Thursday, April 3, 2025
4/3/2025
Investigating the molecular mechanisms underlying aldosterone-mediated sodium appetite - Project Summary / Abstract Sodium plays a vital role in essential physiological processes, including growth, development, and regulation of extracellular fluid volume, making it critical for survival. However, excess sodium intake is associated with an increased risk of hypertension and cardiovascular disorders and, despite efforts by the World Health Organization, average daily salt intake worldwide is approximately twice the recommended level. Due to sodium’s ability to regulate the extracellular fluid volume, and thus impact cardiovascular function, its excretion and intake are tightly regulated with the steroid hormone aldosterone (ALDO) playing a major role. In the adult mouse brain, a single population of neurons located in the nucleus tractus solitarius (NTS) are capable of sensing ALDO due to their co-expression of MR and 11β-hydroxysteroid dehydrogenase type 2 (HSD2), the latter prevents glucocorticoid stimulation of MR. These “NTSHSD2 neurons” have been shown to drive sodium appetite when activated by chemo- or optogenetic tools. Furthermore, chronic treatment with ALDO increases the intrinsic firing rate of NTSHSD2 neurons, though the molecular mechanism is unknown. The objective of this proposal is to investigate the basis for ALDO-induced NTSHSD2 neuron activity and sodium appetite. We hypothesize that ALDO signaling coordinates a transcriptional program that promotes NTSHSD2 neurons activity, ultimately driving sodium appetite. To test this, Aim 1 will determine the importance of ALDO/MR signaling in NTSHSD2 neurons for sodium appetite and investigate the effects of ALDO on NTSHSD2 neurons in vivo. Aim 2 will employ transcriptomics and epigenomics to identify candidate ALDO/MR regulated genes in NTSHSD2 neurons during ALDO treatment that could mediate increased spontaneous activity. Aim 3 will test the role of genes found to be regulated by sodium deficiency or ALDO/MR signaling for their impact on NTSHSD2 neuron activity and sodium appetite. Understanding the regulatory mechanisms of NTSHSD2 neuron activation is crucial to our understanding of sodium appetite and data from this proposal will identify potential therapeutic targets for reducing excess sodium intake.
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