THE ROLE OF ASTROGLIA IN BRAIN STATE DEPENDENT NEURAL ACTIVITY

Awake behavior is accompanied by fluctuations in vigilance shaping the overall activity state of the brain tooptimize cellular and circuit activity. The cellular and molecular mechanisms for such brain state-dependentadjustments in neural activity are not well understood. Using a mouse locomotion paradigm we have recentlyfound that the transition from a resting state to active locomotion is associated with release of theneurotransmitter norepinephrine and leads to Ca2+ activation of astroglia. Astroglia are activatedsimultaneously in brain regions as disparate as the cerebellum and primary visual cortex suggesting that theymight play a major role in mediating global brain state-dependent modulation of neural activity. The precisemolecular mechanism of locomotion-induced astroglia Ca2+ activation as well as the consequences forneuronal activity in the adult brain are not known. In this project we will test the hypothesis that locomotion-induced noradrenergic modulation of neuronal activity is mediated by astroglia. We will apply a combinationof in vivo two-photon Ca2+ imaging and electrophysiology, and acute slice experiments on specific mouselines that have been genetically modified in a cell type-specific manner, to reveal the cellular and molecularmechanisms of astroglia-mediated, brain state-dependent neuromodulation. The focus of our studies will beon the cerebellar cortex leveraging on a circuit that consists only of a handful of cells. A novel application ofa specific Cre mouse line will enable us to selectively manipulate Bergmann glia while leaving velateastrocytes of the cerebellar cortex unperturbed. We will pursue the following aims: (1) Combiningimmunocytochemistry and functional studies with global and cell type-specific knockout mice we willdetermine identity and location of receptors required for locomotion-induced Bergmann glia Ca2+ activation.(2) We will investigate locomotion-induced Ca2+ and electrical signals in Purkinje neurons, the principalneurons of the cerebellar cortex. Using genetic elimination of Bergmann glia global Ca2+ elevations we willisolate components of locomotion-induced Purkinje neuron signaling that are caused by prior Bergmann gliaCa2+ activation. (3) Combining pharmacology and cell type-specific knockout in slice experiments and in vivo,we will dissect the molecular mechanism how cerebellar astroglia impact principal neuron activity dependenton the behavioral state. Cerebellar Bergmann glia share many functional properties with velate astrocytes inthe remainder of the brain, including locomotion-induced, norepinephrine-dependent global Ca2+ activation.Therefore, we anticipate that our mechanistic studies will be instructive for understanding the role of astrogliain brain state-dependent noradrenergic neuromodulation throughout the brain. This body of work will build thegroundwork for future studies on brain state-dependent neural signaling under neurodegenerative andneurobehavioral conditions associated with changes in noradrenergic signaling, such as Alzheimer's disease,Parkinson's disease and autism.