How do astrocytes regulate neuronal circuits?

About This Grant

PROJECT SUMMARY Astrocytes are essential regulators of the nervous system and the vast majority of astrocyte functions in health and disease have been linked to intracellular calcium signaling. This includes the newly recognized participation of astrocytes in neuronal circuits, a level of regulation of neuronal firing largely ignored in our connectome- and electrophysiology-based understanding of brain function. Nevertheless, while decades of research have characterized the input/output relationships of neurons and how they impact circuit function, few studies have explored the rules that govern when astrocytes respond to different neurotransmitters in vivo and how they affect downstream circuit modulation. I previously discovered a mechanism by which an arousal- associated tyramine cue can change which neurotransmitters induce calcium influx in astrocytes. Specifically, I showed that tyramine can “gate” the ability of astrocytes to respond to dopamine by decreasing cAMP concentrations and inhibiting a pathway that internalizes receptors from the plasma membrane. Further, I found that gated dopamine responses can control downstream neuronal activity, demonstrating the power of astrocytes over neuronal circuits. However, key mechanistic questions remain about this newly discovered mechanism. During the mentored award phase, I will learn new approaches to dissecting astrocyte neuromodulation in mice while also developing new tools in Drosophila to manipulate gating in vivo. I will then take these skills to my own laboratory, where I will gain mechanistic understanding of how gating occurs and what impact it has on downstream circuits. In Aim 1, I will delineate the key regulators of dopamine receptor externalization to better understand how gating in astrocytes can affect circuit computations and behavior. In Aim 2, I will use the control of neuronal activity downstream of gated dopamine responses to dissect how astrocytes change neuronal activity and what neurons they can control. In Aim 3, I will translate this gating mechanism to mice, characterizing how dopamine response gating occurs across the mammalian brain, developing new tools to modulate that gating in mice, and determining how gating changes in the context of disease. Together these aims will reveal greater mechanistic detail of how gating occurs and how it impacts the computations that astrocytes perform in the brain. To complete these aims, I have outlined a series of research and career development milestones to prepare me for a successful research career and formed an advisory committee of world-leading scientists committed to mentoring me through my transition to independence. My overarching career goal is to head an independent research lab that combines the genetic power of Drosophila with the circuit complexity of rodents to uncover the fundamental molecular mechanisms of glial cell function and how they change in disease.