Pericytes have been implicated in various neuropathologies, yet, little is known about their function and signaling pathways in health. Here, we characterized calcium dynamics of cortical mural cells in anesthetized or awake Pdgfrb-CreERT2;Rosa26<LSL-GCaMP6s> mice and in acute brain slices. Smooth muscle cells (SMCs) and ensheathing pericytes (EPs), also named as terminal vascular SMCs, revealed similar calcium dynamics in vivo. In contrast, calcium signals in capillary pericytes (CPs) were irregular, higher in frequency and occurred in cellular microdomains. In the absence of the vessel constricting agent U46619 in acute slices, SMCs and EPs revealed only sparse calcium signals whereas CPs retained their spontaneous calcium activity. Interestingly, chemogenetic activation of neurons in vivo and acute elevations of extracellular potassium in brain slices strongly decreased calcium activity in CPs. We propose that neuronal activation and an extracellular increase in potassium suppress calcium activity in CPs, likely mediated by Kir2.2 and KATP channels.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3, 4, 5 and 6.
Animal experimentation: All animal experiments were approved by the local Cantonal Veterinary Office inZürich (license ZH 169/17) and conformed to the guidelines of the Swiss Animal Protection Law, Swiss Veterinary Office, Canton of Zürich(Animal Welfare Act of 16 December 2005 and Animal Protection Ordinance of 23 April 2008). Every effort was made to minimize suffering andconform to the 3Rs principles.
- Mark T Nelson, University of Vermont, United States
© 2021, Glück et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Fusing brain organoids with blood vessel organoids leads to the incorporation of non-neural endothelial cells and microglia into the brain organoids.
The stress response necessitates an immediate boost in vital physiological functions from their homeostatic operation to elevated emergency response. However, neural mechanisms underlying this state-dependent change remain largely unknown. Using a combination of in vivo and ex vivo electrophysiology with computational modeling, we report that corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN), the effector neurons of hormonal stress response, rapidly transition between distinct activity states through recurrent inhibition. Specifically, in vivo optrode recording shows that under non-stress conditions, CRHPVN neurons often fire with rhythmic brief bursts (RB), which, somewhat counterintuitively, constrains firing rate due to long (~2 s) inter-burst intervals. Stressful stimuli rapidly switch RB to continuous single spiking (SS), permitting a large increase in firing rate. A spiking network model shows that recurrent inhibition can control this activity-state switch, and more broadly the gain of spiking responses to excitatory inputs. In biological CRHPVN neurons ex vivo, the injection of whole-cell currents derived from our computational model recreates the in vivo-like switch between RB and SS, providing a direct evidence that physiologically relevant network inputs enable state-dependent computation in single neurons. Together, we present a novel mechanism for state-dependent activity dynamics in CRHPVN neurons.