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Non-thermal atmospheric pressure plasma is a novel approach for wound healing, blood coagulation, and cancer therapy. A recent discovery in the field of plasma medicine is that non-thermal atmospheric pressure plasma not only directly but also indirectly affects cells via plasma-treated liquids. This discovery has led to the use of non-thermal atmospheric pressure plasma as a novel chemotherapy. We refer to these plasma-treated liquids as plasma-activated liquids. We chose Ringer’s solutions to produce plasma-activated liquids for clinical applications. In vitro and in vivo experiments demonstrated that plasma-activated Ringer’s lactate solution has anti-tumor effects, but of the four components in Ringer’s lactate solution, only lactate exhibited anti-tumor effects through activation by non-thermal plasma. Nuclear magnetic resonance analyses indicate that plasma irradiation generates acetyl and pyruvic acid-like groups in Ringer’s lactate solution. Overall, these results suggest that plasma-activated Ringer’s lactate solution is promising for chemotherapy.

Endometriosis is observed in ∼10% of reproductive age women. Ovarian endometriosis not only causes dysmenorrhea but also causes infertility and a high risk of adenocarcinoma. Due to its scattered nature, complete surgical resection is difficult. Endometriosis consists of glandular and stromal cells. Previously, we showed that endometrial stromal cells (ESCs) play a role in the protection against pathologic events caused by monthly repeated hemorrhage. Here, we undertook a preclinical study of non-thermal plasma (NTP) as a surgical treatment of endometriosis. Epithelial cells were most sensitive to NTP-activated medium in vitro, whereas ectopic ESCs were most resistant. We then transplanted excised uteruses into BALB/c mice from donors of the same strain with estradiol supplementation. Four weeks after the transplantation, we exposed NTP to each endometriotic lesion after laparotomy. Immunohistochemical analysis revealed that immediately after NTP exposure, epithelial cells exhibited significantly higher levels of nuclear immunostaining for 8-hydroxy-2'-deoxyguanosine than did stromal cells. Four weeks after NTP exposure, the total surface area consisting of endometriotic cysts was significantly smaller with less epithelial proliferative activity than the helium-exposed control, whereas the number of endometriotic lesions had not changed. Therefore, NTP exposure may be useful to prevent the progression and recurrence of endometriosis.

The administration of fluid irradiated with non-equilibrium atmospheric pressure plasma (NEAPP) has attracted much interest as a novel therapeutic method for cancer. The authors previously reported on the efficacy of plasma-activated medium (PAM) for treating cancer cell lines through the induction of apoptosis. In this study, the therapeutic effect of PAM was evaluated in vivo using a peritoneal metastasis mouse model. Two gastric cancer cell lines were used in proliferation assays performed to optimize the production of PAM by changing the distance between the plasma source and the medium surface and by altering the volume of irradiated medium. Wound-healing and adhesion assays were conducted to determine the effect of PAM therapy on cell migration and adhesion capacity in vitro. Finally, a mouse model established by the intraperitoneal injection of enhanced green fluorescent protein-tagged gastric cancer cells was used to explore the efficacy of PAM administered intraperitoneally in inhibiting peritoneal metastasis formation. Shorter distances between the plasma source and the medium surface and smaller volumes of treated medium increased the anti-tumor effect of PAM. The PAM treatment attenuated gastric cancer cell migration and adhesion in vitro. The intraperitoneal administration of PAM decreased the formation of peritoneal metastatic nodules by 60% in the mouse model, and no adverse events were observed. Plasma-activated liquids may represent a novel therapeutic method for the treatment of peritoneal metastases in gastric cancer.

Non-equilibrium atmospheric pressure pl asma (NEAPP) applications for medicine are attracted attention in plasma irradiated cell culture medium, called as Plasma-Activated-Medium (PAM). Selectively killing effect of cancer cells without killing normally cells was reported for incubation with the PAM1. Even though the effect can apply for cancer cure, the mechanism of antitumor effect has not been elucidated yet.

We previously reported that plasma-activated medium (PAM) selectively kills glioblastoma brain tumor cells by downregulating the signaling molecule, the serine-threonine kinase AKT. AKT kinase plays a key role in survival and proliferation by acting as a hub mol- ecule in the signaling network to inhibit apoptosis. The pathways that contain AKT and that are affected by PAM are unclear. In this study of glioblastoma brain tumor cells, phosphoryla- tion of AKT at both Ser473 and Thr308 was downregulated by PAM, suggesting that upstream signaling by the mammalian target of rapamycin complex 2 (mTORC2) and phosphatidylino- sitol-3 kinase (PI3K)/ 3-phosphoinositide-dependent protein kinase-1 (PDK1) were affected by PAM. Furthermore, the extracellular regulated kinase (ERK) signaling pathway, which is parallel to the AKT signaling pathway, was downregulated by PAM, and the mTORC1 sig- naling pathway, which is a major downstream signaling pathway of AKT and ERK, was also downregulated by PAM. In addition, CD44, a cell membrane-bound receptor that promotes both the AKT pathway and the ERK pathway, was downregulated by PAM. Taken together, these results suggest that PAM completely downregulates the survival and proliferation signal- ing network in glioblastoma brain tumor cells.

Aim: Existing evidence suggests that endothelial lipase (EL) plays an important role in high-densitylipoprotein (HDL) metabolism. Because rabbits are a useful animal model for the study of human lipid metabolism and atherosclerosis, we characterized rabbit EL (rEL) expression and investigated its relationship with plasma HDL levels in normal and hyperlipidemic rabbits.Methods: We cloned the rEL cDNA and analyzed the EL tissue expression using Northern blotting, real-time RT-PCR, Western blotting, and in situ hybridization. We evaluated the effects of rEL antisense on plasma HDL levels.Results: We found that rEL mRNA was highly expressed in cholesterol synthesis-related organs, including the liver, testis, and adrenal along with its expression in the lung, kidney, bone marrow, and small intestine. Interestingly, Watanabe heritable hyperlipidemic (WHHL) rabbits, a model of human familial hypercholesterolemia, had lower plasma levels of HDLs than normal rabbits. The plasma HDL levels in WHHL rabbits were inversely associated with high levels of plasma rEL proteins and hepatic expression of rEL mRNA. Injection of rEL-specific antisense oligonucleotides into rabbits resulted in the elevation of plasma large HDLs. Furthermore, we demonstrated that rEL mRNA was expressed by both endothelial cells and macrophages in the lesions of aortic atherosclerosis of WHHL rabbits.Conclusions: rEL is expressed in multiple tissues and may have many physiological and pathophysiological functions, such as in the regulation of cholesterol metabolism and atherosclerosis. Our results suggest that EL is an important regulator of plasma HDL levels in rabbits.

1. Matrix metalloproteinases (MMP) are associated with the vascular remodelling seen in atherosclerosis and aneurysm. The activation and activity of MMP-2 are regulated by the intrinsic tissue inhibitor of MMP-2 (TIMP-2). The aim of the present study was to examine whether, conversely, MMP-2 can affect the gene and protein expression of TIMP-2. 2. In the present study, we examined the mRNA and protein expression of MMP-2 and TIMP-2 in cultured smooth muscle cells (SMC) from the aortas of MMP-2(+/+) and MMP-2(-/-) mice. We also examined the roles of MMP-2 in SMC cellular events. 3. Western blotting showed that less TIMP-2 protein was present in the conditioned medium of MMP-2(-/-) SMC than in that of MMP-2(+/+) SMC. Real-time reverse transcription polymerase chain reaction analysis showed that MMP-2 deficiency reduced TIMP-2 mRNA expression in SMC. Recombinant MMP-2 enhanced the expression of TIMP-2 protein in cultured SMC from MMP-2(-/-) mice. Furthermore, a siRNA targeting MMP-2 impaired the gene and protein expression of MMP-2 in cultured SMC from MMP-2(+/+) mice. MMP-2 deficiency impaired SMC invasion, but not their proliferation, adhesion or migration. 4. Our findings suggest that MMP-2 is likely to be responsible, at least in part, for regulating TIMP-2 expression and is thus a potential target, in addition to TIMP-2, for therapeutics aimed at preventing cardiovascular remodelling in response to injury.

The authors performed a pathological examination of a 5-year-old female laboratory Japanese monkey who developed cortical blindness and epileptic seizures. Generalized, tonic-clonic seizures started to occur during behavioral training to get the animal to enter a carrying cage for future psychological experiments. Blindness was suspected because of a lack of approaching behavior toward foods such as fruits. Although the monkey was extensively treated with anticonvulsants, the clinical signs did not improve. An increased serum creatine phosphokinase (CPK) level and bilateral occipital brain atrophy were detected. Histopathologically, a severe degree of cerebromalacia was detected bilaterally in the occipital lobe, and necrosis and gliosis were seen mainly in the temporal lobe. Focal inflammation was found in the meninges. No other changes were observed in other nervous tissues or organs, and no signs of a parasitic or viral infection were found in the systemic organs. Spontaneously occurring lesions in the central nervous system have been rarely reported in laboratory monkeys. In the present case, the cause of cerebromalacia could not be confirmed, but the relationship between symptoms such as abnormal vision and the presence of brain lesions was distinct. The authors believe that this case is a valuable historical control case for the laboratory Japanese macaque.

Although it has been suggested that the renin-angiotensin (RA) system and cathepsins contribute to the development and vulnerability of atherosclerotic plaque, the interaction of the RA system and cathepsins is unclear. Thus, we investigated the effects of an angiotensin II type 1 receptor (AT1) antagonist, olmesartan, on the levels of cathepsins in brachiocephalic atherosclerotic plaque and plaque stabilization in apolipoprotein E (apoE)-deficient mice receiving a high-fat diet. Under a high fat diet, treatment with olmesartan (3 mg/kg per day) maintained collagen and elastin at high levels and attenuated the plaque development and cathepsin S (Cat S) level in the atherosclerotic plaque of apoE-deficient mice. The administration of olmesartan suppressed the accumulation of macrophages in plaque. Immunoreactivities of Cat S and AT1 were observed in macrophages. The amount of Cat S mRNA and the macrophage-mediated collagenolytic and elastolytic activities in cultured macrophages were increased by exposure to angiotensin II (Ang II), and these effects were diminished by olmesartan and the NADPH-oxidase inhibitor apocynin. These results suggested that Cat S derived from macrophages is involved in the mechanisms of atherosclerotic plaque vulnerability, and AT1 blocker maintained the plaque stabilization alongside the suppression of Cat S and macrophage activities.

Saccadic eye movements (SEM) are used as a biomarker for psychiatric disorders. However, the relationship between SEM and higher brain function has not been fully elucidated. Therefore, we examined SEM during the Trail Making Test part A (TMT-A), a neuropsychological test of visual attention and processing speed, and assessed the correlation between the frequency of SEM during TMT-A and neuropsychological test results. The eye movements of 43 elderly subjects (>65 y/o, mean 72.4 y/o), with no history of neuropsychiatric disorders, were measured using eye tracking glasses (SensoMotoric Instruments, Germany). Eye movements of more than 1.6 degrees/s were judged to be SEM. We found a significant inverse correlation between the frequency of SEM during TMT-A and the time required to complete TMT-A (r = −0.402, p = 0.008). We found a positive correlation with the Backward block-tapping span (r = 0.371, p = 0.015), a neuropsychological test of spatial working memory, and the Japanese version of the Montreal Cognitive Assessment (r = 0.301, p = 0.021). The lower frequency of SEM during TMT-A reflected lower processing speeds and spatial working memory, which may lead to poorer performance on neuropsychological tests. This result indicates that the frequency of SEM during TMT-A might be an informative biomarker for attention and cognitive function in the elderly.

The dorsal raphe nucleus and its serotonin-releasing neurons are thought to regulate motivation and reward-seeking. These neurons are known to be active during motivated behavior, but the underlying principles that govern their activity are unknown. Here we show that a group of dorsal raphe neurons encode behavioral tasks in a systematic manner, tracking progress toward upcoming rewards. We analyzed dorsal raphe neuron activity recorded while animals performed two reward-oriented saccade tasks. There was a strong correlation between the tonic activity level of a neuron during behavioral tasks and its encoding of reward-related cues and outcomes. Neurons that were tonically excited during the task predominantly carried positive reward signals. Neurons that were tonically inhibited during the task predominantly carried negative reward signals. Neurons that did not change their tonic activity levels during the task had weak reward signals with no tendency for a positive or negative direction. This form of correlated task and reward coding accounted for the majority of systematic variation in dorsal raphe response patterns in our tasks. A smaller component of neural activity reflected detection of reward delivery. Our data suggest that the dorsal raphe nucleus encodes participation in a behavioral task in terms of its future motivational outcomes.

Although it has been demonstrated that statins stabilize atherosclerotic lesions in animal models of advanced atherosclerosis, there is little evidence to suggest that statins have a preventive effect on plaque rupture itself. In the present study, we examined the effect of fluvastatin on plaque disruption using a simple and quick method of plaque disruption in carotid artery lesions in apolipoprotein E-deficient mice. Male apolipoprotein E-deficient mice received normal chow and underwent ligation of the left common carotid artery just proximal to its bifurcation. Four weeks later, a polyethylene cuff was placed around the artery immediately proximal to the ligation site. Fluvastatin (10 mg/kg per day) was given by oral gavage every day starting at 3 days before cuff placement. The administration of fluvastatin suppressed atherosclerotic plaque disruption accompanied by luminal thrombi by 31.5% compared with controls at 4 days after the cuff was placed at the ligated carotid artery. Fluvastatin administration decreased matrix metalloproteinase-9 expression, gelatinolytic activity, endothelial adhesion molecules expression and neutrophil infiltration, and increased type I collagen content in the cuffed region. In summary, fluvastatin was found to prevent plaque disruption through pleiotropic effect on acute inflammation in an animal model using apolipoprotein E-deficient mice.

Non-equilibrium atmospheric pressure plasmas generate a high electron density (on the order of 10(16) electrons per cm(-3)) using Ar gas. Culture medium in air at room temperature was plasma-irradiated for several hundred seconds. Tens of micromolar hydrogen peroxide (H2O2) and millimolar levels of nitrous ion (NO2(-)) were detected in the plasma-irradiated culture medium (plasma activated medium; PAM) and selectively induced the apoptotic death of glioblastoma tumor cells, but did not kill normal mammary epithelial cells. A similar antitumor effect was induced by spiking the medium with comparable concentrations of H2O2 and NO2(-). The PAM remained still a somewhat difference that it should also be assessed for understanding other latent mechanisms.

Aims Transseptal puncture (TSP) has become a common approach in catheter ablation of arrhythmia originating from the left atrium. In paediatric patients, however, TSP can be a challenge due to narrower access vessels and small left atrial size, and the safety of TSP in smaller children is yet to be understood. The purpose of this study was to retrospectively evaluate the feasibility and safety of TSP in children weighing below 30 kg. Methods and results Among 655 paediatric patients who underwent catheter ablation of arrhythmia between July 2009 and April 2015, 43 cases having structurally normal hearts, weighing

Cathepsins are cysteine proteases that participate in various types of tissue remodeling. However, their expressions during myocardial remodeling have not been examined. In this study, we investigated their expressions in the left ventricular (LV) myocardium of rats and humans with hypertension-induced LV hypertrophy or heart failure (HF). Real-time PCR and immunoblot analysis revealed that the abundance of cathepsin S mRNA or protein in the LV tissues was greater in rats or humans with HF than in those with hypertrophy or in control subjects. Immunostaining showed that cathepsin S was localized predominantly to cardiac myocytes and coronary vascular smooth muscle cells, but also overlapped in part with macrophages. Elastic lamina fragmentations significantly increased in the LV intramyocardial coronary arteries of HF rats. The amount of elastolytic activity in the extract of the LV myocardium was markedly increased for HF rats compared with controls, and this activity was mostly because of cathepsin S. Although the amount of elastin mRNA was increased in the LV myocardium of HF rats, the area of interstitial elastin was not. The expression of interleukin 1β was increased in the LV myocardium of HF rats, and this cytokine was found to increase the expression and activity of cathepsin S in cultured neonatal cardiomyocytes. These results suggest that cathepsin S participates in pathological LV remodeling associated with hypertension-induced HF. This protease is, thus, a potential target for therapeutics aimed at preventing or reversing cardiac remodeling.

Objective— The development of a murine model of atherosclerotic plaque rupture. Methods and Results— The left common carotid arteries of male apolipoprotein E (apoE)–deficient mice (9 weeks old) were ligated just proximal to their bifurcations. After 4 weeks on a standard diet, the mice received polyethylene cuff placement just proximal to the ligated site, and the animals were then processed for morphological studies at specific time points. Ligation of the carotid artery in apoE-deficient mice for 4 weeks induced marked intimal hyperplasia, which is a lipid- and collagen-rich lesion that contains a number of macrophages, T lymphocytes, and smooth muscle cells. Subsequently, the cuff placement evoked intraplaque hemorrhage and plaque rupture with fibrin(ogen)-positive luminal thrombus in this region accompanying a decrease in collagen content as well as an increase in apoptotic cells in the intima within a few days after cuff placement. Conclusions— We demonstrated the murine model of human plaque rupture, which is simple, fast, and highly efficient. This model would help us not only to understand the mechanism of human plaque rupture but also to assess various already-known and as-yet-unknown agents in the future.

Expectation of reward motivates our behaviors and influences our decisions. Indeed, neuronal activity in many brain areas is modulated by expected reward. However, it is still unclear where and how the reward-dependent modulation of neuronal activity occurs and how the reward-modulated signal is transformed into motor outputs. Recent studies suggest an important role of the basal ganglia. Sensorimotor/cognitive activities of neurons in the basal ganglia are strongly modulated by expected reward. Through their abundant outputs to the brain stem motor areas and the thalamocortical circuits, the basal ganglia appear capable of producing body movements based on expected reward. A good behavioral measure to test this hypothesis is saccadic eye movement because its brain stem mechanism has been extensively studied. Studies from our laboratory suggest that the basal ganglia play a key role in guiding the gaze to the location where reward is available. Neurons in the caudate nucleus and the substantia nigra pars reticulata are extremely sensitive to the positional difference in expected reward, which leads to a bias in excitability between the superior colliculi such that the saccade to the to-be-rewarded position occurs more quickly. It is suggested that the reward modulation occurs in the caudate where cortical inputs carrying spatial signals and dopaminergic inputs carrying reward-related signals are integrated. These data support a specific form of reinforcement learning theories, but also suggest further refinement of the theory.

Complex motor skill often consists of a fixed sequence of movements. Recent studies show that a stereotyped temporal pattern or rhythm emerges as we learn to perform a motor sequence. This is because the sequence is reorganized during learning as serial chunks of movements in both a sequence- specific and subject-specific manner. On the basis of human imaging studies we propose that the formation of chunk patterns is controlled by the cerebellum, its posterior and anterior lobes contributing, respectively, to the temporal patterns before and after chunk formation. The motor rhythm can assist the motor networks in the cerebral cortex to control automatic movements within chunks and the cognitive networks to control non-automatic movements between chunks, respectively. In this way, organized motor skill can be performed automatically and flexibly.

A novel model to induce occlusive thrombus formation was developed in mice in vivo. Mice were simultaneously treated with ligation and cuff placement at the left carotid artery. At 7 days after the treatment, occlusive thrombus was observed at the intracuff region, but not in the distal and proximal regions of the cuff, and not induced by a single treatment of ligation or cuff placement. The plasma levels of von Willebrand factor (vWF), which represent the endothelial status, were significantly increased in combined treatment of ligation and cuff placement 1 day after the operation. Whereas no significant changes in plasma vWF were observed in either single treatment of ligation or cuff placement. The expression of vWF, considered to be the endothelial marker, was detected on the luminal surface distal and proximal to the cuff and the carotid artery in the single treatment groups treated with either ligation or cuff placement, but was not detected in the intracuff region. Furthermore, the binding of Griffolia Simplicifolia Lectin-I (GSL-I) and endothelial nitric oxide synthase (eNOS) expression indicating the endothelial integrity was not detected in the intracuff region. Intermittent injections of ancrod, which decreases the plasma fibrinogen, inhibited occlusive thrombus formation in the intracuff region. The expression of eNOS was detected at the distal and proximal but not the intracuff region of the carotid artery treated with ancrod. Daily administration of aspirin significantly suppressed the thrombus formation in this model. These results indicate that occlusive thrombus formation accompanied by endothelial damage or dysfunction is induced by the combined application of ligation and cuff placement at the carotid artery, and suggest that this endothelial damage or dysfunction may be one pathogenesis of thrombogenesis in this model.

Serotonin is one of the oldest neurotransmitters in evolutionary terms, and the serotonergic system is complex and multifaceted. Serotonin-producing neurons in the raphe nuclei provide serotonin innervations throughout various parts of the brain, modulating cellular excitability and network properties of targeted brain areas, and regulating mood, cognition and behavior. Dysfunctions of the serotonergic system are implicated in neuropsychiatric disorders including depression, schizophrenia, and drug abuse. Although the system has been studied for many years, an integrative account of its functions and computational principles remains elusive. This is partly attributed to the high variability and heterogeneity in terms of neuronal properties and receptor types, and its extensive connections with other brain regions. This Frontiers Research Topic e-book is a collection of recent experimental and computational work and approaches at multiple scales that provide the latest information regarding the integrated functions of the serotonergic system. The contributed papers include a variety of experimental and computational work, and human clinical studies.

Choroidal neovascularization (CNV) is the main pathogenesis of age-related macular degeneration (AMD), which leads to severe vision loss in many aged patients in most advanced country. CNV compromises vision via hemorrhage and retinal detachment on account of pathological neovascularization penetrating the retina. Plasma medicine represents the medical application of ionized gas "plasma" that is typically studied in the field of physical science. Here we examined the therapeutic ability of plasma-activated medium (PAM) to suppress CNV. The effect of PAM on vascularization was assessed on the basis of human retinal endothelial cell (HREC) tube formation. In mice, laser photocoagulation was performed to induce CNV (laser-CNV), followed by intravitreal injection of PAM. N-Acetylcysteine was used to examine the role of reactive oxygen species in PAM-induced CNV suppression. Fundus imaging, retinal histology examination, and electroretinography (ERG) were also performed to evaluate PAM-induced retinal toxicity. Interestingly, HREC tube formation and laser-CNV were both reduced by treatment with PAM. N-acetylcysteine only partly neutralized the PAM-induced reduction in laser-CNV. In addition, PAM injection had no effect on regular retinal vessels, nor did it show retinal toxicity in vivo. Our findings indicate the potential of PAM as a novel therapeutic agent for suppressing CNV.

Recent studies have shown that frontoparietal cortices and interconnecting regions in the basal ganglia and the cerebellum are related to motor skill learning. We propose that motor skill learning occurs independently and in different coordinates in two sets of loop circuits: cortex–basal ganglia and cortex–cerebellum. This architecture accounts for the seemingly diverse features of motor learning.

Oxalate was synthesized in the glucose solution by irradiation with non-equilibrium atmospheric pressure plasma (NEAPP), in which the NEAPP plume contacted the solution surface, via the generation of several intermediate organic products such as gluconic acid. A thermodynamically unstable phase of calcium oxalate dihydrate crystallized rapidly during incubation of a NEAPP-irradiated glucose solution that contained calcium ions and was buffered at neutral pH. Longer irradiation times increased the growth rate and the number of seed crystals.

Ovarian clear cell carcinoma (CCC) is a histological type of epithelial ovarian cancer that is less responsive to chemotherapy and associated with a poorer prognosis than serous and endometrioid carcinoma. Non-thermal atmospheric pressure plasma which produces reactive species has recently led to an explosion of research in plasma medicine. Plasma treatment can be applied to cancer treatment to induce apoptosis and tumor growth arrest. Furthermore, recent studies have shown that a medium exposed to plasma also has an anti-proliferative effect against cancer in the absence of direct exposure to plasma. In this study, we confirmed whether this indirect plasma has an anti-tumor effect against CCC, and investigated whether this efficacy is selective for cancer cells. Non-thermal atmospheric pressure plasma induced apoptosis in CCC cells, while human peritoneal mesothelial cells remained viable. Non-thermal atmospheric pressure plasma exhibits selective cytotoxicity against CCC cells which are resistant to chemotherapy.

As one of the phylogenetically and ontogenetically oldest neurotransmitters, the monoamine serotonin (5-HT) is derived from tryptophan in neurons within the raphe nuclei, and innervates various parts of the nervous system (Jacobs and Azmitia, 1992). The serotonergic system is complex and can generate multifarious actions (Barnes and Sharp, 1999; Smythies, 2005). There are seven general families of serotonin receptors with multiple receptor subtypes, all of which are G protein-coupled receptors (GPCRs) except one (5-HT3 receptor), which is a ligand-gated ion channel, and these receptors can modulate the release of many major neurotransmitters such as glutamate, GABA, dopamine, acetylcholine, and norepinephrine (Barnes and Sharp, 1999; Smythies, 2005). It can also modulate neuronal excitability and network properties of many targeted brain areas, and regulate mood, cognition and behavior (Smythies, 2005). Dysfunctions of the serotonergic system are implicated in neuropsychiatric disorders including depression and schizophrenia (Muller and Jacobs, 2009). The serotonergic system has been the target of pharmaceuticals for decades, primarily to treat biological and neuropsychiatric disorders. These include antidepressants, antipsychotics, hallucinogens, antimigraine agents, and gastroprokinetic agents (Nichols and Nichols, 2008). Hence, the study of serotonin has high societal impacts. Although the serotonergic system has been studied for many years, an integrative account of its underlying functions remains elusive. This could be partly attributed to the high variability and heterogeneity in terms of neuronal properties and receptor subtypes, and its extensive connections with other brain regions. Indeed, it has been claimed that serotonin is in involved “in virtually everything, but responsible for nothing” (Jacobs and Fornal, 1995). While there have already been many excellent reviews and books on serotonin and related neural systems (e.g., Jacobs and Azmitia, 1992; Barnes and Sharp, 1999; Smythies, 2005; Muller and Jacobs, 2009), we hope that this collection of recent works provides a complementary and updated coverage of their diverse functions. In particular, unlike previous collections, neurobiologically based computational studies are included in this collection as we consider them to be important toward elucidating some of the underlying principles, especially at the systems level. Hence, we have made a concerted effort to invite both experimental and computational articles in this Research Topic. These works include original results, reviews, and hypothesis over multiple levels: from receptors and channels, to neuronal circuits and finally to behavior and neuropsychiatric disorders. At the receptor and cellular levels, Maejima et al. (2013) discussed various GPCRs and ion channels in the serotonin regulation and introduced optogenetic techniques that modulate intracellular signaling to more finely control the serotonergic systems for studies of their functions. The activation of the serotonin receptors was determined by its release and uptake dynamics. Unlike other more commonly studied neurotransmitters such as acetylcholine for example, the release and uptake dynamics of serotonin is not well characterized. Dankowski and Wightman (2013) reviewed the challenges and developments of fast-scan cyclic voltammetry to monitor serotonin at the subsecond (maybe millisecond) timescale in both in vitro and in vivo conditions. At the neuronal circuit level, Celada et al., 2013 provided a comprehensive review on cortical modulation of serotonin. In particular, the prefrontal cortex, linked to executive brain functions, seemed to form closed-loop interactions with the serotonin neurons in the dorsal raphe nucleus. This review was well complemented by biologically realistic computational modeling works of serotonin modulation on the prefrontal cortex. In Wang and Wong-Lin (2013), a biologically motivated model was developed to investigate how the co-modulation of serotonin and dopamine in the prefrontal cortex could result in complex, non-intuitive neuronal circuit dynamics, thus challenging current simpler theories on neuromodulation. Cano-Colino et al. (2013) incorporated serotonin modulation into an established computational model of the prefrontal cortex performing spatial working memory tasks. The model showed that excessive serotonin could impede task performance, and interestingly predicted that serotonin levels could affect neuronal memory fields. Besides the cortex, serotonin is also known to modulate important subcortical brain regions. Using a mathematical model of multiple brain regions, Reed et al. (2013) demonstrated the potential roles of serotonin in maintaining homeostasis in the basal ganglia (via the frontal cortex) under dopamine depletion (e.g., in Parkinson's disease). In Nakamura (2013), the neural circuit architecture of the dorsal raphe nucleus and other key subcortical brain regions involved in reward-based decision making and learning were discussed with emphasis on the neural circuit. The dorsal raphe nucleus has strong anatomical and functional connectivity with neighboring structures including the pendunculopontine tegmental nucleus (PPTg) and the locus coeruleus (LC), where many acetylcholine and noradrenergic neurons are found, respectively, (Koyama and Koyama, 1993; Martinez-Gonzalez et al., 2011). Indeed, Okada and Kobayashi (2013) showed that PPTg neurons exhibit similar tracking of future reward expectation as neurons in the dorsal raphe nucleus. Tsuruoka et al. (2012) reviewed the role of LC on pain control, which might be involved in aversive information processing. It has been proposed that reinforcement learning models can be used as a platform for studying neurological and neuropsychiatric disorders (Maia and Frank, 2011). In this collection, Herzallah et al. (2013) dissociated among depressed patients with and without antidepressant medication, and healthy control subjects by observing the performance in learning from positive (reward) and negative (punishment) feedback. Castro-Rodrigues and Oliveira-Maia (2013) provided a useful commentary on this important original work. Finally, the comprehensive review by Asher et al. (2013) proposed a closed-loop paradigm toward understanding serotonergic roles in decision making by involving behavioral experiments, game theory, computational modeling, and human–robotic interaction, a truly integrative neuroscience approach. We hope that this issue will provide a comprehensive review of the diverse and complex functions and computations of serotonergic and related systems at multiple scales of investigation. We wish that this will motivate and inspire a more integrative research approach from cellular to systems level toward understanding neuromodulatory systems.

Background Idiopathic ventricular tachycardia of left anterior fascicular origin (IVT-LAF) is a rare condition, and radiofrequency catheter ablation (RFCA) therapy has not been reported in children. Objective This study aimed to evaluate the procedures and outcomes of RFCA for pediatric IVT-LAF. Methods Pediatric IVT-LAF cases for which RFCA was performed between June 2006 and May 2012 at our hospital were reviewed. Results Of 537 pediatric cases of RFCA, 6 had IVT-LAF; 4 had anterior fascicular involvement only, while 2 had both anterior and posterior fascicular involvement. All 6 of them underwent RFCA at the median age of 8.8 years (range 4.3–14.3 years). RFCA was successful in all patients, but 4 had recurrence and underwent 1–3 additional sessions of RFCA. In a total of 10 RFCA sessions, the overall recurrence rate was 50%. The site of RFCA was determined on the basis of detection of diastolic potential during ventricular tachycardia (7 sessions) or isolated delayed potential during sinus rhythm (1) or by pace mapping (2). During the median follow-up period of 33 months, no further recurrence was reported except for 1 patient, who had a recurrence and was scheduled for additional session at the time of this report. Major complications included 1 case of complete atrioventricular block and 1 case of complete left bundle branch block. Conclusion Despite a high recurrence rate and a few complications, RFCA of the site of isolated delayed potential or diastolic potential, if applied cautiously, is a possible treatment of choice for pediatric IVT-LAF.

We previously demonstrated that the organization of a learned sequential movement, after long-term practice, is based on the entire sequence and that the information pertaining to the sequence is largely specific to the hand used for practice. However, it remained unknown whether these characteristics are present from the beginning of learning. To answer the question, we examined the performance of four monkeys for the same sequential procedure in the early stage of learning. The monkeys' task was to press five consecutive pairs of buttons (which were illuminated), in a correct order for every pair, which they had to find by trial-and-error during a block of trials. We first examined whether the memory of a sequential procedure that was learned once was specific to the hand used for practice. The second time that the monkeys attempted to learn a novel sequence, they were required to use either the same hand they used the first time or the opposite hand. The number of errors decreased to a similar degree in the same-hand condition and in the opposite-hand condition. The performance time decreased in the same-hand condition, but not in the opposite-hand condition. The results suggest that, in the early stage of learning, memory of the correct performance of a sequential procedure is not specific to the hand originally used to perform the sequence (unlike the well-learned stage, where the transfer was incomplete), whereas memory of the fast performance of a sequential procedure is relatively specific to the hand used for practice (like the well-learned stage). We then examined whether memory of a sequential procedure depends on the entire sequence, not individual stimulus sets. For the second learning block, we had the monkey learn the sequence in the same or reversed order. In the reversed order, the order within each set was identical, but the order of sets was reversed. The number of errors decreased in both the same-order and reversed-order conditions to a similar degree for two out of four monkeys; the decrease was larger in the same-order condition for the other two monkeys. For all monkeys, the performance time decreased in the same-order condition, but not in the reversed-order condition. The results suggest that the memory structure for correct performance varies among monkeys in the early stage of learning (unlike the well-learned stage, where the memory of individual sets was consistently absent). On the other hand, memory of the fast performance of a sequential procedure is relatively specific to the learned order used for practice (like the well-learned stage).

Recent studies have shown that multiple brain areas contribute to different stages and aspects of procedural learning. On the basis of a series of studies using a sequence-learning task with trial-and-error, we propose a hypothetical scheme in which a sequential procedure is acquired independently by two cortical systems, one using spatial coordinates and the other using motor coordinates. They are active preferentially in the early and late stages of learning, respectively. Both of the two systems are supported by loop circuits formed with the basal ganglia and the cerebellum, the former for reward-based evaluation and the latter for processing of timing. The proposed neural architecture would operate in a flexible manner to acquire and execute multiple sequential procedures.

To examine the role of the medial frontal cortex, supplementary motor area (SMA), and pre-SMA in the acquisition and control of sequential movements, we locally injected muscimol into 43 sites in the medial frontal cortex while monkeys (n = 2) performed a sequential button-press task. In this task, the monkey had to press two of 16 (4 × 4 matrix) buttons illuminated simultaneously in a predetermined order. A total of five pairs were presented in a fixed order for completion of a trial. To clarify the differential contribution of the medial frontal cortex for new acquisition and control of sequential movements, we used novel and learned sequences (that had been learned after extensive practice). We found that the number of errors increased for novel sequences, but not for learned sequences, after pre-SMA inactivations. A similar, but insignificant, trend was observed after SMA injections. The reaction time of button presses for both novel and learned sequences was prolonged by inactivations of both SMA and pre-SMA, with a trend for the effect to be larger for SMA inactivations. These findings suggest that the medial frontal cortex, especially pre-SMA, is related to the acquisition, rather than the storage or execution, of the correct order of button presses.

Kae Nakamura1, 2), Yoko Yoshida1), Shuichiro Yoshida1), Takeshi Sasaki2), Mitsuhiro Fujino2), Yuki Kawasaki2), Eiji Ehara2), Yosuke Murakami2), Shinichi Ito3), Shintaro Kishimoto4), and Tsugutoshi Suzuki1) 1) Department of Pediatric Electrophysiology, Osaka City General Hospital (OCGH), Osaka, Japan 2) Department of Pediatric Cardiology, Osaka City General Hospital (OCGH), Osaka, Japan 3) Ito Pediatric and Cardiology Clinic, Oita, Japan 4) Department of Pediatric Cardiology, Kurume University, Fukuoka, Japan

Four isomers of acetoxycineoles, (trans and cis)-2- and 3-acetoxy-1,8-cineoles, were identified as the odorous components of the rhizomes of greater galangal. Their structures were confirmed by comparing the retention indices by GC and the mass spectra with those of synthesized compounds. The concentration of trans-3-acetoxy-1,8-cineole was the highest among the isomers. The isomers presented individual odor features: the (trans and cis)-2 isomers respectively exhibited woody and sweet aromas, while the (trans and cis)-3 isomers respectively showed sweet floral and camphoraceous aromas. Of these, trans-2-acetoxy-1,8-cineole seemed to have the strongest qualitative effect on the characteristic flavor of greater galangal. Keywords: Alpinia galanga Willd.; greater galangal; rhizome; flavor component; trans-2-acetoxy-1,8-cineole; cis-2-acetoxy-1,8-cineole; trans-3-acetoxy-1,8-cineole; cis-3-acetoxy-1,8-cineole

Pharmacological experiments have shown that the modulation of brain serotonin levels has a strong impact on value-based decision making. Anatomical and physiological evidence also revealed that the dorsal raphé nucleus (DRN), a major source of serotonin, and the dopamine system receive common inputs from brain regions associated with appetitive and aversive information processing. The serotonin and dopamine systems also have reciprocal functional influences on each other. However, the specific mechanism by which serotonin affects value-based decision making is not clear. To understand the information carried by the DRN for reward-seeking behavior, we measured single neuron activity in the primate DRN during the performance of saccade tasks to obtain different amounts of a reward. We found that DRN neuronal activity was characterized by tonic modulation that was altered by the expected and received reward value. Consistent reward-dependent modulation across different task periods suggested that DRN activity kept track of the reward value throughout a trial. The DRN was also characterized by modulation of its activity in the opposite direction by different neuronal subgroups, one firing strongly for the prediction and receipt of large rewards, with the other firing strongly for small rewards. Conversely, putative dopamine neurons showed positive phasic responses to reward-indicating cues and the receipt of an unexpected reward amount, which supports the reward prediction error signal hypothesis of dopamine. I suggest that the tonic reward monitoring signal of the DRN, possibly together with its interaction with the dopamine system, reports a continuous level of motivation throughout the performance of a task. Such a signal may provide “reward context” information to the targets of DRN projections, where it may be integrated further with incoming motivationally salient information.

Epithelial ovarian carcinoma (EOC) is the leading cause of cancer-related death in women in Western countries. Once patients experience recurrence, complete cure is almost impossible. We elucidated the effect of nonequilibrium atmospheric pressure plasma on the growth of EOC, particularly in plasma-activated medium (PAM). Furthermore, we examined the role of reactive oxygen species (ROS) or their scavengers in chronic antineoplastic-resistant EOC cells. As a result, we showed PAM induced the antitumor effect of EOC cells in vitro and in vivo, even in chemoresistant cells. To apply the plasma treatment for advanced or recurrent EOC, we suggest adopting indirect plasma therapy instead of direct plasma considering intraperitoneal administration in the future. However, there are several problems under investigation, including intracellular mechanism of antitumor effect by PAM and adverse event in vivo.

PurposeNonequilibrium atmospheric pressure plasma (NEAPP) therapy has recently been focused on as a novel medical practice. Using cells with acquired paclitaxel/cisplatin resistance, we elucidated effects of indirect NEAPP-activated medium (NEAPP-AM) exposure on cell viability and tumor growth in vitro and in vivo.MethodsUsing chronic paclitaxel/cisplatin-resistant ovarian cancer cells, we applied indirect NEAPP-exposed medium to cells and xenografted tumors in a mouse model. Furthermore, we examined the role of reactive oxygen species (ROS) or their scavengers in the above-mentioned EOC cells.ResultsWe assessed the viability of NOS2 and NOS3 cells exposed to NEAPP-AM, which was prepared beforehand by irradiation with NEAPP for the indicated time. In NOS2 cells, viability decreased by approximately 30% after NEAPP-AM 120-sec treatment (PConclusionWe demonstrated that plasma-activated medium also had an anti-tumor effect on chemo-resistant cells in vitro and in vivo. Indirect plasma therapy is a promising treatment option for EOC and may contribute to a better patient prognosis in the future.

Octahedral particulates several tens of microns in size were synthesized in a culture medium irradiated through contact with a plume of non-equilibrium atmospheric-pressure plasma (NEAPP). The particulates were identified in the crystalline phase as calcium oxalate dihydrate (COD). The original medium contained constituents such as NaCl, d-glucose, CaCl2, and NaHCO3 but not oxalate or oxalic acid. The oxalate was clearly synthesized and crystallized in the medium as thermodynamically unstable COD crystals after the NEAPP irradiation.

Two independent ovarian cancer cell lines and fibroblast controls were treated with nonequilibrium atmospheric pressure plasma (NEAPP). Most ovarian cancer cells were detached from the culture dish by continuous plasma treatment to a single spot on the dish. Next, the plasma source was applied over the whole dish using a robot arm. In vitro cell proliferation assays showed that plasma treatments significantly decreased proliferation rates of ovarian cancer cells compared to fibroblast cells. FACS and Western blot analysis showed that plasma treatment of ovarian cancer cells induced apoptosis. NEAPP could be a promising tool for therapy for ovarian cancers.

Objective Matrix metalloproteinases (MMPs) have been implicated in the process of vascular calcification. However, the exact roles of individual MMPs in vascular calcification are poorly understood. To study the putative role of MMP-2 in atherogenic calcification in vivo and in vitro , we investigate whether or not MMP-2 deficiency affects aortic atherosclerotic calcification in apolipoprotein E-deficient (Apoe −/− ) mice and cultured smooth muscle cell (SMC) calcification. Methods and results The area of calcified lesions in aortic intima was significantly larger in MMP-2 +/+ Apoe −/− mice at 45 and 60 weeks of age than in MMP-2 −/− Apoe −/− mice. In these aortic calcified atherosclerotic lesions, the expression of type II collagen, osteoprotegerin, bone morphogenetic protein (BMP)-2 and osteocalcin which are chondrocyte maker and bone-related proteins, was observed. MMP-2 deficiency reduced BMP-2 and osteocalcin expression in aortae in Apoe −/− mice at 30 weeks and 45–60-weeks-old, respectively. The expressions of MMP-2 and that of α-SMC actin were observed in chondrocyte-like cells of calcified lesions. Beta-glycerophosphate administration induced calcium deposition in MMP-2 +/+ aorta-derived cultured SMCs, and this calcium deposition was significantly suppressed in MMP-2 −/− aorta-derived cultured SMCs. Conclusions These results suggest that MMP-2 may contribute to the mechanisms of calcification associated with atherosclerosis.

Consultation-liaison (C-L) psychiatry has been developing for the past 10 years as a new clinical service field in Japan. Although this kind of service had been practiced previously, it was not recognized as an independent clinical field. Still in the developing phase, clinical research in C-L psychiatry has been reported, although its quality has been variable. The authors describe the development and a typology of C-L psychiatry (seven types) in Japan. This article reports time spent on C-L psychiatry activity in a general hospital. Although C-L psychiatry requires much time and labor, hardly any of the C-L psychiatry services are reimbursed in the Japanese insurance system. The authors propose a “new department” as one option to continue providing C-L psychiatry service to general hospital patients and for further development of C-L psychiatry in Japan.

1. Matrix metalloproteinases (MMP) are associated with the vascular remodelling seen in atherosclerosis and aneurysm. The activation and activity of MMP-2 are regulated by the intrinsic tissue inhibitor of MMP-2 (TIMP-2). The aim of the present study was to examine whether, conversely, MMP-2 can affect the gene and protein expression of TIMP-2. 2. In the present study, we examined the mRNA and protein expression of MMP-2 and TIMP-2 in cultured smooth muscle cells (SMC) from the aortas of MMP-2(+/+) and MMP-2(-/-) mice. We also examined the roles of MMP-2 in SMC cellular events. 3. Western blotting showed that less TIMP-2 protein was present in the conditioned medium of MMP-2(-/-) SMC than in that of MMP-2(+/+) SMC. Real-time reverse transcription polymerase chain reaction analysis showed that MMP-2 deficiency reduced TIMP-2 mRNA expression in SMC. Recombinant MMP-2 enhanced the expression of TIMP-2 protein in cultured SMC from MMP-2(-/-) mice. Furthermore, a siRNA targeting MMP-2 impaired the gene and protein expression of MMP-2 in cultured SMC from MMP-2(+/+) mice. MMP-2 deficiency impaired SMC invasion, but not their proliferation, adhesion or migration. 4. Our findings suggest that MMP-2 is likely to be responsible, at least in part, for regulating TIMP-2 expression and is thus a potential target, in addition to TIMP-2, for therapeutics aimed at preventing cardiovascular remodelling in response to injury.

Item does not contain fulltext Serotonin, like dopamine (DA), has long been implicated in adaptive behavior, including decision making and reinforcement learning. However, although the two neuromodulators are tightly related and have a similar degree of functional importance, compared with DA, we have a much less specific understanding about the mechanisms by which serotonin affects behavior. Here, we draw on recent work on computational models of dopaminergic function to suggest a framework by which many of the seemingly diverse functions associated with both DA and serotonin-comprising both affective and activational ones, as well as a number of other functions not overtly related to either-can be seen as consequences of a single root mechanism.

Background— Exercise stimulates the vascular response in pathological conditions, including ischemia; however, the molecular mechanisms by which exercise improves the impaired hypoxia-induced factor (HIF)-1α–mediated response to hypoxia associated with aging are poorly understood. Here, we report that swimming training (ST) modulates the vascular response to ischemia in aged (24-month-old) mice. Methods and Results— Aged wild-type mice (MMP-2 +/+ ) that maintained ST (swimming 1 h/d) from day 1 after surgery were randomly assigned to 4 groups that were treated with either vehicle, LY294002, or deferoxamine for 14 days. Mice that were maintained in a sedentary condition served as controls. ST increased blood flow, capillary density, and levels of p-Akt, HIF-1α, vascular endothelial growth factor, Fit-1, and matrix metalloproteinase-2 (MMP-2) in MMP-2 +/+ mice. ST also increased the numbers of circulating endothelial progenitor cells and their function associated with activation of HIF-1α. All of these effects were diminished by LY294002, an inhibitor of phosphatidylinositol 3-kinase; enhanced by deferoxamine, an HIF-1α stabilizer; and impaired by knockout of MMP-2. Finally, bone marrow transplantation confirmed that ST enhanced endothelial progenitor cell homing to ischemic sites in aged mice. Conclusions— ST can improve neovascularization in response to hypoxia via a phosphatidylinositol 3-kinase–dependent mechanism that is mediated by the HIF-1α/vascular endothelial growth factor/MMP-2 pathway in advanced age.

Nitroalkene derivatives of nitro-linoleic acid (LNO 2 ) and nitro-oleic acid (OA-NO 2 ) are nitrated unsaturated fatty acids that can be detected in healthy human plasma, red blood cells and urine. It has been shown that nitroalkenes have potent anti-inflammatory properties in multiple disease models. In the present study, we are the first to investigate the apoptotic effects of nitroalkenes in rat aortic smooth muscle cells (RASMCs). We observed that nitroalkenes induce RASMCs apoptosis in a dose-dependent manner. In addition, nitroalkenes stimulate extrinsic caspase-8 and intrinsic caspase-9 activity to trigger the caspase-3 apoptotic signaling cascade, resulting in RASMCs death. Furthermore, the pro-apoptotic protein, Bad was upregulated and antiapoptotic protein, Bcl-xl was downregulated during nitroalkene-induced apoptosis. These results demonstrate that nitroalkenes can induce RASMCs apoptosis via stimulation of caspase activity and the regulation of apoptotic protein expression levels.

Pd/Co multilayer films were prepared by rf sputtering, with a buffer layer of Pt, Pd, Cu or SiAlON between the multilayer film and the glass substrate. The type of buffer layer was found to have an effect on the structure as well as the perpendicular magnetic anisotropy and coercive force of the multilayer film. A Pt buffer layer improves the layer structure and ≪111≫ orientation, as well as increasing the anisotropy, while SiAlON and Cu do not improve the layer structure but do increase the coercivity.

Lysosomal protease cathepsin (Cat) overexpressed in atherosclerotic lesions has a strong proteolytic activity. Given that reactive oxygen species (ROS) are also implicated in protease activation in atherogenesis, we examined a possible role of the ROS-induced cathepsin activation system in neointima formation and atherosclerotic plaque in stability. Murine vascular injury-induced neointima formation was examined by use of a carotid artery ligation model, which demonstrated that cathepsin K deficiency impaired neointima formation and that cystatin C deficiency enhanced it (9-week-old males; n = 18 for each group, P< 0.01). To examine statin-mediated pleiotropic actions on neointima formation and plaque stability, a mouse plaque disruption model (a combination of ligation and cuff placement treatment) was applied to apoE-deficient mice (9-week-old males). The apoE-deficient mice (n = 24–30 for each group) maintained on a normal diet were treated with (1) vehicle (0.5% carboxymethyl cellulose), pitavastatin (1 mg/kg/d), pitavastatin (10 mg/kg/d) for 10 days (before and after cuff treatment; all given by oral gavage every day). Pitavastatin suppressed not only macrophage infiltration but also levels of NADPH oxidase component mRNAs (p22 phox and gp91 phox ) and O2-production in the atherosclerotic lesions. Moreover, pitavastatin increased the collagen fraction and reduced media elastic lamina fragmentation concomitant with decreases in the levels of cathepsin K mRNA and protein. Among these beneficial effects, high doses of pitavastatin further reduced intraplaque hemorrhage. The pitavastatin-mediated vascular-protective effects were mimicked by cathepsin K deficiency in apoE-deficient mice. Pitavastatin lowered the serum levels of cathepsin K but not plasma lipid profile. Pitavastatin inhibited H 2 O 2 -induced Cat K expression and activity in cultured smooth muscle cells and macrophages. Cathepsin K deficiency suppressed vascular injury-induced neointima formation. The data suggested that short-term administration of statin attenuates neointima formation and atherosclerotic plaque stability at least in part by inhibiting the oxidative stress-dependent Cat activation system.

The dopamine system has been thought to play a central role in guiding behavior based on rewards. Recent pharmacological studies suggest that another monoamine neurotransmitter, serotonin, is also involved in reward processing. To elucidate the functional relationship between serotonin neurons and dopamine neurons, we performed single-unit recording in the dorsal raphe nucleus (DRN), a major source of serotonin, and the substantia nigra pars compacta, a major source of dopamine, while monkeys performed saccade tasks in which the position of the target indicated the size of an upcoming reward. After target onset, but before reward delivery, the activity of many DRN neurons was modulated tonically by the expected reward size with either large- or small-reward preference, whereas putative dopamine neurons had phasic responses and only preferred large rewards. After reward delivery, the activity of DRN neurons was modulated tonically by the received reward size with either large- or small-reward preference, whereas the activity of dopamine neurons was not modulated except after the unexpected reversal of the position–reward contingency. Thus, DRN neurons encode the expected and received rewards, whereas dopamine neurons encode the difference between the expected and received rewards. These results suggest that the DRN, probably including serotonin neurons, signals the reward value associated with the current behavior.

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