McDonough, M. C. | bioRxiv Science

bioRxiv2026

Aldosterone drives HSD2 neuron activity and molecular remodeling of synaptic function to promote sodium appetite

Sodium deficiency increases aldosterone, which signals through the mineralocorticoid receptor (MR) to restrict sodium excretion and promote salt appetite. Despite aldosterone's importance in maintaining hydromineral balance, its role in regulating neuronal function is poorly understood. Here, we define the transcriptional response to aldosterone in neurons and demonstrate that MR signaling in HSD2 neurons is essential for aldosterone-induced sodium appetite. Disruption of MR in HSD2 neurons impaired sodium appetite following deficiency and abolished saline intake in response to aldosterone. Single-nucleus RNA sequencing of the caudal nucleus of the solitary tract (NTS) revealed that aldosterone selectively regulates gene expression in HSD2 neurons, with enrichment for transcripts associated with synaptic function. Consistent with this, aldosterone increased the paired-pulse ratio at HSD2 neuron synapses, indicating reduced synaptic depression during repeated stimulation. Notably, Sv2c, encoding synaptic vesicle glycoprotein 2C, exhibited the greatest increase in expression after aldosterone treatment, and its disruption in HSD2 neurons reduced saline ingestion, identifying SV2C as a mediator of mineralocorticoid-induced sodium appetite. Together, these findings reveal a selective aldosterone-induced transcriptional program associated with enhanced synaptic transmission in HSD2 neurons and identify a molecular mechanism through which aldosterone promotes sodium appetite.

neuroscience↗

bioRxiv2024

HSD2 neurons are evolutionarily conserved and required for aldosterone-induced salt appetite

Excessive aldosterone production increases the risk of heart disease, stroke, dementia, and death. Aldosterone increases both sodium retention and sodium consumption, and increased sodium consumption predicts end-organ damage in patients with aldosteronism. Preventing this increase may improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its pre-receptor regulator, 11-beta-hydroxysteroid dehydrogenase 2 (HSD2). Here, we identify HSD2 neurons in the human brain and use a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirm that dietary sodium deprivation increases aldosterone production, HSD2 neuron activity, and salt intake. Next, we show that activating HSD2 neurons causes a large and specific increase in salt intake. Finally, we use dose-response studies and genetically targeted ablation of HSD2 neurons to show that aldosterone-induced salt intake requires these neurons. Identifying HSD2 neurons in the human brain and their necessity for aldosterone-induced salt intake in mice improves our understanding of appetitive circuits and highlights this small cell population as a therapeutic target for moderating dietary sodium.

neuroscience↗