Properties and functional consequences of astrocyte-neuron signaling in the dorsolateral striatum

University Of Minnesota, Minneapolis MN

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Abstract

? DESCRIPTION (provided by applicant): It was historically thought that astrocytes, which are non-neuronal cells in the brain, serve strictly structural and support roles, but recent research has revealed that astrocytes play important functional roles by modulating neuronal activity and synaptic function. Given their participation in the tripartite synapse, characterized by a pre- and post-synaptic neuron with a surrounding astrocyte, astrocytes are able to not only receive and respond (via calcium elevations) to synaptically-released neurotransmitters, but also release their own signaling molecules, termed gliotransmitters. It has recently been shown that manipulating astrocytic function in the hippocampus and other brain regions modulates neuronal activity, yet it remains unknown whether the same is true for the dorsolateral striatum (DLS), an area implicated in habit-type decision-making. Thus, the overall goal of this proposal is to examine the properties and functional consequences of neuron-astrocyte signaling in the DLS. Experiments in the first aim will assess bidirectional signaling between DLS neurons (medium spiny neurons (MSNs), the main cell type in the striatum) and astrocytes. Specifically, these experiments will test the hypotheses that astrocytes respond to MSN activity (Aim 1a) and influence MSN activity (Aim 1b) via calcium elevations and subsequent gliotransmitter release. Slice preparation electrophysiology will be used to measure synaptic transmission, and two-photon microscopy will be used to measure astrocyte calcium elevations. Astrocyte activity will be manipulated in Aim 1b via optogenetic and designer receptors exclusively activated by designer drugs (DREADDs) approaches to evaluate effects of selectively manipulating astrocyte activity on MSN synaptic transmission and excitability. Experiments in the second aim will assess in vivo effects of selective astrocyte manipulation (same manipulations as in Aim 1b) on DLS neuronal oscillation activity and behavioral performance. Specifically, these experiments will test the hypotheses that manipulating astrocyte calcium signals will influence DLS local circuitry (Aim 2a) and behavioral performance in a DLS-specific task (Aim 2b). In vivo extracellular recording will be used to measure local field potentials in the DLS, and behavioral performance analysis during a habit-forming task will be used to measure automation to the task. The task consists of training mice to turn left, right, or to alternate toward a food reward source, a task that is in part dependent on the DLS. As of now, it remains an open question whether astrocytes, which have been shown to play an important functional role in other brain regions, similarly modulate neuronal activity in the DLS and ultimately behavior. Such a finding will have significant implications for our understanding of the actual cellular mechanisms underlying brain function particularly in the DLS, and more generally in the brain as a whole.