters, including serotonin, are thought to regulate sodium intake. In the present study, we used genetic deletion to test whether serotonergic neurons are necessary for regulating sodium appetite. First, we confirmed that Pet1-Cre;Lmx1bflox/flox (Lmx1bf/f/p) mice have nearly complete deletion of serotonergic neurons, with only sporadic cells remaining. Next, we measured baseline intake of water and 3% NaCl and found that Lmx1bf/f/p mice consume more salt than Cre-negative littermate-control mice (Lmx1bf/f). Finally, we tested the necessity of serotonergic neurons for thirst and sodium appetite inhibition. After 24-h water deprivation, mice lacking serotonergic neurons exhibited an intact thirst response by increasing water intake just like Cre-negative littermates. After furosemide diuresis followed by 24-h sodium deprivation, mice lacking serotonergic neurons exhibited an intact sodium appetite response by increasing salt and water intake like Cre-negative littermates. Interestingly, the baseline daily salt intake of Lmx1bf/f/p mice increased between tests relative to their initial baseline. Together, these findings indicate that although serotonergic neurons are not the primary mechanism controlling sodium appetite, they act as a "brake," limiting sodium consumption. This tonic inhibitory role may protect against excess sodium intake and suggests the possibility that serotonergic medications may influence dietary sodium consumption.NEW & NOTEWORTHY This study demonstrates a fundamental role for serotonergic neurons in limiting sodium intake. Mice with genetic deletion of serotonin-producing neurons consume more salt, indicating that serotonergic neurons act like a brake to restrain sodium appetite. These findings advance our understanding of how the brain controls salt-seeking behavior.