Biology subjects

Geerling, J. C.

Publications and source records attributed to Geerling, J. C..

6 recordsLinked to original sources

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↗

bioRxiv2025

NPS neurons receive extensive input from auditory brainstem nuclei

Neurons that produce NPS send output to brain regions implicated in circadian function and threat responses, but less is known about the afferent control of NPS neurons. In this study, we used a conventional retrograde tracer, cholera toxin beta subunit (CTb), to identify afferents to the rostral-lateral parabrachial region that contains the main concentration of NPS neurons. We then used Cre-dependent rabies retrograde tracing in Nps-2A-Cre mice to identify inputs specifically to NPS neurons. Nps-expressing neurons receive heavy input from auditory brainstem structures, including the inferior colliculus, nucleus of the lateral lemniscus, superior olivary complex, and cochlear nucleus. These findings suggest an unexpected role for auditory information in controlling the activity of NPS neurons.

neuroscience↗

bioRxiv2024

Renovating the Barnes maze for mouse models of Dementia with STARR FIELD: A 4-day protocol that probes learning rate, retention and cognitive flexibility.

Land-based spatial mazes are a low-stress method to evaluate learning in rodent models of dementia. By using innate exploratory and hiding behavior, the Barnes maze requires fewer trials, allowing examination of early learning rate and retention, as well as executive and motivational features that can be characteristic of non-amnestic dementias. However, unwanted odor cues may disrupt interpretation of acquisition rate during typical learning trials. We designed and tested our Barnes FIELD protocol (Find the Invisible Exit to Locate the Domicile) to improve reproducibility, allow evaluation of learning trials, and limit experimenter influence. The protocol uses 3D-printed escape shuttles and docking tunnels, allowing mice to exit the maze to the home cage. We show evidence that our shuttles mitigate the possibility of undesired cues. We demonstrate the feasibility of our protocol across several models of cognitive impairment and aging, and develop an additional stage, the STARR (Spatial Training And Rapid Reversal) maze, to better challenge behavioral flexibility. By examining commonly used outcome measures we identify important considerations for interpretation. These insights are used to evaluate several models of cognitive change, including deficits in an Alzheimers disease mouse model, and behavioral flexibility in a model of brainstem dysfunction. This work provides comprehensive instructions to build, perform, and analyze a robust spatial maze that expands the range of behavioral and motivational outcomes that can be identified and screened. Our findings will aid interpretation of traditional protocols, enhance rigor and reproducibility, and provide an updated method to screen for cognitive changes in mice.

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↗

bioRxiv2023

Efferent projections of Nps-expressing neurons in the parabrachial region

In the brain, connectivity determines function. Neurons in the parabrachial nucleus (PB) relay diverse information to widespread brain regions, but the connections and functions of PB neurons that express Nps (neuropeptide S) remain mysterious. Here, we use Cre-dependent anterograde tracing and whole-brain analysis to map their output connections. While many other PB neurons project ascending axons through the central tegmental tract, NPS axons reach the forebrain via distinct periventricular and ventral pathways. Along the periventricular pathway, NPS axons target the tectal longitudinal column and periaqueductal gray then continue rostrally to target the paraventricular nucleus of the thalamus. Along the ventral pathway, NPS axons blanket much of the hypothalamus but avoid the ventromedial and mammillary nuclei. They also project prominently to the ventral bed nucleus of the stria terminalis, A13 cell group, and magnocellular subparafasciular nucleus. In the hindbrain, NPS axons have fewer descending projections, targeting primarily the superior salivatory nucleus, nucleus of the lateral lemniscus, and periolivary region. Combined with what is known about NPS and its receptor, the output pattern of Nps-expressing neurons in the PB region predicts a role in threat response and circadian behavior.

neuroscience↗

bioRxiv2023

Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily impact cortical and subcortical structures and lead to restricted behavioral impacts

Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops -syn aggregates in DLB and PDD. To investigate the consequences of -syn pathology in the cortex, we injected human -syn pre-formed fibrils into the PFC of wildtype mice. We report that PFC PFFs: 1) induced -syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; 3) increased open field exploration; and 4) did not affect susceptibility to an inflammatory challenge. This model of cortical-dominant pathology aids in our understanding of how local -syn aggregation might impact some symptoms in PDD and DLB.

animal behavior and cognition↗