| Summary: | Summary: The underlying mechanisms of how positive emotional valence (e.g., pleasure) causes preference of an associated context is poorly understood. Here, we show that activation of astrocytic μ-opioid receptor (MOR) drives conditioned place preference (CPP) by means of specific modulation of astrocytic MOR, an exemplar endogenous Gi protein-coupled receptor (Gi-GPCR), in the CA1 hippocampus. Long-term potentiation (LTP) induced by a subthreshold stimulation with the activation of astrocytic MOR at the Schaffer collateral pathway accounts for the memory acquisition to induce CPP. This astrocytic MOR-mediated LTP induction is dependent on astrocytic glutamate released upon activation of the astrocytic MOR and the consequent activation of the presynaptic mGluR1. The astrocytic MOR-dependent LTP and CPP were recapitulated by a chemogenetic activation of astrocyte-specifically expressed Gi-DREADD hM4Di. Our study reveals that the transduction of inhibitory Gi-signaling into augmented excitatory synaptic transmission through astrocytic glutamate is critical for the acquisition of contextual memory for CPP. : Nam et al. demonstrate that activation of hippocampal astrocytic μ-opioid receptor causes glutamate release, which increases the release probability by neuronal presynaptic mGluR1 activation and potentiates synaptic plasticity at the SC-CA1 pathway. This enhanced synaptic transmission and synaptic plasticity account for the acquisition of memory associated with CPP. Keywords: astrocyte, hippocampus, μ-opioid receptor, conditioned place preference, long-term potentiation opioid
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