Control of sodium appetite by hindbrain aldosterone-sensitive neurons.

Mineralocorticoids play a key role in hydromineral balance by regulating sodium retention and potassium wasting. Through favoring sodium, mineralocorticoids can cause hypertension from fluid overload under conditions of hyperaldosteronism, such as aldosterone-secreting tumors. An often-overlooked mechanism by which aldosterone functions to increase sodium is through stimulation of salt appetite. To drive sodium intake, aldosterone targets neurons in the hindbrain which uniquely express 11ß-hydroxysteroid dehydrogenase type 2 (HSD2). This enzyme is a necessary precondition for aldosterone-sensing cells as it metabolizes glucocorticoids - preventing their activation of the mineralocorticoid receptor. In this review, we will consider the role of hindbrain HSD2 neurons in regulating sodium appetite by discussing HSD2 expression in the brain, regulation of hindbrain HSD2 neuron activity, and the circuitry mediating the effects of these aldosterone-sensitive neurons. Reducing the activity of hindbrain HSD2 neurons may be a viable strategy to reduce sodium intake and cardiovascular risk, particularly for conditions of hyperaldosteronism.

Aldosterone-induced salt appetite requires HSD2 neurons.

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 may worsen end-organ damage in patients with aldosteronism. Preventing this increase could improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we previously identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its pre-receptor regulator, 11-beta-hydroxysteroid dehydrogenase 2 (HSD2). In the present study, we identified HSD2 neurons in the human brain, then used a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirmed that dietary sodium deprivation increases aldosterone production, salt intake, and HSD2 neuron activity. Next, we showed that continuous chemogenetic stimulation of 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 these neurons are necessary for aldosterone-induced salt intake. Identifying HSD2 neurons in the human brain and establishing 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.

Using deep learning to quantify neuronal activation from single-cell and spatial transcriptomic data.

Neuronal activity-dependent transcription directs molecular processes that regulate synaptic plasticity, brain circuit development, behavioral adaptation, and long-term memory. Single cell RNA-sequencing technologies (scRNAseq) are rapidly developing and allow for the interrogation of activity-dependent transcription at cellular resolution. Here, we present NEUROeSTIMator, a deep learning model that integrates transcriptomic signals to estimate neuronal activation in a way that we demonstrate is associated with Patch-seq electrophysiological features and that is robust against differences in species, cell type, and brain region. We demonstrate this method's ability to accurately detect neuronal activity in previously published studies of single cell activity-induced gene expression. Further, we applied our model in a spatial transcriptomic study to identify unique patterns of learning-induced activity across different brain regions in male mice. Altogether, our findings establish NEUROeSTIMator as a powerful and broadly applicable tool for measuring neuronal activation, whether as a critical covariate or a primary readout of interest.

Neuropeptide S (NPS) neurons: Parabrachial identity and novel distributions.

Neuropeptide S (NPS) increases wakefulness. A small number of neurons in the brainstem express Nps. These neurons are located in or near the parabrachial nucleus (PB), but we know very little about their ontogeny, connectivity, and function. To identify Nps-expressing neurons within the molecular framework of the PB region, we used in situ hybridization, immunofluorescence, and Cre-reporter labeling in mice. The primary concentration of Nps-expressing neurons borders the lateral lemniscus at far-rostral levels of the lateral PB. Caudal to this main cluster, Nps-expressing neurons scatter through the PB and form a secondary concentration medial to the locus coeruleus (LC). Most Nps-expressing neurons in the PB region are Atoh1-derived, Foxp2-expressing, and mutually exclusive with neurons expressing Calca or Lmx1b. Among Foxp2-expressing PB neurons, those expressing Nps are distinct from intermingled subsets expressing Cck or Pdyn. Examining Nps Cre-reporter expression throughout the brain identified novel populations of neurons in the nucleus incertus, anterior hypothalamus, and lateral habenula. This information will help focus experimental questions about the connectivity and function of NPS neurons.