Exposure of rodents to early-life stress has been shown to affect emotional behavior in adulthood, suggesting a significant impact of stress on brain development. There is a hypothesis that the developing central nervous system is more sensitive to stress than the adult. To test this hypothesis, we compared long-lasting effects of systemic corticosterone (CORT) administrations in mice of an early developmental period. Mice exposed to early-neonatal CORT treatment on postnatal days (PD) 2-4 displayed impaired extinction of contextually conditioned fear memory, an amygdala-related behavior. These results suggest age-dependent consequences of neonatal CORT exposure in amygdala neurons and provide evidence for a detrimental influence of early-neonatal stress on adolescent fear-memory processing.

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Fear-related disorders are disproportionately prevalent in women. To reveal molecular mechanisms of this sex differences, some researchers have studied sex differences in fear extinction which forms a new memory of safety that inhibits expression of original fear memory. Because patients with post-traumatic stress disorder, one of fear-related disorders, show deficient fear extinction, understanding the molecular mechanisms in fear extinction will be useful for understanding sex differences in fear-related disorders and for developing its effective treatments.

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Exposure therapy has recently been gaining increasing attention for the treatment of a range of anxiety disorders. Recently, strategies to facilitate extinction of fear memory have attracted increasing attention for enhancing the effectiveness of exposure therapy. There is a strong clinical need for an anxiolytic drug that 1)does have potent anxiolytic effect, 2)does not impair recognition memory, 3)does not impair (or even facilitates) extinction learning and 4)attenuates reconsolidation of fear memory. A drug with these features would enhance exposure therapy without the undesired side effects reported for benzodiazepines, SSRIs and D-cycloserine.

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Recently, the dietary intake ratio of n-3 fatty acids has dramatically decreased during several decade. Although the health influence in the change of these food habits has not been considered to be many topics until now, in a recent study, the functional relationship between n-3 fatty acids and pain or psychiatric disease or has been the focus of many studies. However, the detailed mechanisms of these disorders are fully not elucidated. 　G-protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFAR1) is activated by long-chain fatty acids such as docosahexaenoic acid (DHA) . This receptor is expressed predominantly in the central nervous system (CNS) and in β-cells of the pancreatic islets. Previously, we found that GPR40/FFAR1 is widely expressed in the CNS, and showed that the activation of GPR40/FFAR1 signaling relates to the modulation of the descending inhibition of pain. More recent our studies demonstrated that brain GPR40/FFAR1 is associated with anxiety- and depression-related behavior regulated by the increment of noradrenaline in the brain. Therefore, it is possible that brain n-3 fatty acid - GPR40/FFAR1 signaling may play a key role in the modulation of the endogenous pain control system and emotional function. In this review, we discuss the role of brain n-3 fatty acids - GPR40/FFAR1 signaling in a pain and an emotional behavior, and we review the current status and future prospects of brain GPR40/FFAR1.

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Major depression is a highly prevalent disorder, and its symptoms include a depressed mood, loss of interest or pleasure, suicidal thoughts, reduced motivation, and hopelessness. While the etiology of this disorder is multifactorial and poorly understood, increasing evidence suggests that impaired neuronal plasticity contributes to one of the key underlying mechanisms. Neuronal plasticity includes sustained modifications in synaptic structure and function that require de novo gene expression. The regulation of gene expression is a critical molecular mechanism mediating stable adaptations and maladaptations in the brain. Indeed, disruptions in transcription occur in various brain areas in preclinical models of depression and in patients with depression. Recent studies have suggested that histone deacetylases SIRTs-mediated gene transcription and/or SIRT1-dependent regulation of cellular homeostasis have important roles in the pathophysiology and the treatment of depression. Genetic studies suggest that the SIRT1 gene is associated with mood and anxiety disorders. Animal studies also suggest important roles of SIRTs in neuroplasticity, depression-like behavior, and stress responses. Here, we review new information regarding current understanding of SIRTs-mediated pathways that may impact depression. These novel mechanisms of action may lead to new therapeutic strategies for treating major depression.

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Delta opioid receptor (DOP) agonists have been proposed as attractive candidates for the novel psychotropic drugs. Recently, we have demonstrated that a DOP agonist, KNT-127, shows clear anxiolytic-like effects in rat models of innate anxiety, without memory impairment, motor coordination deficits, or ethanol interactions. We have also demonstrated that KNT-127 shows clear antidepressant-like effects in rats. In addition, KNT-127 produces no convulsive effect and does not impair spatial memory. Therefore, we proposed that DOP should be considered as an attractive target for the development of novel psychotropic drug.

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We recently demonstrated that fatty acid-binding protein 3 (FABP3) and Rabex-5, a GTP exchange factor for Rab 5 bind to the dopamine D2 receptor long isoform (D2LR) , which has 29-amino acid insert region in the third cytoplasmic loop. We then reported that fatty acid binding protein 3 (FABP3) knock-out (Fabp3^-/-) mice exhibit abnormal dopamine-related behaviors such as enhanced dopamine D2 receptor antagonist-induced catalepsy behaviors. Fabp3 null mice also exhibit cognitive deficits, hyperlocomotion and impaired fear extinction, and thus show post-traumatic stress disorder (PTSD) -like behaviors. Notably, chronic administration of ramelteon (1.0 mg/kg, p.o.) , a melatonin receptor agonist, improved all PTSD-like behaviors tested in Fabp3^-/- mice. We also report that novel signaling through the intracellularly localized D2R long isoform (D2LR) elicits extracellular signal-regulated kinase (ERK) activation and dendritic spine formation through Rabex-5/platelet-derived growth factor receptor-β (PDGFRβ) -mediated endocytosis in mouse striatum. We found that D2LR directly binds to and activates Rabex-5, promoting early endosome formation. Endosomes containing D2LR and PDGFRβ are then transported to the Golgi apparatus, where those complexes trigger Gαi3-mediated ERK signaling. Moreover, intracellular D2LR signaling mediated catalepsy behavior by a typical antipsychotic drug, haloperidol. Taken together, intracellular D2LR signaling through Rabex-5/PDGFRβ is critical for ERK activation, dendritic spine formation and neuronal activity in striatopallidal MSNs of mice.

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