Adenosine 2A Receptors Link Astrocytic Alpha-1 Adrenergic Signaling to Wake-Promoting Dopamine Neurons.

Autor: Petersen N; Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA., McCann KE; Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA., Stavarache MA; Neurosurgery, Weill Cornell Medical College, New York, NY, 10065, USA., Kim LY; School for Science and Math at Vanderbilt, Nashville, TN, 37232, USA., Weinshenker D; Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA., Winder DG; Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA; Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA; Department of Neurobiology, UMass Chan Medical School, Worcester, MA, 01605, USA. Electronic address: danny.winder@umassmed.edu.
Jazyk: angličtina
Zdroj: Biological psychiatry [Biol Psychiatry] 2024 Oct 15. Date of Electronic Publication: 2024 Oct 15.
DOI: 10.1016/j.biopsych.2024.09.030
Abstrakt: Background: Sleep and arousal disorders are common, but the underlying physiology of wakefulness is not fully understood. The locus coeruleus promotes arousal via alpha-1 adrenergic receptor (α 1 AR) driven recruitment of wake-promoting dopamine (DA) neurons in the ventral periaqueductal gray (vPAG DA neurons). α 1 AR expression is enriched on vPAG astrocytes, and chemogenetic activation of astrocytic G q signaling promotes wakefulness. Astrocytes can release extracellular "gliotransmitters," such as ATP and adenosine, but the mechanism underlying how vPAG astrocytic α 1 ARs influence sleep/wake behavior and vPAG DA neuron physiology is unknown.
Methods: In this study, we utilized genetic manipulations with ex vivo calcium imaging in vPAG DA neurons and astrocytes, patch-clamp electrophysiology, and behavioral experiments in mice to probe our hypothesis that astrocytic α 1 ARs mediate noradrenergic modulation of wake-promoting vPAG DA neurons via adenosine signaling.
Results: Activation of α 1 ARs with phenylephrine increased calcium transients in vPAG DA neurons and vPAG astrocytes, and increased vPAG DA neuron excitability ex vivo. Chemogenetic Gq-DREADD activation of vPAG astrocytes similarly increased vPAG DA neuron calcium activity and intrinsic excitability. Conversely, shRNA knockdown of vPAG astrocytic α 1 ARs reduced the excitatory effect of phenylephrine on vPAG DA neurons and blunted arousal during the wake phase. Pharmacological blockade of adenosine 2A (A 2A ) receptors precludes the α 1 AR-induced increase in vPAG DA calcium activity and excitability in brain slices, as well as the wake-promoting effects of vPAG α 1 AR activation in vivo.
Conclusions: We have identified a crucial role for vPAG astrocytic α 1 AR receptors in sustaining arousal through heightened excitability and activity of vPAG DA neurons mediated by local A 2A receptors.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
Externí odkaz: