ETHANOL AND BRAIN STATE- DEPENDENT NEURAL SIGNALING

Alcohol consumption impairs motor coordination, attentional efforts and memory function. Alcohol-impaireddriving accounted in 2013 for ~31% of all traffic accidents resulting in 10,076 fatalities and $59 billion crash-related cost. We propose to study the mechanisms how ethanol affects brain state-dependent neuralsignaling. Brain state-dependent signaling comprises adjustments in cellular and circuit activity to optimizehow the brain processes information in a distinct behavioral context. We and others have used a locomotionparadigm to reveal that noradrenergic signaling is involved when such optimizations occur. At transitionsfrom rest to locomotion astroglia, the support cells in the central nervous system, are norepinephrine-dependently activated simultaneously in brain regions as disparate as the cerebellum and primary visualcortex. The noradrenergic system is involved to support attentional efforts and in gating synaptic plasticity. Ithas long been known that alcohol can suppress the activity of locus coeruleus, the structure wherenoradrenergic neurons are clustered; however, it is still unclear what the consequences are for the activity ofindividual brain cells during active behavior. We propose to test the hypothesis that alcohol severely impairsbrain state-dependent noradrenergic neuromodulation in an astroglia-dependent manner. Our approach is tocombine specific mouse lines for cell type-selective genetic manipulation and expression of Ca2+ sensors withour motorized linear treadmill and two-photon microscopy to study Ca2+ dynamics and electrical activity inwell-controlled behavioral states. These in vivo investigations will be complemented with acute slice Ca2+imaging and electrophysiology experiments. We will focus our investigations on the cerebellum for itsrelatively straightforward circuit arrangement that facilitates mechanistic studies. The novel utilization of aspecific Cre mouse line will enable us to selectively manipulate Bergmann glia, the astrocytes of thecerebellar molecular layer, but not astrocytes of the granule cell layer. We will pursue the following aims: (1)We will define extent and mechanism of the effect of acute ethanol on locomotion-induced Bergmann gliaCa2+ activation. (2) We will reveal ethanol-sensitive components of locomotion-induced Purkinje cell Ca2+dynamics and dissect the relationship to Bergmann glia function. (3) We will investigate how locomotion-induced Purkinje cell Ca2+ dynamics regulate intrinsic and synaptic activity. Upon conclusion of our proposedstudies we will have learned what components of brain state-dependent noradrenergic neural signaling areimpaired by ethanol. This work will reveal how ethanol might exert its detrimental effects on attentionalefforts and memory on the cellular and circuit level. These studies will further build the groundwork for futureresearch on brain state-dependent neural signaling under neurodegenerative and neurobehavioral conditionsassociated with changes in noradrenergic signaling, such as Alzheimer's disease, Parkinson's disease andautism spectrum disorder.