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  • Both anxiety like behavior and sucrose preference

    2021-09-08

    Both anxiety-like behavior and sucrose preference/intake were reduced in GPR40/FFAR1 KO male mice, while social behavior was normal in KO mice. These findings indicate that brain GPR40/FFAR1 is involved in the modulation of anxiety- and depression-like behavior in rodents. Previous studies have demonstrated that emotional behavior is regulated by fatty acids, which are the endogenous ligands that bind to GPR40/FFAR1 (1), (3). For instance, short or long term exposure to a high-fat diet containing higher levels of saturated fatty acids leads to alteration of anxiety-like behavior, locomotor activity, and social interaction (23), (24). Similarly, dietary intake or deprivation of ω-3 PUFA affects several emotional behaviors, suggesting that fatty acids play a crucial role in the regulation of emotional function (25), (26). Accumulating evidences have demonstrated that GPR40/FFAR1 has a role as a sensor in mediating the action evoked by fatty acids. Therefore, these findings suggest that dietary fatty acid-induced alteration of some emotional behaviors is mediated by the modulation of GPR40/FFAR1 signaling in the brain. Furthermore, endogenous ligands for GPR40/FFAR1, such as ARA and DHA, are essential components that are associated with the development of the central nervous system (27), (28). Therefore, it is possible that GPR40/FFAR1 deficiency affects the development of the central nervous system and instinctive behavior. In EPM and open field tests, GPR40/FFAR1 KO mice showed reduced anxiety-like behavior. It has been reported that fatty acids can regulate anxiety-like behavior. For example, systemic administration of palmitic acid, which is a long chain saturated fatty acid, has been shown to increase anxiety-like behavior (29), indicating that increased levels of free fatty Anti-cancer Compound Library in the plasma cause an anxiogenic effect by activation of GPR40/FFAR1 signaling in the brain. Consistent with these findings, this study revealed that deficiency of GPR40/FFAR1 signaling produces an anxiolytic effect. It has been reported that mice deficient in fatty acid binding protein 7 (FABP7), which belongs to a family of intracellular lipid binding proteins, showed abnormal composition of brain fatty acid and increased anxiety-like behavior (30), indicating that the development of an anxiety disorder is associated with the abnormal state of brain fatty acids. On the other hand, EPM was utilized to measure impulsive-like behaviors based upon the percentage of time spent in the open arms of the maze (31). GPR40/FFAR1 KO mice showed the number of entries into open arms and spent a longer time in open arms, indicating that GPR40/FFAR1 KO mice may promote impulsivity-like behavior. Therefore, these findings, including our results, suggest that the abnormal function of GPR40/FFAR1 signaling contributes to the pathological mechanism of anxiety or impulsivity-like behavior. Furthermore, we found that GPR40/FFAR1 KO mice show reduced sucrose preference and intake. Generally, the sucrose preference test is used to evaluate depression-like behavior, which is characterized as anhedonia (32). We have previously demonstrated that GPR40/FFAR1 is localized in the hypothalamic proopiomelanocortin-expressing neurons and is involved in the secretion of β-endorphin, which is one of the endogenous opioid peptides (33). It is well known that sucrose intake can release opioids, including β-endorphin, and is suppressed by treatment with opioid receptor antagonists (34), (35). Therefore, these findings suggest that the decreased sucrose intake in GPR40/FFAR1 KO mice is associated with β-endorphin release. Because there is no study suggesting that sucrose can activate GPR40/FFAR1 signaling, sucrose intake may indirectly release β-endorphin, which is mediated by brain GPR40/FFAR1 signaling. Next, GPR40/FFAR1 KO mice had increased monoamine levels in the hippocampus. Hippocampus is one of the most highly connected regions of the brain and function as a brain integrator of emotion and cognition (36). Femenía et al. showed that serotonergic, noradrenergic and dopaminergic neuron project to hippocampus area (37). It has been reported that GPR40/FFAR1 is widely expressed in the brain of mice and GPR40/FFAR1 agonists activate cultured neurons derived from the hippocampus and cortex (17). Of all, hippocampal GPR40/FFAR1 signaling is associated with neurogenesis mediated by the cAMP response element-binding protein (CREB) pathway, which is also regulated by brain-derived neurotrophic factor (BDNF) (38). Therefore, these findings suggest that the hippocampus is a crucial brain region associated with the physiological function of GPR40/FFAR1. The brain monoamine system plays a central role in the regulation of emotional function. Previous studies have demonstrated that anxiety-like behavior is regulated by the hippocampal monoamine system (39), (40), (41). Furthermore, to clarify whether other area of brain may affect by the deletion of GPR40/FFAR1, we tested the changes of monoamine levels in other brain region of GPR40/FFAR1 KO mice. We found that the increment of noradrenaline level in the medulla oblongata, hypothalamus and midbrain was observed in GPR40/FFAR1 KO mice compared to wild mice, but not serotonin and dopamine. We have previously demonstrated that GPR40/FFAR1 is expressed in noradrenergic neurons, and activation of GPR40/FFAR1 increased c-fos, a neuronal activation maker, expression in neurons (13), indicating that GPR40/FFAR1 can regulate the function of noradrenergic and serotonergic neurons. In addition, it has been reported that dietary deprivation of ω-3 PUFA impairs brain monoamine systems (42), (43). In addition, it is reported that anxiety disorder including post-traumatic stress disorder (PTSD) (44), (45) shows the abnormal noradrenergic system in the brain, suggesting that the increment of noradrenaline in the wide brain area may induce, at least in part, abnormal behavior in GPR40/FFAR1 KO mice. Our findings suggest that GPR40/FFAR1 signaling may contribute to the regulation of monoaminergic system in mice. Furthermore, it is thought that deletion of GPR40/FFAR1 could be induced abnormal development of noradrenergic neuron and might alter emotional behavior mediated by the abnormal state of monoamine systems in the brain.