Biology subjects

Schwalbe, D. C.

Publications and source records attributed to Schwalbe, D. C..

3 recordsLinked to original sources

bioRxiv2023

Molecular Disambiguation of Heart Rate Control by the Nucleus Ambiguus

The nucleus ambiguus (nAmb) provides parasympathetic control of cardiorespiratory functions as well as motor control of the upper airways and esophagus. A subset of nAmb neurons innervates the heart through the vagus nerve to control cardiac function at rest and during key autonomic reflexes such as the mammalian diving reflex. Yet, how these cardiovagal nAmb neurons differ from other nAmb neurons in the adult brain remains unclear. We therefore classified adult mouse nAmb neurons molecularly, anatomically, and functionally. First, our integrated analysis of single-nucleus RNA-sequencing data predicted multiple molecular subtypes of nAmb neurons. Mapping the axon projections of one nAmb neuron subtype, Npy2r-expressing nAmb neurons, showed that they innervate cardiac ganglia but not the upper airways or esophagus. Chemogenetically stimulating Npy2r+ nAmb neurons robustly decreased heart rate through peripheral muscarinic acetylcholine receptors. Finally, Npy2r+ nAmb neurons are activated during voluntary underwater diving, consistent with a cardiovagal function for this nAmb subtype. These results together reveal the molecular organization of nAmb neurons and its control of heart rate.

neuroscience↗

bioRxiv2023

Molecular organization of autonomic, respiratory, and spinally-projecting neurons in the mouse ventrolateral medulla

The ventrolateral medulla (VLM) is a crucial region in the brain for visceral and somatic control. It also serves as a significant source of synaptic input to the spinal cord. Experimental studies have shown that gene expression in individual VLM neurons is predictive of their function. However, the organizing principles of the VLM have remained uncertain. This study aimed to create a comprehensive dataset of VLM cells using single-cell RNA sequencing. The dataset was enriched with targeted sequencing of spinally-projecting and adrenergic/noradrenergic VLM neurons. Based on differentially expressed genes, the resulting dataset of 114,805 VLM cells identifies 23 subtypes of neurons, excluding those in the inferior olive, and 5 subtypes of astrocytes. Spinally-projecting neurons were found to be abundant in 7 subtypes of neurons, which were validated through in-situ hybridization. These subtypes included adrenergic/noradrenergic neurons, serotonergic neurons, and neurons expressing gene markers associated with pre-motor neurons in the ventromedial medulla. Further analysis of adrenergic/noradrenergic neurons and serotonergic neurons identified 9 and 6 subtypes, respectively, within each class of monoaminergic neurons. Marker genes that identify the neural network responsible for breathing were concentrated in 2 subtypes of neurons, delineated from each other by markers for excitatory and inhibitory neurons. These datasets are available for public download and for analysis with a user-friendly interface. Collectively, this study provides a fine-scale molecular identification of cells in the VLM, forming the foundation for a better understanding of the VLMs role in vital functions and motor control.

neuroscience↗

bioRxiv2023

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons which inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons predicted at least 21 afferent subtypes in the mouse mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), inhibitory neurons which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons causes over-eating and weight gain and attenuates liraglutides effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons, and reveal a circuit through which GLP-1RAs suppress appetite.

neuroscience↗