Biology subjects

Schwaber, J. S.

Publications and source records attributed to Schwaber, J. S..

5 recordsLinked to original sources

bioRxiv2020

A spatially-tracked single cell transcriptomics map of neuronal networks in the intrinsic cardiac nervous system

We developed a spatially-tracked single neuron transcriptomics map of an intrinsic cardiac ganglion - the right atrial ganglionic plexus (RAGP) that is a critical mediator of vagal control of the sinoatrial node (SAN) activity. We developed a 3D representation of RAGP with extensive mapping of neurons and used neuronal tracing to identify the spatial distribution of the subset of neurons that project to the SAN. RNAseq of laser capture microdissected neurons revealed a distinct composition of RAGP neurons compared to CNS neuronal subtypes. High-throughput qPCR of hundreds of laser capture microdissected single neurons led to a surprising finding that cholinergic and catecholaminergic neuronal markers Th and Chat were correlated, suggesting multipotential phenotypes that can drive neuroplasticity within RAGP. Interestingly, no single gene or module was an exclusive marker of RAGP neuronal connectivity to SAN. Neuropeptide-receptor coexpression analysis revealed a combinatorial paracrine neuromodulatory network within RAGP, informing follow-on studies on the vagal control of RAGP to regulate cardiac function in health and disease.

neuroscience↗

bioRxiv2020

3D single cell scale anatomical map of sex-dependent variability of the rat intrinsic cardiac nervous system

We developed and analyzed a single cell scale anatomical map of the rat intrinsic cardiac nervous system (ICNS) across 4 male and 3 female hearts. We find the ICNS has a reliable structural organizational plan across individuals that may provide the foundation for further analyses of the ICNS in cardiac function and disease. The distribution of the ICNS was evaluated by 3D visualization and using data-driven clustering. The pattern, distribution and clustering of ICNS neurons across all male and female rat hearts is highly conserved, demonstrating a coherent organizational plan in which distinct clusters of neurons are consistently localized. Female hearts had fewer neurons, lower packing density and slightly reduced distribution, but with the same localization. We registered the anatomical data from each heart to a geometric scaffold, normalizing their 3D coordinates for the standardization of common anatomical planes and providing the path where multiple experimental results and data types can be integrated and compared.

neuroscience↗

bioRxiv2020

Treating the Network: Targeted inhibition of two specific microRNAs in the brainstem prevents the development of hypertension

We here test the concept that disease states may result not from a single cause but from small changes in a network that are collectively significant. We recently showed that development of hypertension (HTN) in the spontaneously hypertensive rat (SHR) model of human essential hypertension is accompanied by changes in microRNA expression levels in the brainstem tracking the development of HTN 1,2. This led to the hypothesis that preventing the change in microRNA levels could prevent the development of HTN. We propose that hypertension emerges from a network that has been pushed out of a normotensive equilibrium into a compensatory, pathological state. We show that small perturbations in the gene regulatory networks in the brainstem by selectively blocking two microRNAs highlighted in our previous results, miR-135a and miR-376a, is sufficient to prevent development of hypertension in the SHR model. This effect appears driven by only modest changes in the expression of rate-limiting genes, many of which are targets of these miRNAs, suggesting that the combination of genes that are targeted in the network is responsible for the effect. The demonstration that hypertension is an emergent property of an underlying regulatory network suggests that a new treatment paradigm altogether is needed. One Sentence SummaryA brief summary of the main result of your paper, without excessive jargon.

systems biology↗

bioRxiv2020

PHENOTYPIC SHIFTS IN NEURONS OF THE DORSAL MOTOR NUCLEUS OF THE VAGUS RESULTING FROM CHRONIC CARDIAC ISCHEMIA

Heart disease remains the number one cause of mortality in the world in spite of significant efforts aimed at treatment. The use of vagal stimulation in the treatment of heart failure has shown mixed successes (Dicarlo et al. 2013; Zannad et al. 2015), suggesting that the treatment has potential, but that the mechanism incompletely understood. Vagal activity confers a robust cardioprotective effect in both humans and animal models, preferentially originating specifically from the dorsal motor nucleus of the vagus (DMV) and deriving a significant benefit from intact gut projections, not just cardiac (Shinlapawittayatorn et al. 2013; Mastitskaya et al. 2012; Basalay et al. 2012). In order to examine the DMV response to heart failure, myocardial infarction was induced in male Sprague Dawley rats. DMV neurons were isolated in small pools of single cells using laser capture microdissection 1 week and 3 weeks after infarction and their gene expression assayed. The results show a transcriptional shift towards a neurosecretory phenotype starting at 1 week and increasing in recruitment of neurons to 3 weeks. The LAD ligation shift appears mediated in part by upregulation of Pax4a, a transcription factor most active during stem cell development of neurosecretory cells during embryonic development. This phenotype is characterized by upregulation of Cacna1d (Cav1.3) and Hcn2 along with increased expression of Cck and Sst. This work suggests that the neurons of the DMV adaptively respond to the dynamics present in the periphery, elucidating the means by which the nature of vagal activity responds to heart failure. Significance StatementThe autonomic nervous system plays a significant role in the pathogenesis of cardiovascular disease. Through demonstration of shifting neuronal phenotypes in central neurons in response to peripheral stimuli, we suggest that neuron peptide or neurotransmitter phenotypes are not static in adult rodents. This suggests that even "reflexes" are modifiable dynamic systems. With such plasticity in the transcriptional programming existing in autonomic brain regions there can be new potential therapeutic interventions for cardiovascular disease aimed at leveraging the autonomic nervous system.

systems biology↗

bioRxiv2019

Comprehensive Integrated Anatomical And Molecular Atlas Of Rodent Intrinsic Cardiac Nervous System

In this study, we developed, coordinated, and integrated several technologies including novel whole organ imaging, software development to support the very first precise 3D neuroanatomical mapping and molecular phenotyping of the intracardiac nervous system (ICN). While qualitative and gross anatomical descriptions of the anatomy of the ICN have been presented, we here bring forth the first comprehensive atlas at large scale of the entire ICN in rat at a single cell resolution. Our work for the first time provides a novel 3D model to precisely integrate anatomical, functional and molecular data in the 3D digitally reconstructed whole heart with high resolution at the micron scale. This work represents the cutting edge in a long history of attempts to understand the anatomical substrate upon which the neuronal control of cardiac function is built. To our knowledge, there has not yet been a comprehensive histological mapping to generate a neurocardiac atlas at cellular and molecular level for the whole heart of any species. We now display the full extent and the position of neuronal clusters on the base and posterior left atrium, and the distribution of molecular phenotypes in that context. In addition we display in this context distinct molecular phenotypes that are defined along the base-to-apex axis, and the present novel discovery of their phenotypical spatial gradients, have not been previously described. The development of these approaches needed to acquire these data has produced method pipelines which can not only achieve the goals of anatomical and molecular mapping of the heart, but also provide the method pipelines for mapping other organs (e.g., stomach, lung, kidney, and liver).

neuroscience↗