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ASTRocyte Adrenoceptors: Light on Intracellular Signaling

Project description

Research sheds light on how astrocytes govern neural connections

Funded by the Marie Skłodowska-Curie Actions programme, the ASTRALIS project seeks to increase understanding of how intracellular signalling complexity is generated in the brain. The project will focus on brain cells called astrocytes that are highly interconnected but electrically silent and signal through G protein-coupled receptors and second messengers in response to norepinephrine. These brain cells will be used as models to study whether intracellular signalling in vivo is governed extrinsically or intrinsically. Elucidating the largely disregarded contribution of astrocytes in noradrenergic signalling at the cellular and network level should further understanding of the pathophysiology of related disorders and help conceive better therapeutic strategies.

Objective

ASTRALIS proposes all-optical strategies to shed light on holes in our understanding of how intracellular signaling complexity, downstream of specific G protein-coupled receptors (GPCRs), is generated in the brain. We focus on the understudied cells of the brain, astrocytes, which are highly interconnected but electrically silent, and signal through GPCRs and second messengers in response to norepinephrine (NE). We use them as models to study whether intracellular signaling in vivo is governed extrinsically, by noradrenergic afferent fibers releasing neuromodulators in defined spatiotemporal patterns –and therefore by receptor-specific activation dynamics– or rather intrinsically, by compartmentalization of cellular components, resulting in spatiotemporally different signaling outputs. During the outgoing phase, I will use advanced optical approaches to: (1) measure the spatiotemporal dimension of NE release in vivo, and (2) characterize the cellular and subcellular heterogeneity of astrocytic signals in response to NE in vitro and their relevance to the circuit, by simultaneously monitoring astrocytic and neuronal activity. During the incoming phase, I will (3) combine knowledge generated within the outgoing phase about in vivo noradrenergic signaling with the optical technologies developed by the host lab, in order to dissect the contribution of receptor dynamics to the spatiotemporally defined signaling of adrenoceptors. Significance: Current strategies to study intracellular signaling downstream of GPCRs widely neglect the spatiotemporal component of the inputs to which receptors are exposed naturally. Clarifying these aspects of receptor function would radically change the way we probe and study these proteins. In addition, elucidating the largely disregarded contribution of astrocytes in noradrenergic signaling at the cellular and network level will help understand the pathophysiology of related disorders and conceive better therapeutic strategies.

Coordinator

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Net EU contribution
€ 264 669,12
Address
ROBERT ROSSLE STRASSE 10
13125 Berlin
Germany

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Region
Berlin Berlin Berlin
Activity type
Research Organisations
Links
Total cost
€ 264 669,12

Partners (1)