Trevor C. Butler

Summary: 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.

Prefrontal neurons exhibit diverse activity during cognitive functions such as working memory, attention, and timing; however, the importance of this heterogeneity is unclear. Our goal was to better understand the diversity of prefrontal activity through anatomical connectivity. We harnessed circuit-specific tools in mice to capture activity within prefrontal projections during interval timing, a highly translational cognitive process that requires working memory for temporal rules and attention to the passage of time to estimate a temporal interval of several seconds. We used neuronal recordings to capture prefrontal activity during interval timing, with major patterns characterized by monotonic time-dependent ramping over a temporal interval. We then leveraged retrograde viruses to interrogate prefrontal cortex (PFC) projections to the mediodorsal thalamus (PFC-MD) and the dorsomedial striatum (PFC-DMS). We report three main findings. First, circuit-specific fiber photometry revealed that PFC-MD and PFC-DMS activity encoded distinct temporal signals, with PFC-MD projections ramping down and PFC-DMS ramping up to interval timing response times. Second, circuit-specific inactivation revealed that suppressing PFC-DMS projections disrupted animals’ internal estimates of time. Third, circuit-specific single-nucleus RNA sequencing of projection-defined prefrontal neurons revealed distinct transcriptomic profiles of PFC-MD and PFC-DMS projections, with enrichment of cortical layer-associated genes as well as genes such as Cux2, Camk2n1, Htr4, and Foxp2 . These data suggest that differences in gene expression and connectivity distinguish prefrontal activity during interval timing. These findings advance our fundamental understanding of prefrontal function and dysfunction in human disease.