br Conclusion br Conflict of interest br Acknowledgements

Conclusion
Conflict of interest
Acknowledgements
Introduction The brain contains abundant fatty acids, which serve as constituents of membranes and as an energy source. In addition, fatty acids and their metabolites contribute to signal transduction between neurons or neurons and glial cells, suggesting that fatty acids play a crucial role in development and functional maintenance in the central nervous system (1). It is well known that polyunsaturated fatty acids (PUFA), including arachidonic Parecoxib Sodium australia (ARA; 20:4 ω-6) and docosahexaenoic acid (DHA; 22:6 ω-3), are associated with cognitive and emotional function in healthy or pathological conditions (2), (3). For instance, the nutritional deficiency of these fatty acids of rodents causes decrease in learning performance and vulnerability to stress which is susceptible to the development of emotional dysfunction (4). Similarly, alterations in PUFA levels in the plasma and brain are observed in subjects with neuropsychiatric disorders (5). However, although fatty acids have become increasingly important for the modulation of neuronal function in the brain, the molecular mechanisms remain unknown. The free fatty acid receptor 1 (GPR40/FFAR1) is a G protein-coupled receptor, which is activated by long chain fatty acids, such as ARA and DHA (6), (7). Accumulating evidence has demonstrated that GPR40/FFAR1 plays a crucial role in the regulation of glucose homeostasis mediated by the free fatty acid-induced potentiation of insulin secretion (8). In addition to the regulation of endocrine function, GPR40/FFAR1 is involved in bone remodeling, taste preference for fatty acids, and inflammation (9), (10), (11). These findings suggest that free fatty acids exert their physiological functions by the activation of GPR40/FFAR1. Recent studies have indicated that GPR40/FFAR1 contributes to physiological function in the central nervous system. We have previously demonstrated that activation of brain GPR40/FFAR1 exerts an antinociceptive effect mediated by the modulation of the endogenous opioid system or monoamine system, which is known as the descending pain control system (12), (13). We found that activation of GPR40/FFAR1 facilitates the release of endogenous opioid peptides and activates noradrenergic and serotonergic neurons in the brain. In addition to pain control, it is well known that brain opioids and the monoamine system are associated with the regulation of emotional behavior (14), (15). Moreover, it has been reported that brain GPR40/FFAR1 signaling is associated with post-ischemic hippocampal neurogenesis in primates (16). Similarly, Zamarbide et al. reported that GPR40/FFAR1 is expressed in the hippocampus and cortex of mice (17). Therefore, it is possible that brain GPR40/FFAR1 signaling regulates emotional and cognitive function. Previously, we found that repeated activation of brain GPR40/FFAR1 decreases immobility behavior in the forced swim test (18), although the involvement of brain GPR40/FFAR1 in emotional behavior remains unclear.
Materials and methods
Results
Discussion In this study, to investigate the involvement of GPR40/FFAR1 in emotional function, we evaluated the emotional-related behavior of GPR40/FFAR1 KO male mice for the first time. It has been reported that GPR40/FFAR1 KO mice show loss of increased glucose-stimulated insulin secretion induced by free fatty acids and reduced bone density (8), (20), indicating the possibility that non-emotional components induced by the deficiency of GPR40/FFAR1 affect emotional behavior. However, GPR40/FFAR1 KO mice showed normal locomotor activity, which provided important information about interpretation of the results of the behavioral testing. Moreover, it has been reported that GPR40/FFAR1 KO mice show normal regulation of energy balance and food intake (21), (22). Therefore, we speculated that the emotional behavior of GPR40/FFAR1 KO mice was appropriately evaluated using behavioral test without the influence of body activity and other non-emotional factors. Moreover, these findings suggest that GPR40/FFAR1 is not involved in the regulation of locomotor activity. However, we cannot exclude the possibility that the sensory impairments (visual, olfactory) could affect behavior of knockout animals in this study.