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ASTRocyte Adrenoceptors: Light on Intracellular Signaling

ASTRocyte Adrenoceptors: Light on Intracellular Signaling

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)

Address

Robert Rossle Strasse 10
13125 Berlin

Germany

Activity type

Research Organisations

EU Contribution

€ 264 669,12

Partners (1)

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THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Project information

Grant agreement ID: 839561

Status

Ongoing project

  • Start date

    1 April 2019

  • End date

    31 March 2022

Funded under:

H2020-EU.1.3.2.

  • Overall budget:

    € 264 669,12

  • EU contribution

    € 264 669,12

Coordinated by:

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)

Germany