Adaptive transcriptional dynamics of A2 neurons and central cardiovascular control pathways

Abstract

In order to provide an example of useful interaction between systems biology and computational neuroscience traditions, here we aim to identify the molecular response process through which elevated blood pressure induces a temporal sequence of gene expression changes. This initial response may then continually evolve as an adaptive response, altering central blood pressure set-point control. Our approach involves using a set of 96 quantitative PCR gene assays, which represent the molecular process associated with neuronal responses to angiotensin II type 1 receptor (AT1R) activation. We use this set as a probe to search for the AT1R signalling-triggered expression programme in individual neurons and groups of neurons involved in homeostatic regulation of cardiorespiratory function. Specifically, we focus on tissue samples from the nucleus tractus solitarii, as well as groups of A2 neurons and individual A2 cells within the nucleus tractus solitarii, and in the ventrolateral medulla and central amygdala. We assay these neural samples at rest and in response to elevated blood pressure. Analysis of the resulting high-dimensional data set reveals a remarkable complexity and heterogeneity of the samples and of their response to changes in blood pressure. These results demonstrate differential expression programmes for each anatomically distinct neuronal group and neuronal type. Single-cell expression analysis shows that A2 cells also are variable, and that the subset that responds to blood pressure with elevated Fos expression differs from other A2 cells. We present models of gene regulatory networks and of signalling cascades related to AT1R and broadly discuss the opportunities for valuable interactions between systems biology and computational neuroscience. © 2012 The Authors. Journal compilation © 2012 The Physiological Society.