The free fatty acid receptor 1 (FFAR1) is suggested to function as a G protein-coupled receptor for medium-to longchain free fatty acids. We have previously demonstrated that FFAR1 is found to be expressed on noradrenergic and serotonergic neurons in the locus coeruleus and rostral ventromedial medulla (RVM), respectively, and local application of a FFAR1 agonist, GW9508, into these areas evokes a descending endogenous pain control system. These results suggest that one of the functions of FFAR1 in the CNS might control central monoaminergic system. Thus, to further pursue this hypothesis in this study, we have tested whether FFAR1 plays a role in the regulation of striatal monoamine release. We also analyzed cocaine-induced locomotor stimulation activity in both FFAR1-/-mice and mice treated with a FFAR1 antagonist to evaluate functional significance of FFAR1. Furthermore, we evaluated possible involvement of FFAR1 signaling in the development of negative emotional behaviors after peripheral inflammation and nerve injury in mice. Our data support that FFAR1 signaling is involved in an important mechanism underlying negative emotional behaviors in the inflammatory and neuropathic pain conditions, and enhancement of FFAR1system may be a new strategy to manage at least comorbid pain and negative emotions.

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The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor (PAC1) are widely distributed in the central nervous system. Although it has been reported that PACAP-PAC1 signaling contributes to learning and memory, it is not clear what mechanism is involved in neuroplasticity. In this study, we investigated the involvement of PACAP-PAC1 signaling in astrocytes for working memory. First, to confirm the expression of PAC1 in hippocampal astrocytes, we obtained astrocyte-specific mRNA using the Ribo-tag method, and RT-qPCR revealed that astrocytes expressed PAC1 six times higher than all cell types. A selective knockout of hippocampal astrocytic PAC1 resulted in the impaired working memory of the Y-maze test. To investigate the origin of PACAP neurons projecting to hippocampal astrocytes, we infected the hippocampus of PACAP-Cre mice with adeno-associated virus (AAV), which is retrogradely transported and expresses mCherry in a Cre-dependent manner, and observed mCherry-positive cells. We found some mCherry-positive cells in the rhinal cortex. Furthermore, we infected the rhinal cortex of PACAP-cre mice with AAV, which expresses a synaptophysin-EGFP chimeric protein credependently. We found many synaptophysin-EGFP positive punctate around hippocampal astrocytes, suggesting PACAP neurons in the rhinal cortex sent axons to the hippocampal astrocytes. These findings suggested that PACAP from the rhinal cortex might act on hippocampal astrocytic PAC1 and contribute to the working memory.

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