The Role of Dorsal Raphe Serotonin Neurons in the Balance between Reward and Aversion

Background: Reward processing is fundamental for animals to survive and reproduce. Many studies have shown the importance of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons in this process, but the strongly correlative link between the activity of DRN 5-HT neurons and rewarding/aversive potency is under debate. Our primary objective was to reveal this link using two different strategies to transduce DRN 5-HT neurons. Methods: For transduction of 5-HT neurons in wildtype mice, adeno-associated virus (AAV) bearing the mouse tryptophan hydroxylase 2 (TPH2) gene promoter was used. For transduction in Tph2-tTA transgenic mice, AAVs bearing the tTA-dependent TetO enhancer were used. To manipulate the activity of 5-HT neurons, optogenetic actuators (CheRiff, eArchT) were expressed by AAVs. For measurement of rewarding/aversive potency, we performed a nose-poke self-stimulation test and conditioned place preference (CPP) test. Results: We found that stimulation of DRN 5-HT neurons and their projections to the ventral tegmental area (VTA) increased the number of nose-pokes in self-stimulation test and CPP scores in both targeting methods. Concomitantly, CPP scores were decreased by inhibition of DRN 5-HT neurons and their projections to VTA. Conclusion: Our findings indicate that the activity of DRN 5-HT neurons projecting to the VTA is a key modulator of balance between reward and aversion

Randomized Controlled Trial Comparing the Usefulness of Endoscopic Ultrasound Processor

[Background] Although endoscopic ultrasonography (EUS) is a useful tool for diagnosing pancreatobiliary diseases, not many facilities perform this technique as it is difficult to master. Currently, two new EUS systems exist: EU-ME2/GF-UCT260, manufactured by Olympus, and SU-1/EG-580UT, manufactured by Fujifilm. Some reports have compared new EUS models to older versions, but the operability and image quality of these two latest systems have not been compared. Our study aimed to compare the usefulness of these two types of EUS. [Methods] Forty consecutive patients were recruited and randomized in a two-arm clinical trial; Arm 1: EU-ME2/GF-UCT260 was used only for observation and SU-1/EG-580UT for EUS-fine needle aspiration (FNA); Arm 2: SU-1/EG-580UT was used only for observation and EU-ME2/GF-UCT260 for EUS-FNA. Using a crossover design, we evaluated image findings, ease of scope insertion, and visibility of the gastrointestinal (GI) tract. Each procedure was scored using a 5-point scale (Clinical Trial ID: UMIN000031373). [Results] SU-1/EG-580UT was significantly better in terms of lesion-delineating capacity: lesion border (P < 0.001), internal echo (P < 0.001). Significantly easier scope insertion was observed with SU-1/EG-580UT with respect to any insertion into the piriform recess (P = 0.018), the pylorus ring (P < 0.001), and the superior duodenal angle (P < 0.001). Visibility during gastrointestinal observation was also significantly better with the SU-1/EG-580UT (P < 0.001) than with the EU-ME2/GF-UCT260. [Conclusion] SU-1/EG-580UT EUS demonstrated superior performance during ultrasonic endoscopic GI observation, operability, and ultrasonic image quality. The result of the superior ultrasound imaging quality of SU-1/EG-580UT EUS will aid in the identification of small pancreatic malignancies with unclear borders and prove useful in evaluating mural nodules of IPMN in detail. These findings could result in an increased use of EUS and improve identification and prognosis of patients with pancreatobiliary diseases

Safety analysis of two different regimens of uracil–tegafur plus leucovorin as adjuvant chemotherapy for high-risk stage II and III colon cancer in a phase III trial comparing 6 with 18 months of treatment: JFMC33-0502 trial

PURPOSE: The JFMC33-0502 trial is a phase III clinical study designed to determine the most appropriate duration of postoperative adjuvant chemotherapy with uracil–tegafur (UFT) plus leucovorin in patients with stage IIB or III colon cancer. We report the interim results of preplanned safety analyses. METHODS: Patients with stage IIB or III colon cancer who had undergone curative resection were randomly assigned to receive UFT (300 mg/m(2)) plus leucovorin (75 mg/day) for 6 months (control group, 4 weeks of treatment followed by a 1-week rest, five courses) or for 18 months (study group, 5 days of treatment followed by a 2-day rest, 15 courses). Treatment status and safety were evaluated. RESULTS: A total of 1,071 patients were enrolled, and 1,063 were included in safety analyses. Treatment completion rate at 6 months was 74.0 % in the control group and 76.7 % in the study group. Treatment completion rate in the study group at 18 months was 56.0 %. The overall incidence of adverse events (AEs) was 75.3 % in the control group and 77.6 % in the study group. The incidences of grade 3 or higher AEs were low in both groups. During the first 6 months, the incidences of the subjective AEs were significantly lower in the study group. CONCLUSIONS: Oral UFT plus leucovorin given by either dosage schedule is a very safe regimen for adjuvant chemotherapy. In particular, 5 days of treatment followed by a 2-day rest was a useful treatment option from the viewpoint of toxicity even when given for longer than 6 months. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-014-2461-5) contains supplementary material, which is available to authorized users

Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion

不快感を誘発するセロトニン神経を発見 --セロトニン神経の多様性が明らかに--. 京都大学プレスリリース. 2022-12-23.Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli. Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HTMRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity. Our findings revealed an essential function of MRN serotonergic neurons, including 5-HTMRN→IPN, in the processing of reward and aversive stimuli

Association Between Serum Soluble Low-Density Lipoprotein Receptor Levels and Metabolic Factors in Healthy Japanese Individuals

Background: Soluble low-density lipoprotein receptor (sLDL-R) is formed by cleavage of the extracellular domain of lowdensity lipoprotein receptor (LDL-R). It is unclear whether serum sLDL-R is a marker of diseases associated with triglyceride (TG) metabolism. We investigated the association between serum sLDL-R concentrations and other biochemical parameters in healthy Japanese individuals. Methods: Study subjects consisted of 102 healthy adult Japanese volunteers (42 men, 60 women) with body mass index (BMI) &lt; 30 kg/m 2 and serum TGs, LDL cholesterol (LDL-C), aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, and glucose concentrations within normal ranges. Serum sLDL-R concentrations were determined by enzyme-linked immunosorbent assay and their correlations with biochemical parameters were analyzed. Results: Mean serum sLDL-R concentration was 120.9 ± 39.9 ng/ml. Serum sLDL-R levels were significantly and positively correlated with BMI (rs = 0.252) and TG (rs = 0.408) and LDL-C (rs = 0.325) concentrations. Multiple regression analysis adjusted for age, gender, and smoking showed that BMI (β = 0.274), TG (β = 0.328), and LDL-C (β = 0.224) were factors independently correlated with sLDL-R levels. Conclusion: Serum sLDL-R concentration may be a marker of diseases associated with TG metabolism. This is the first report to date describing the clinical relevance of sLDL-R

Dorsal raphe serotonergic neurons preferentially reactivate dorsal dentate gyrus cell ensembles associated with positive experience

Summary: Major depressive disorder (MDD) is among the most common mental illnesses. Serotonergic (5-HT) neurons are central to the pathophysiology and treatment of MDD. Repeatedly recalling positive episodes is effective for MDD. Stimulating 5-HT neurons of the dorsal raphe nucleus (DRN) or neuronal ensembles in the dorsal dentate gyrus (dDG) associated with positive memories reverses the stress-induced behavioral abnormalities. Despite this phenotypic similarity, their causal relationship is unclear. This study revealed that the DRN 5-HT neurons activate dDG neurons; surprisingly, this activation was specifically observed in positive memory ensembles rather than neutral or negative ensembles. Furthermore, we revealed that dopaminergic signaling induced by activation of DRN 5-HT neurons projecting to the ventral tegmental area mediates an increase in active coping behavior and positive dDG ensemble reactivation. Our study identifies a role of DRN 5-HT neurons as specific reactivators of positive memories and provides insights into how serotonin elicits antidepressive effects