ASTRocyte Adrenoceptors: Light on Intracellular Signaling

Informations projet

ASTRALIS

N° de convention de subvention: 839561

DOI

10.3030/839561

Projet clôturé

Date de signature de la CE 4 Avril 2019

Date de début 30 Juillet 2019

Date de fin 29 Août 2023

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 264 669,12

Contribution de l’UE

€ 264 669,12

Coordonné par

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

Periodic Reporting for period 2 - ASTRALIS (ASTRocyte Adrenoceptors: Light on Intracellular Signaling)

Période du rapport: 2021-07-30 au 2022-07-29

Résumé du contexte et des objectifs généraux du projet

The ASTRALIS project aims at deepening our understanding of how intracellular signaling specificity is achieved in the brain. For this project we have focused on astrocytes—which are brain cells that are highly interconnected and capable of reciprocal communication with neurons. Such two-way communication is achieved by means of neurotransmitters and neuromodulators released by the neurons themselves: these substances can reach the astrocytes surface, and there bind to G protein-coupled receptors. Then, specific "cascades" of intracellular signals are activated in astrocytes downstream of specific GPCRs, which then leads to molecules being released from astrocytes onto neurons. Many clinical drugs used to treat psychiatric conditions—such as depression, schizophrenia, psychosis—target such receptors, and so do most recreational drugs.

Here, astrocytes are used as models to study whether intracellular signaling in vivo is dictated extrinsically—by neuromodulator inputs—or intrinsically—by the GPCRs that sense neuromodulators and their intracellular partners. Is it the cell—with its distribution of receptors on its surface—that dictates intracellular signals regardless of the patterns of extracellular release of neuromodulators?

Elucidating how signaling specificity is accomplished, and how astrocytes are involved in processing neuromodulator signals at the cellular and network level will further our understanding of the pathophysiology of related disorders as well as the functioning of drugs in general, and thus guide the scientific community in conceiving better therapeutic strategies.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

For this project, we have focused on the prefrontal cortex—an associative area of the brain that is of paramount importance in higher-order cognitive functions such as decision making and behavioral flexibility. Dysfunctions of this brain area have been linked to depression and schizophrenia. The prefrontal cortex lays deep in the brain, and because imaging deep structures is complicated by light scattering, relatively little research has aimed at imaging the prefrontal cortex despite its paramount importance in cognition. In the ASTRALIS project, we leveraged two recently-developed techniques for imaging deep brain structures—GRIN lenses and fiber photometry—to gain first-time insight into the intracellular activity of astrocytes during behavior and in relation to neuromodulator release. Thanks to these approaches, we have discovered that astrocytes in this brain area behave differently compared to those in other parts of the brain, both in relation to response to behavioral stimuli, to the type of neuromodulators they can listen to, and in terms of the intracellular signals initiated in response to neuromodulators. Further, we have investigated whether astrocytes in this brain region respond to dopamine, which is an important subcortical input to the prefrontal cortex. Using cyclic AMP and calcium imaging along with dopamine uncaging and pharmacology, we have found that astrocytes respond to dopamine with fast intracellular calcium signals that depend on alpha 1 adrenergic receptors, whose endogenous ligand is norepinephrine—a closely-related but distinct neuromodulator. Finally, we have shown that dopamine is able to activate alpha 1 adrenergic receptors directly using in vitro experiments. The molecular mechanisms that allow such non-specific interaction between dopamine and adrenergic receptors, along with its evolutionary advantage (or disadvantage), and whether this effect is specific to astrocytes of the prefrontal cortex remains to be elucidated in future investigations.

Exploitation:
Not planned for this project.

Dissemination:
(1) work published in Cell Reports (title: Dopamine activates astrocytes in prefrontal cortex via α1-adrenergic receptors; doi: 10.1016/j.celrep.2022.111426);
(2) invited 20-min talk at the 11th IBRO World Congress of Neuroscience (Granada, Spain, 9–13 Sept 2023), within the "PARALLEL SYMPOSIUM 15: GLIA AS CONDUCTORS OF CIRCUIT FORMATION AND FUNCTION" organised by Vilaiwan Fernandes (UCL, UK); talk details: S0055 - Mouse cortical astrocytes detect dopamine via non-cognate receptors (ID 534);
(3) selected 10-min talk at the 1st iNAMES symposium 2022, Beyond IMAGEination (Berlin, Germany, 23–24 Nov 2022);
(4) invited 15-min talk at the Philadelphia SPINE 2021 (online, 10 May 2021), which is an annual event to showcase the best postdoctoral talent in neuroscience research in the US, followed by faculty interviews (link: https://www.spinephilly.org/prior-fellows);
(5) selected 10-min talk at the NeuroMatch 3.0 conference (online, 2020).
(6) poster at the Catecholamines Gordon Research Conference 2019 (Newry, ME, USA, 11–16 Aug 2019).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Our findings challenge previous assumptions on how neurons, astrocytes, and neuromodulators interact to govern brain function. First, a long-standing view in neuroscience research is that astrocytes are a homogeneous population across the brain, only providing support and nutrients to neurons, with limited contribution to cognitive functions. First, the ASTRALIS project shows that astrocytes in a specific brain area—the prefrontal cortex—are capable of responding to dopamine—an important neuromodulator involved in psychiatric disorders. Second, we show that astrocytic signals in prefrontal cortex are not linked to locomotory behaviors as happens in other brain areas. These results not only support the view that astrocytic signals are heterogeneous across brain areas—a concept that only recently has started to gain acceptance—but also add to the known repertoire of stimuli that can target both cortical neurons and astrocytes to control brain function. Because the prefrontal cortex is the highest order association area of the brain, we believe these results have the potential to revolutionize our understanding of and the treatment options for psychiatric conditions associated with prefrontal dysfunction such as mood disorders. Finally, we demonstrate that prefrontal astrocytes are capable of initiating intracellular signals in response to dopamine, albeit via receptors for norepinephrine, even in behaving rodents. This surprising finding expands our knowledge of the complexity of signal transduction in vivo. Strikingly, a similar unspecific binding to many monoamine receptors has been reported for most antidepressant and antipsychotic drugs, suggesting that non-specificity may be originating at the receptor level, and that fully understanding the building blocks of how signal transduction is accomplished downstream of specific receptors in specific cells and brain areas will contribute to developing better therapeutic strategies for psychiatric disorders. In all, the results of the ASTRALIS project contribute fundamental knowledge on the interaction between neuromodulatory signaling pathways in the brain.

Astrocytes in the brain—can you spot their heart?