Activity-dependent regulation of Sonic hedgehog signaling incortical astrocytes

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PROJECT ABSTRACT Understanding the mechanisms by which the CNS adapts to novel experiences and changing environments is a fundamental goal of neuroscience. Following experience and neural activity, neurons undergo changes in gene expression and synaptic organization that facilitate such adaptation. Though historically regarded as simple support cells for neurons, astrocytes are gaining increasing recognition as essential elements of the synapse, modulating synaptic connectivity and function. This suggests that reciprocal interactions between neurons and astrocytes are likely to be involved in experience-dependent synaptic plasticity. The molecular mechanisms underlying neuronal interactions with astrocytes during experience-dependent activity are not well understood. In previous studies, we identified astrocytes as the predominant cell type transducing Sonic hedgehog (Shh) signaling derived from neurons in the postnatal and adult cortex. Selective disruption of Shh activity in astrocytes impairs structural and functional properties of cortical neurons, demonstrating that Shh signaling is required for the proper establishment of developing circuits. In this study, we propose to examine the role of activity in regulating Shh signaling. We will use an enriched environment with complex stimuli that include novelty, increased physical activity and social interactions, to investigate the role of experience in stimulating Shh. In Aim 1, we will identify the stimuli that promote experience-dependent Shh activity and determine whether it is modality-specific. In Aim 2, we will use genetic marking strategies and chemogenetic approaches to identify the cells that initiate experience-dependent Shh signaling and determine whether neuronal activity stimulates Shh activity. These data will lay the foundation for further mechanistic studies aimed at elucidating the molecular programs initiated by activity-dependent neuron-astrocyte communication mediated by Shh signaling.