Rett syndrome is an X-linked neurodevelopmental disorder characterised by cognitive, attentional, and communicative impairments along with sensory and motor deficits. Optimal activation of dopamine D1 receptor signalling in the prefrontal cortex (PFC) is essential for cognition and object-based attention. Ghrelin has been observed to modulate dopaminergic neurotransmission and improve cognitive function and attention impairments in various animal models. Herein, we investigated the effects of ghrelin on D1 receptor-mediated dopaminergic neurotransmission in the PFC of male Mecp2 knockout (KO) mice, a mouse model of Rett syndrome, using in vivo microdialysis. External stimuli, such as saline injection and novelty induced increases in the dopamine levels in the PFC of wild-type mice, and the dopamine release was bidirectionally regulated by D1 receptors. In the PFC of Mecp2 KO mice, the dopaminergic responses to external stimuli were attenuated, and the dopamine reuptake system was upregulated. Pharmacological analyses revealed that the ability of D1 receptor signalling to inhibit dopamine release would be upregulated and/or its ability to stimulate dopamine release would be downregulated in Mecp2 KO mice. Ghrelin injection (8.6 μg/mouse, s.c.) restored dopaminergic responses to external stimuli by adjusting the altered function of D1 receptor signalling. While ghrelin injection failed to improve the impaired object recognition ability in Mecp2 KO mice, it enhanced attention and exploratory activity toward objects. These findings in Mecp2 KO mice suggest that ghrelin may enhance D1 receptor-mediated dopaminergic neurotransmission and exert beneficial effects on dopamine-related behaviour, such as attention and investigatory motivation towards objects, in Rett syndrome.

Abstract Social defeat stress is a recognized method to induce depressive-like behaviors in mice. Our study found that when mice subjected to social defeat stress were later administered with cocaine, their depressive state significantly worsened. Notably, the typical anti-depressive effects gained from overexpressing DFosB in the nucleus accumbens (NAc), a region known for mediating anti-depressive states, failed to counteract the exacerbating effects of cocaine. Interestingly, a pre-treatment involving electrical shocks to the brain triggered the induction of endogenous DFosB, generating an anti-depressive effect. Nevertheless, even in this mitigated state, subsequent cocaine administration reinstated the depressive behaviors. To robustly verify the intensification of the depressive state, behavioral paradigms like the elevated plus maze and forced swim test were conducted both before and after cocaine treatment. A notable deterioration in performance was observed specifically in the forced swim test post-cocaine administration. Given our understanding that male attractiveness in mice is influenced by physical appearance and perceived confidence, we postulated how this intensified depressive state might affect a male's attractiveness. Observations revealed that during the depressive state induced by social defeat, dopaminergic neurons in the ventral tegmental area (VTA) exhibit hyperactivity. Building on this, we employed a retrograde AAV DIO Gi and Gq injection into the NAc of TH-cre mice. The objective is to delineate the impact of dopaminergic neuron activity on both male attractiveness and the depressive state under the combined influence of social defeat and cocaine. In conclusion, this study illuminates the intricate relationship between cocaine, social defeat-induced depression, and male attractiveness, providing crucial insights into the underlying neurobiological mechanisms and potential therapeutic interventions.

Depression can be associated with chronic systemic inflammation, and production of peripheral proinflammatory cytokines and upregulation of the kynurenine pathway have been implicated in pathogenesis of depression. However, the mechanistic bases for these comorbidities are not yet well understood. As tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), which convert tryptophan to kynurenine, are rate-limiting enzymes of the kynurenine pathway, we screened TDO or IDO inhibitors for effects on the production of proinflammatory cytokines in a mouse macrophage cell line. The TDO inhibitor 680C91 attenuated LPS-induced pro-inflammatory cytokines including IL-1β and IL-6. Surprisingly, this effect was TDO-independent, as it occurred even in peritoneal macrophages from TDO knockout mice. Instead, the anti-inflammatory effects of 680C91 were mediated through the suppression of signal transducer and activator of transcription (STAT) signaling. Furthermore, 680C91 suppressed production of proinflammatory cytokines and STAT signaling in an animal model of inflammatory bowel disease. Specifically, 680C91 effectively attenuated acute phase colon cytokine responses in male mice subjected to dextran sulfate sodium (DSS)-induced colitis. Interestingly, this treatment also prevented the development of anxiodepressive-like neurobehaviors in DSS-treated mice during the recovery phase. The ability of 680C91 to prevent anxiodepressive-like behavior in response to chemically-induced colitis appeared to be due to rescue of attenuated dopamine responses in the nucleus accumbens. Thus, inhibition of STAT-mediated, but TDO-independent proinflammatory cytokines in macrophages can prevent inflammation-associated anxiety and depression. Identification of molecular mechanisms involved may facilitate the development of new treatments for gastrointestinal-neuropsychiatric comorbidity.

The role of the prefrontal cortex (PFC), particularly the prelimbic region (PL), in determining male dominance has been previously reported (Zhou, et.al, Science, 2017). Apart from this established dominance hierarchy, our team has developed a Female-Male Preference Test (FMPT) by comparing four male mice. This test effectively differentiates between males perceived as attractive and unattractive from a female mouse's perspective. The correlation between a male's dominance and its attractiveness to females remains elusive.

We've found the presence of attractive or unattractive male mice among four littermate male mice by behavior-based measurement with video camera tracking system. This trend of preference disappeared by hiding male mice with four-layered air-permeable filter. Furthermore, genetically blind female mice showed completely different trend of preference against the same male mice set, indicating that appearance may be one of major factors of male attractiveness.

Rett syndrome is an X-linked neurodevelopmental disorder characterized by cognitive impairments along with sensory and motor deficits. Ghrelin is known to improve cognitive function in various animal models with cognitive deficits. Optimum activation of dopamine D1 receptor signaling in the prefrontal cortex (PFC) plays a critical role in cognitive performance. In this study, we investigated the effects of ghrelin on cognitive function and D1 receptor-mediated dopamine neurotransmission in the PFC of Mecp2 knockout (KO) mice, a mouse model for Rett syndrome. In the modified novel object recognition test, cognitive function was impaired in Mecp2 KO mice, and ghrelin injection (8.6 µg/mouse, s.c.) improved the cognition of objects and investigatory behaviors. In in vivo microdialysis studies, external stimuli such as saline injection and novelty induced increases in dopamine levels in the PFC of wild-type mice, and the dopamine release was bidirectionally regulated by D1 receptors. In the PFC of Mecp2 KO mice, the dopamine responses to external stimuli were attenuated and the dopamine reuptake system was upregulated. Pharmacological analyses revealed that the ability of D1 receptor signaling to inhibit dopamine release would be upregulated and/or its ability to stimulate dopamine release would be downregulated in Mecp2 KO mice. Ghrelin injection restored dopamine responses to external stimuli by adjusting the altered function of D1 receptor signaling. These results suggest that the ability of ghrelin to restore dopamine neurotransmission via D1 receptor-mediated mechanisms likely contributes to its therapeutic effects on cognitive deficits in Mecp2 KO mice.

Occasional incidents of drug addiction among celebrities have been reported, and sometimes the presence of the opposite sex flickers. Even trafficking of women sometimes involves the use of illegal drugs. Whether drugs induce not only drug dependence but also an associated preference for the opposite sex is an important question in understanding and solving such cases.

Cast immobilization causes sensory hypersensitivity, which is also a symptom of neuropathic pain and chronic pain. However, the mechanisms underlying immobilization-induced hypersensitivity remain unclear. The present study investigated the role of dopamine neurotransmission in the nucleus accumbens shell (NAcSh) of rats with cast immobilization-induced mechanical hypersensitivity using in vivo microdialysis. Cast immobilization of the hind limb decreased the paw withdrawal threshold (PWT). Mechanical stimulation of the cast-immobilized hind limb induced a decrease in dopamine in the NAcSh, and this decrease was associated with the upregulation of presynaptic D2-like receptors. A D2-like receptor antagonist infused into the NAcSh reversed the decrease in PWT in rats with cast immobilization, whereas a D2-like receptor agonist infused into the NAcSh induced a decrease in PWT in control rats. In addition, the expression of the D2 receptor (Drd2) mRNA in the NAcSh was increased by cast immobilization. Importantly, systemic administration of the D2-like receptor antagonist reversed the decrease in PWT in rats with cast immobilization. As dopamine levels regulated by presynaptic D2-like receptors did not correlate with the PWT, it is presumed that the D2-like receptor antagonist or agonist acts on postsynaptic D2-like receptors. These results suggest that immobilization-induced mechanical hypersensitivity is attributable to the upregulation of postsynaptic D2-like receptors in the NAc. Blockade of D2-like receptors in the NAcSh is a potential therapeutic strategy for immobilization-induced hypersensitivity.

The striatum is the main structure of the basal ganglia. The striatum receives inputs from various cortical areas, and its subregions play distinct roles in motor and emotional functions. Recently, striatal maps based on corticostriatal connectivity and striosome-matrix compartmentalization were developed, and we were able to subdivide the striatum into seven subregions. Dopaminergic modulation of the excitability of medium spiny neurons (MSNs) is critical for striatal function. In this study, we investigated the functional properties of dopamine signaling in seven subregions of the striatum from male mice. By monitoring the phosphorylation of PKA substrates including DARPP-32 in mouse striatal slices, we identified two subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Low D1 receptor signaling in the two subregions was maintained by phosphodiesterase (PDE)10A and muscarinic M4 receptors. In an animal model of 6-hydroxydopamine (6-OHDA)-induced hemi-parkinsonism, D1 receptor signaling was upregulated in almost all subregions including the DL-IR, but not in the IC. When L-DOPA-induced dyskinesia (LID) was developed, D1 receptor signaling in the IC was upregulated and correlated with the severity of LID. Our results suggest that the function of the striatum is maintained through the subregion-specific regulation of dopamine D1 receptor signaling and that the aberrant activation of D1 receptor signaling in the IC is involved in LID. Future studies focusing on D1 receptor signaling in the IC of the striatum will facilitate the development of novel therapeutics for LID. SIGNIFICANCE STATEMENT Recent progress in striatal mapping based on corticostriatal connectivity and striosome-matrix compartmentalization allowed us to subdivide the striatum into seven subregions. Analyses of D1 receptor signaling in the seven subregions identified two unique subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Aberrant activation of D1 receptor signaling in the IC is involved in L-DOPA-induced dyskinesia (LID). Previous studies of LID have mainly focused on the DL-IR, but not on the IC of the striatum. Future studies to clarify aberrant D1 receptor signaling in the IC are required to develop novel therapeutics for LID.

Abstract Background Dopamine neurotransmission plays a critical role in reward in drug abuse and drug addiction. However, the role of dopamine in the recognition of drug-associated environmental stimuli, retrieval of drug-associated memory, and drug-seeking behaviors is not fully understood. Methods Roles of dopamine neurotransmission in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in the cocaine-conditioned place preference (CPP) paradigm were evaluated using in vivo microdialysis. Results In mice that had acquired cocaine CPP, dopamine levels in the PFC, but not in the NAc, increased in response to cocaine-associated cues when mice were placed in the cocaine chamber of an apparatus with 2 separated chambers. The induction of the dopamine response and the development of cocaine CPP were mediated through activation of glutamate NMDA (N-methyl-D-aspartate)/AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor signaling in the PFC during conditioning. Activation of dopamine D1 or D2 receptor signaling in the PFC was required for cocaine-induced locomotion, but not for the induction of the dopamine response or the development of cocaine CPP. Interestingly, dopamine levels in the NAc increased in response to cocaine-associated cues when mice were placed at the center of an apparatus with 2 connected chambers, which requires motivated exploration associated with cocaine reward. Conclusions Dopamine neurotransmission in the PFC is activated by the exposure to the cocaine-associated cues, whereas dopamine neurotransmission in the NAc is activated in a process of motivated exploration of cues associated with cocaine reward. Furthermore, the glutamate signaling cascade in the PFC is suggested to be a potential therapeutic target to prevent the progression of drug addiction.

Role of dopamine neurotransmission in retrieval of drug-associated memory is not fully understood. The present study provides direct evidences that dopamine neurotransmission is differentially activated in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in the cocaine conditioned place preference (CPP) paradigm in behaving mice using in vivo microdialysis. In mice that had acquired cocaine CPP, the dopamine levels in the PFC, but not in the NAc, increased in response to the cocaine-associated cue, when mice were placed in the cocaine chamber of two-separated chamber apparatus. The induction of the dopamine response and the development of cocaine CPP were mediated through activation of glutamate NMDA/AMPA receptor signaling in the PFC during conditioning. Activation of dopamine D1 or D2 receptors signaling in the PFC was required for the cocaine-induced locomotion, but not for the induction of the dopamine response or the development of cocaine CPP. Interestingly, dopamine levels in the NAc increased in response to the cocaine-associated cue, when mice were placed at the center of two-connected chamber apparatus, which requires the motivated exploratoration of cocaine reward. In summary, dopamine neurotransmission in the PFC is activated to retrieve the context-associated reward memory of cocaine, whereas dopamine neurotransmission in the NAc is activated in the process of motivated exploration of cocaine reward. The present findings suggest the nature of difference in dopamine transmission in the PFC and NAc to the psychological reward cues.

Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments. Because of its projections to brain regions regulating reward and anxiety, the ventral hippocampus is uniquely poised to translate the experience of stress into altered brain function and pathological mood, though the cellular and molecular mechanisms of this process are not fully understood. Here, we use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. We establish molecular, cellular, and circuit-level mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression.

The dopamine (DA) D1 receptors in the nucleus accumbens (NAc) is implicated in cocaine-induced conditioned place preference (CPP), which is driven by the cocaine-associated cue. However, the effect of the cocaine-associated cue on DA release in the prefrontal cortex (PFC) has little been studied. The present study examined the effects of cocaine-associated cues on the extracellular DA levels in the NAc and PFC using in vivo microdialysis. Furthermore, the role of D1, D2, and ionotropic glutamate receptors in cocaine (7.5 mg/kg i.p.)-induced CPP, locomotor and DA release were investigated. Cocaine-associated cues increased DA levels in the PFC, but unexpectedly had no effects on DA levels in the NAc. Pharmacological inhibition of D1 and D2 receptors and chemogenetic inhibition of D1 receptor-expressing cells by Gi-DREADD in the PFC during the cocaine conditioning procedure suppressed the cocaine-induced locomotor response, but did not affect the CPP. Pharmacological modulation of ionotropic glutamate receptors by antagonists and agonists in the PFC suppressed the cocaine-induced CPP, but did not affect the locomotor response. The DA response to the cocaine-associated cue in the PFC was abolished by pharmacological inhibition of ionotropic glutamate receptors, but not of D1 or D2 receptors.

Some men sometimes invite an interested woman to bar for alcohol drinking. Alcohol makes them cheerful and improves their relationship occasionally. The man expects alcohol could decrease the threshold to open her mind, and, in some cases, lose accurate judgments about him as a sexual partner. In this research, we are trying to reveal a part of the neural activities and behavioral characteristics in male and female using a mouse model in such situation.

Neural proliferation in the dentate gyrus (DG) is closely linked with learning and memory, but the transcriptional programming that drives adult proliferation remains incompletely understood. Our lab previously elucidated the critical role of the transcription factor ΔFosB in the dorsal hippocampus (dHPC) in learning and memory, and the FosB gene has been suggested to play a role in neuronal proliferation. However, the subregion-specific and potentially cell-autonomous role of dHPC ΔFosB in neurogenesis-dependent learning has not been studied. Here, we crossed neurotensin receptor-2 (NtsR2) Cre mice, which express Cre within the subgranular zone (SGZ) of dHPC DG, with floxed FosB mice to show that knockout of ΔFosB in hippocampal SGZ neurons reduces antidepressant-induced neurogenesis and impedes hippocampus-dependent learning in the novel object recognition task. Taken together, these data indicate that FosB gene expression in SGZ is necessary for both hippocampal neurogenesis and memory formation.

Depression is a leading cause of disability. Current pharmacological treatment of depression is insufficient, and development of improved treatments especially for treatment-resistant depression is desired. Understanding the neurobiology of antidepressant actions may lead to development of improved therapeutic approaches. Here, we demonstrate that dopamine D1 receptors in the dentate gyrus act as a pivotal mediator of antidepressant actions in mice. Chronic administration of a selective serotonin reuptake inhibitor (SSRI), fluoxetine, increases D1 receptor expression in mature granule cells in the dentate gyrus. The increased D1 receptor signaling, in turn, contributes to the actions of chronic fluoxetine treatment, such as suppression of acute stress-evoked serotonin release, stimulation of adult neurogenesis and behavioral improvement. Importantly, under severely stressed conditions, chronic administration of a D1 receptor agonist in conjunction with fluoxetine restores the efficacy of fluoxetine actions on D1 receptor expression and behavioral responses. Thus, our results suggest that stimulation of D1 receptors in the dentate gyrus is a potential adjunctive approach to improve therapeutic efficacy of SSRI antidepressants.

Major depression is a psychiatric disorder with high lifetime prevalence. Selective serotonin reuptake inhibitors (SSRIs) are commonly used for treatment of depression, but mechanisms of SSRIs to improve symptoms of depression are not fully understood. In addition, development of improved treatments especially for treatment-resistant depression is desired. Recently, chronic administration of SSRI is reported to increase the expression of dopamine D1 receptors in mature granule cells of the hippocampal dentate gyrus. In this study, we investigated the role of D1 receptors in the dentate gyrus in antidepressant actions of SSRIs.