Noradrenergic gating of astrocyte calcium-mediated homeostasis in vivo

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PROJECT SUMMARY Humans and mice show various brain states which are integral for survival and well-being. In awake mice, alert brain states are distinguished by locomotion, whisking, or pupil dilation in the absence of overt behavior. These accompany changes in neural function within the cortex such as reduced population correlation, increased sensory response, and reduced oscillatory activity. In addition, norepinephrine (NE) levels are increased in cortex during these activated periods. These findings are consistent with a long literature linking NE to alertness, attention, and behavioral performance in primates and rodents. Our project is focused on understanding changes in cortical astrocyte activity during these aroused brain states. Astrocyte calcium activity increases during both running and pupil dilation, but the heterogeneity of this response and the relative contribution of neuromodulators or local changes in neural activity to these astrocytic calcium events is not well understood. Conversely, astrocyte calcium events may be important for regulating processes such as glutamate homeostasis that directly impact neural activity on short timescales, but these effects have not been well-characterized in vivo. Thus, the overall goal of this project is to understand the local and global factors contributing to changes in astrocyte calcium activity and the effect of astrocyte calcium on local networks of neurons. We hypothesize that noradrenergic neuromodulation drives calcium-mediated increases in glutamate homeostasis that facilitate and/or support changes in local neuronal brain state. To test this hypothesis, we will first investigate the heterogeneity of somatic and microdomain calcium waves in response to NE increases during alert brain states. We will then test the effects of artificially reducing astrocyte calcium on state changes in local populations of neurons, and whether reducing astrocyte calcium responses to NE locally affects glutamate homeostasis. Our final experiment will use optogenetics to test the sufficiency of NE signaling pathways for any observed changes and the necessity of astrocyte calcium for these induced changes. The results of this project will more clearly define the upstream and downstream mechanisms of calcium signaling within astrocytes across different brain states and their effect on neural populations.