Addition of small amounts of NaCl or soy sauce on dashi enhances its palatability to a great extent. Here we hypothesized that NaCl enhances umami taste caused by monosodium L-glutamate (MSG) in humans. Fifteen healthy university students were used for sensory evaluations. MSG at 0.3% was employed as the basic standard solution (S0). Other 5 standard solutions were prepared with increased concentrations of 1.3-fold steps. Umami intensity and palatability of various salts on S0 (S0 + salts) were evaluated by comparing with 6 standard solutions. NaCl enhanced both umami intensity and palatability of MSG in a concentration-dependent manner. Other Na+ salts (Na2SO4, NaHCO3) on a molar basis also enhanced both umami intensity and palatability comparable to NaCl. The Cl- salts (MgCl2, CaCl2, KCl) showed only modest to weak enhancement of umami intensity with no increase in palatability. These results suggest there are Na+-dependent enhancing mechanisms for umami taste in humans.

1. Exposure to 1-100% dashi enhanced subsequent dried bonito dashi preference. 2. Exposure to reconstituted dashi also enhanced subsequent dashi preference. 3. Exposure to 0.1% IMP produced modest enhancement of subsequent dashi preference. 4. Exposure to neither NaCl, MSG, histidine, lactic acid, nor glucose were effective. 5. IMP is a key substance that produces experience-based enhancement of preference..

Dioxins have been suggested to induce inflammation in the intestine and brain and to induce neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), partly due to deficits in parvalbumin-positive neurons in the brain that are sensitive to inflammatory stress. Previously, we reported ADHD traits with increased aggressiveness in children with prenatal exposure to dioxins in Vietnam, whereas dried bonito broth (DBB) has been reported to suppress inflammation and inhibit aggressive behavior in animal and human studies. In the present study, we investigated the association between dioxin exposure and the prevalence of children with highly aggressive behaviors (Study 1), as well as the effects of DBB on the prevalence of children with highly aggressive behaviors (Study 2). METHODS: In Study 1, we investigated the effects of dioxin exposure on the prevalence of children with high aggression scores, which were assessed using the Children's Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP) in dioxin-contaminated areas. The data were analyzed using a logistic regression model after adjusting for confounding factors. In Study 2, we performed nutritional intervention by administering DBB for 60 days to ameliorate the aggressiveness of children with high scores on the C-SHARP aggression scale. The effects of DBB were assessed by comparing the prevalence of children with high C-SHARP scores between the pre- and post-intervention examinations. RESULTS: In Study 1, only the prevalence of children with high covert aggression was significantly increased with an increase in dioxin exposure. In Study 2, in the full ingestion (>80% of goal ingestion volume) group, the prevalence of children with high covert aggression associated with dioxin exposure was significantly lower in the post-ingestion examination compared with in the pre-ingestion examination. However, in other ingestion (<20% and 20-79%) groups and a reference (no intervention) group, no difference in the prevalence of children with high covert aggression was found between the examinations before and after the same experimental period. CONCLUSIONS: The findings suggest that DBB ingestion may ameliorate children's aggressive behavior, which is associated with perinatal dioxin exposure.

Dried bonito dashi is a traditional Japanese fish broth that enhances palatability of various dishes due to its specific flavor. The present study examined influences of dietary fat levels (10% vs. 45% fat), presentation order of dried bonito dashi (ascending vs. descending concentrations), and prior experience with dashi on subsequent dashi intake and preference using two-bottle choice tests in two rodent strains, Sprague-Dawley (SD) rats and C57BL/6 N (B6N) mice. In the ascending concentration tests, SD rats on a low fat diet preferred 10-100% dashi to water, whereas B6N mice showed a blunted preference for dashi. Consumption of a high fat diet reduced dashi preference in SD rats. The B6N mice on the high fat diet never preferred dashi at any concentration. In the descending concentration tests, SD rats on the low fat diet preferred dashi over a wide range (0.03-100% dashi). The B6N mice showed a trend similar to that of SD rats. Ingestion of the high fat diet in both strains reduced dashi preference in the descending concentration tests. However, introduction of the high fat diet to dashi experienced rats maintained on the low fat diet, reduced neither dashi intake nor dashi preference. Dashi intake affected neither high fat diet intake, caloric intake, nor preference for high fat diet. These results suggest that preference for dried bonito dashi is influenced at least by 1) dietary fat levels, 2) presentation order of dashi, and 3) prior experience with dashi.

ABSTRACTObjectives: Dried bonito dashi, a traditional Japanese fish broth made from dried bonito tuna, enhances food palatability due to its specific umami flavor characteristics. However, the pattern of brain activation following dashi ingestion has not been previously investigated. Methods: We mapped activation sites of the rat brain after intragastric loads of dried bonito dashi by measuring neuronal levels of the Fos protein, a functional marker of neuronal activation. Results: Compared to intragastric saline, intragastric dashi administration produced enhanced Fos expression in four forebrain regions: the medial preoptic area, subfornical organ, habenular nucleus, and central nucleus of the amygdala. Interestingly, the medial preoptic area was found to be the only feeding-related hypothalamic area responsive to dashi administration. Moreover, dashi had no effect in the nucleus accumbens and ventral tegmental area, two connected sites known to be activated by highly palatable sugars and fats. In the hindbrain, dashi administration produced enhanced Fos expression in both visceral sensory (caudal nucleus of the solitary tract, dorsal part of the lateral parabrachial nucleus, and area postrema) and autonomic (rostral ventrolateral medulla, and caudal ventrolateral medulla) sites. Discussion: The results demonstrate the activation of discrete forebrain and hindbrain regions following intragastric loads of dried bonito dashi. Our data suggest that the gut-brain axis is the principal mediator of the postingestive effects associated with the ingestion of dashi.

Dried bonito dashi is often used in Japanese cuisine with a number of documented positive health effects. Its major taste is thought to be umami, elicited by inosine 5'-monophosphate (IMP) and L-amino acids. Previously we found that lactic acid, a major component of dried bonito dashi, enhanced the contribution of many of these amino acids to the taste of dried bonito dashi, and reduced the contribution of other amino acids. In addition to amino acids, dried bonito dashi also has a significant mineral salt component. The present study used conditioned taste aversion methods with mice (all had compromised olfactory systems) to compare the taste qualities of dried bonito dashi with four salts (NaCl, KCl, CaCl2 and MgCl2), with and without lactic acid or citric acid. A conditioned taste aversion to 25% dried bonitio dashi generalized significantly to NaCl and KCl, with or without 0.9% lactic acid added but not when citric acid was added. Generalization of the CTA to dried bonito dashi was much stronger to the divalent salts, but when either lactic acid or citric acid was added, this aversion was eliminated. These results suggest that these salts contribute to the complex taste of dried bonito dashi and that both organic acids appear able to modify the tastes of divalent salts.

OBJECTIVES: Emerging evidence suggests that traditional diets and nutrition have a significant impact on brain development, and could contribute to the promotion of mental health and prevention of psychiatric disorders in children and adolescents. Moreover, deficits in parvalbumin (PV)-immunoreactive and/or GABAergic neurons are closely associated with various psychiatric disorders in children and adolescents. To investigate the possible neural mechanisms of diet involvement in mental health, we analyzed the effects of dried-bonito dashi (Japanese fish broth) (DBD) on PV-immunoreactive neurons and emotional behaviors in young mice. METHODS: Male mice after weaning were fed DBD for 60 days, and tested with a resident-intruder test for aggressiveness and a forced swimming test for depression-like symptoms. After the behavioral testing, PV-immunoreactive neurons in the brain were immunohistochemically analyzed. RESULTS: The results indicated that DBD intake decreased aggressiveness and depression-like symptoms, and increased the densities of PV-immunoreactive neurons in the medial prefrontal cortex (mPFC), amygdala, hippocampus, and superior colliculus. These behavioral changes were correlated with the densities of PV-immunoreactive neurons in the mPFC, amygdala, and hippocampus. However, subdiaphragmatic vagotomy did not affect the effects of DBD on emotional behaviors, although it nonspecifically decreased the densities of PV-immunoreactive neurons. DISCUSSION: The results suggest that DBD might modulate emotional behaviors by promoting PV-immunoreactive and/or GABAergic neuronal activity through parallel routes. The present results highlight a new mechanism for diet involvement in brain functions, and suggest that DBD might have therapeutic potential for the promotion of mental health.

Previous behavioral studies have suggested that l-glutamate, an umami substance, is detected in the gut, and that this information regarding glutamate is conveyed from the gut to the amygdala and the lateral hypothalamus (LH) through the vagus nerve to establish glutamate preference. In this study, we investigated the roles of the amygdala and LH in the information processing of gut glutamate. We recorded the activity of amygdalar and LH neurons during the intragastric administration of five test solutions (monosodium l-glutamate [MSG, 60 mmol/L]; inosine monophosphate [IMP, 60 mmol/L]; a mixture of MSG and IMP; NaCl [60 mmol/L]; or physiological saline) in intact and subdiaphragmatic vagotomized awake rats. In intact rats, 349 and 189 neurons were recorded from the amygdala and LH, respectively, while in vagotomized rats, 104 and 90 neurons were recorded from the amygdala and LH, respectively. In intact rats, similar percentages of neurons (30-60%) in the amygdala and LH responded to the intragastric infusion of the solutions. Vagotomy significantly altered responses to the MSG and NaCl solutions. In particular, vagotomy suppressed the inhibitory responses to the NaCl solution. Furthermore, vagotomy increased the response similarity between the MSG and NaCl solutions, suggesting that vagotomy impaired the coding of the postingestive consequences of the MSG solution in the amygdala and LH, which are unique for glutamate. The present results provide the first neurophysiological evidence that amygdalar and LH neurons process glutamate signals from the gut.

Dried bonito dashi, a traditional Japanese fish stock, enhances palatability of various dishes because of its specific flavor. Daily intake of dashi has also been shown to improve mood status such as tension-anxiety in humans. This study aimed at investigating beneficial effects of dashi ingestion on anxiety/depression-like behaviors and changes in amino acid levels in the brain and plasma in rats. Male Wistar rats were given either dried bonito dashi or water for long-term (29 days; Experiment 1) or single oral administration (Experiment 2). Anxiety and depression-like behaviors were tested using the open field and forced swimming tests, respectively. Concentrations of amino acids were measured in the hippocampus, hypothalamus, cerebellum, and jugular vein. During the long-term (29 days) consumption, rats given 2% dashi frequently entered the center zone and spent more time compared with the water controls in the open field test. However, the dashi was ineffective on depression-like behavior. In the hippocampus, concentrations of hydroxyproline, anserine, and valine were increased by dashi while those of asparagine and phenylalanine were decreased. In the hypothalamus, the methionine concentration was decreased. In a single oral administration experiment, the dashi (1%, 2% or 10%) showed no effects on behaviors. Significance was observed only in the concentrations of α-aminoadipic acid, cystathionine, and ornithine in the hippocampus. Dried bonito dashi is a functional food having anxiolytic-like effects. Daily ingestion of the dashi, even at lower concentrations found in the cuisine, reduces anxiety and alters amino acid levels in the brain.

The primary taste of dried bonito dashi is thought to be umami, elicited by inosine 5'-monphosphate (IMP) and L-amino acids. The present study compared the taste qualities of 25% dashi with 5 basic tastes and amino acids using conditioned taste aversion methods. Although wild-type C57BL/6J mice with compromised olfactory systems generalized an aversion of dashi to all 5 basic tastes, generalization was greater to sucrose (sweet), citric acid (sour), and quinine (bitter) than to NaCl (salty) or monosodium L-glutamate (umami) with amiloride. At neutral pH (6.5-6.9), the aversion generalized to l-histidine, L-alanine, L-proline, glycine, L-aspartic acid, L-serine, and monosodium L-glutamate, all mixed with IMP. Lowering pH of the test solutions to 5.7-5.8 (matching dashi) with HCl decreased generalization to some amino acids. However, adding lactic acid to test solutions with the same pH increased generalization to 5'-inosine monophosphate, L-leucine, L-phenylalanine, L-valine, L-arginine, and taurine but eliminated generalization to L-histidine. T1R1 knockout mice readily learned the aversion to dashi and generalized the aversion to sucrose, citric acid, and quinine but not to NaCl, glutamate, or any amino acid. These results suggest that dashi elicits a complex taste in mice that is more than umami, and deleting T1R1 receptor altered but did not eliminate their ability to taste dashi. In addition, lactic acid may alter or modulate taste transduction or cell-to-cell signaling.

Chronic hyperglycemia has deleterious effects on pancreatic β-cell function, a process known as glucotoxicity. This study examined whether chronic high glucose (CHG) induces cellular hypoxia in rat INS-1 β cells, and whether hyperoxia (35% O2) can reverse glucotoxicity-induced inhibition of insulin secretion. CHG (33.3 mm, 96 h) reduced insulin secretion, and down-regulated insulin and pancreatic duodenal homeobox factor 1 gene expression. CHG also increased intracellular pimonidazole-protein adducts, a marker for hypoxia. CHG also enhanced hypoxia-inducible factor 1α (HIF-1α) protein expression and its DNA-binding activity, which was accompanied by a decrease in mRNA expression of glucose transporter 2 (GLUT2), glucokinase and uncoupling protein-2 and an increase in mRNA expression of GLUT1 and pyruvate dehydrogenase kinase 1. Hyperoxia restored the decrease in insulin secretion and the gene expression except for GLUT2, and suppressed intracellular hypoxia and HIF-1α activation. These results suggest that glucotoxicity may cause β-cell hypoxia. Hyperoxia might prevent glucotoxicity-induced β-cell dysfunction and improve insulin secretion.

The flavor of dashi, the broth prepared from dried bonito tuna, is attractive to humans and rodents. The present experiments examined the ability of dashi to serve as an oral and/or postoral rewarding stimulus for conditioned flavor preferences in mice. In Experiment 1, C57BL/6J (B6) mice were infused intragastrically with dashi when they consumed a conditioned stimulus (CS)+ flavor and with water when they drank a CS- flavor on alternate days. Postoral dashi did not condition a CS+ preference. The combined effects of oral and postoral dashi exposure were examined in Experiment 2, in which B6 mice consumed a CS+ flavored dashi solution and CS- flavored water on alternate days. The mice did not prefer the CS+ to CS- when both flavors were presented in water. Yet, the B6 mice in both experiments preferred dashi to water in oral tests. Experiment 3 showed that taste-impaired Trpm5 knockout (KO) mice did not learn to prefer dashi after exposure to it, in contrast to previous findings with the umami prototype monosodium glutamate. This was not due to an inability to taste dashi, because Trpm5 KO mice learned a strong preference for dashi after it was mixed with glucose. The impact of dashi on reward may largely reflect an enhancement of association of oral and postoral effects of food.

Taste components in liquid released from salt-pickled suguki (Brassica rapa var. neosuguki; a traditional vegetable in Kyoto, Japan) were analyzed to clarify why the liquid is tasty. The liquid contained an approximately 4-fold higher amount of glutamate (an umami substance) than that in kelp dashi (broth) or other kinds of dashi. However, the liquid from salt-pickled giant turnips (Brassica rapa; omi-kabura) as a control also contained a comparable amount of glutamate to that from pickled suguki, suggesting that components other than glutamate would differentiate the palatability between liquids from pickled suguki and pickled turnips. Compared with pickled turnip liquid, pickled suguki liquid contained significantly higher amounts of sweet amino acids, total amino acids, lactate and minerals such as Ca, Mg, Fe, and inorganic phosphorus. Stimulation of gustatory sweet and sour receptors and extracellular calcium-sensing receptors by these components may produce the well-balanced sweetness, sourness and kokumi of pickled suguki liquid.

Tocotrienols, members of the vitamin E family, have been shown to possess anti-inflammatory properties and display activity against a variety of chronic diseases, such as cancer, cardiovascular and neurological diseases. However, whether tocotrienols contribute to the prevention of inflammatory responses in adipose tissue remains to be elucidated. In this study, we examined the effects of γ-tocotrienol, the most common tocotrienol isomer, on tumor necrosis factor-α (TNF-α)-induced inflammatory responses by measuring the expression of the adipokines, monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and adiponectin in 3T3-L1 adipocytes. Exposure to TNF-α (10 ng/ml) for 24 h increased MCP-1 and IL-6 secretion, and decreased adiponectin secretion and peroxisome proliferator-activated receptor-γ (PPARγ) mRNA expression. γ-tocotrienol effectively improved the TNF-α-induced adverse changes in MCP-1, IL-6 and adiponectin secretion, and in MCP-1, IL-6, adiponectin and PPARγ mRNA expression. Furthermore, TNF-α-mediated IκB-α phosphorylation and nuclear factor-κB (NF-κB) activation were significantly suppressed by the γ-tocotrienol treatment. Our results suggest that γ-tocotrienol may improve obesity-related functional abnormalities in adipocytes by attenuating NF-κB activation and the expression of inflammatory adipokines.

Neuroanatomical studies suggest that hippocampal formation (HF) receives information from all sensory modalities including taste via the parahippocampal cortices. To date, however, no neurophysiological study has reported that HF neurons encode taste information. In the present study, we recorded CA1 HF neurons from freely behaving rats during performance of a visually-guided licking task in two different triangular chambers. When a cue lamp came on, the rats were required to press a bar to trigger a tube to protrude into the chambers for 3 s. During this period, the rats could lick one of six sapid solutions: [0.1M NaCl (salty), 0.3M sucrose (sweet), 0.01 M citric acid (sour), 0.0001 M quinine HCl (bitter), 0.01 M monosodium L-glutamate (MSG, umami), and a mixture of MSG and 0.001 M disodium-5'-inosinate (IMP) (MSG+IMP)], and distilled water. Of a total 285 pyramidal and interneurons, the activity of 173 was correlated with at least one of the events in the task-illumination of cue lamps, bar pressing, or licking the solution. Of these, 137 neurons responded during licking, and responses of 62 of these cells were greater to sapid solutions than to water (taste neurons). Multivariate analyses of the taste neurons suggested that, in the HF, taste quality might be encoded based on hedonic value. Furthermore, the activity of most taste neurons was chamber-specific. These results implicate the HF in guiding appetitive behaviors such as conditioned place preference.

Recent studies suggest the protective effects of adrenomedullin (AM) on ischemic brain damage. The present study was aimed at investigating the effects of AM and its receptor antagonist, AM₂₂₋₅₂, on ischemia-induced cerebral edema and brain swelling in rats using magnetic resonance imaging. Rats were subjected to 60 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. Intravenous injection of AM (1.0 μg/kg), AM₂₂₋₅₂ (1.0 μg/kg), or saline was made before MCAO. Effects of AM injection just after reperfusion were also investigated. One day after ischemia, increases in T₂-weighted signals in the brain were clearly observed. Total edema volume, as well as brain swelling, was greatly and significantly reduced by pre-treatment of AM (reduced by 53%). Extent of brain swelling was significantly correlated with the volume of cerebral edema. The protective effect of AM against edema was more clearly observed in the cerebral cortex (reduced by 63%) than the striatum (reduced by 31%). Increased T₂ relaxation time in the cortex was recovered partially by pre-treatment of AM. Post-treatment of AM had no effects. Pre-treatment of AM₂₂₋₅₂ tended to exacerbate the edema. In another line of experiment, cocktail administration of AM with melatonin, a pineal product having neuroprotective potential as a free radical scavenger, failed to enhance the protective effects of AM alone. The present study clearly suggests the prophylactic effects of AM against cerebral edema, especially the cortical edema, in a rat stroke model.

Although the umami compound monosodium glutamate (MSG) is a widely used flavor enhancer, controversy still persists regarding the effects of MSG intake on body weight. It has been claimed, in particular, that chronic MSG intake may result in excessive body weight gain and obesity. In this study we assessed the effects of chronic (16 weeks) ad libitum MSG on body weight and metabolism of C57BL6/J mice. Adult male mice were divided in four experimental groups and fed with either a low-fat (LF) or high-fat (HF) diet and with either two bottles of plain water or one bottle containing 1% MSG and another one containing water according to a factorial design. Mice were monitored weekly for body weight and food/fluid intake for 15 weeks. At the end of the experiments, the circulating levels of leptin, insulin, total protein, total cholesterol, triglyceride, blood urea nitrogen, and non-esterified fatty acids were also analyzed. Our results show that MSG intake did not influence body weight in either LF or HF groups. Interestingly, although animals overall displayed strong preferences for MSG against water, preferences were relatively higher in LF compared to HF group. Consistent with the body weight data, while significant differences in leptin, insulin, total cholesterol, and non-esterified fatty acids were found between HF and LF groups, such an effect was not influenced by MSG intake. Finally, indirect calorimetry measurements revealed similar energy expenditure levels between animals being presented water only and MSG only. In summary, our data does not support the notion that ad libitum MSG intake should trigger the development of obesity or other metabolic abnormalities.

Intravenous administration of arginine was shown to be protective against cerebral ischemic insults via nitric oxide production and possibly via additional mechanisms. The present study aimed at evaluating the neuroprotective effects of oral administration of lysine (a basic amino acid), arginine, and their combination on ischemic insults (cerebral edema and infarction) and hemispheric brain swelling induced by transient middle cerebral artery occlusion/reperfusion in rats. Magnetic resonance imaging and 2,3,5-triphenyltetrazolium chloride staining were performed 2 days after ischemia induction. In control animals, the major edematous areas were observed in the cerebral cortex and striatum. The volumes associated with cortical edema were significantly reduced by lysine (2.0 g/kg), arginine (0.6 g/kg), or their combined administration (0.6 g/kg each). Protective effects of these amino acids on infarction were comparable to the inhibitory effects on edema formation. Interestingly, these amino acids, even at low dose (0.6 g/kg), were effective to reduce hemispheric brain swelling. Additionally, the effects of in vivo microiontophoretic (juxtaneuronal) applications of these amino acids on glutamate-evoked neuronal activity in the ventromedial hypothalamus were investigated in awake rats. Glutamate-induced neuronal activity was robustly inhibited by microiontophoretic applications of lysine or arginine onto neuronal membranes. Taken together, our results demonstrate the neuroprotective effects of oral ingestion of lysine and arginine against ischemic insults (cerebral edema and infarction), especially in the cerebral cortex, and suggest that suppression of glutamate-induced neuronal activity might be the primary mechanism associated with these neuroprotective effects.

l-Glutamate is a multifunctional amino acid involved in taste perception, intermediary metabolism, and excitatory neurotransmission. In addition, recent studies have uncovered new roles for l-glutamate in gut-brain axis activation and energy homeostasis. l-Glutamate receptors and their cellular transduction molecules have recently been identified in gut epithelial cells. Stimulation of such l-glutamate receptors by luminal l-glutamate activates vagal afferent nerve fibers and then parts of the brain that are targeted directly or indirectly by these vagal inputs. Notably, 3 areas of the brain-the medial preoptic area, the hypothalamic dorsomedial nucleus, and the habenular nucleus-are activated by intragastric l-glutamate but not by glucose or sodium chloride. Furthermore, the chronic, ad libitum ingestion of a palatable solution of monosodium l-glutamate (1% wt:vol) by rats has also been found to reduce weight gain, fat deposition, and plasma leptin concentrations compared with rats that ingest water alone. No difference in food intake was observed. Such effects may also be vagally mediated. Together, such findings contribute to the growing knowledge base that indicates that l-glutamate signaling via taste and gut l-glutamate receptors may influence multiple physiologic functions, such as thermoregulation and energy homeostasis.

BACKGROUND & AIMS: The gut-brain axis, which transmits nutrient information from the gastrointestinal tract to the brain, is important for the detection of dietary nutrients. We used functional magnetic resonance imaging of the rat forebrain to investigate how this pathway conveys nutrient information from the gastrointestinal tract to the brain. METHODS: We investigated the contribution of the vagus nerve by comparing changes of blood oxygenation level-dependent signals between 24 control rats and 22 rats that had undergone subdiaphragmatic vagotomy. Functional data were collected under alpha-chloralose anesthesia continuously 30 minutes before and 60 minutes after the start of intragastric infusion of L-glutamate or glucose. Plasma insulin, L-glutamate, and blood glucose levels were measured and compared with blood oxygenation level-dependent signals. RESULTS: Intragastric administration of L-glutamate or glucose induced activation in distinct forebrain regions, including the cortex, hypothalamus, and limbic areas, at different time points. Vagotomy strongly suppressed L-glutamate-induced activation in most parts of the forebrain. In contrast, vagotomy did not significantly affect brain activation induced by glucose. Instead, blood oxygenation level-dependent signals in the nucleus accumbens and amygdala, in response to gastrointestinal glucose, varied along with fluctuations of plasma insulin levels. CONCLUSIONS: These results indicate that the vagus nerve and insulin are important for signaling the presence of gastrointestinal nutrients to the rat forebrain. These signal pathways depend on the ingested nutrients.

The role of the dopaminergic cells in the ventral tegmental area (VTA) in response to natural rewards is important in understanding palatability-induced feeding behavior. In this study, we first investigated whether dopaminergic lesions in the VTA would influence the taste preferences of rats for sodium chloride (NaCl), monosodium glutamate (MSG), disodium inosine-5'-monophosphate (IMP), disodium guanine-5'-monophosphate (GMP) and sucrose. Among these taste stimuli, only the preference of sucrose solutions decreased significantly in the VTA lesioned rats, preferences for the other taste stimuli were unaffected. Secondly, we tested whether VTA lesioned rats made slightly deficient in the amino acid lysine (by feeding rats a lysine deficient diet for five days) would detect the deficient amino acid in a choice test. Both the VTA lesioned rats and the control rats chose to consume the lysine solution and there was no difference between these two groups. These results suggest that the dopaminergic neurons in the VTA influence sucrose consumption, but do not alter the consumption of palatable umami compounds and salt. They also do not inhibit the animal's ability to recognize the essential amino acid lysine when the animal is deficient in it. Different central pathways must underlie sucrose preference and preferences for these amino acids and ribonucleotides.

The preference for foods or fluids in rats is partly dependent on its postingestive consequences. Many studies have investigated postingestive effect of high caloric substances, such as carbohydrate or fat. In this study, we examined postingestive effect of L-glutamate at the preferable concentration using conditioned flavor preference paradigm. Adult male rats with chronic intragastric (IG) cannula were trained to drink a flavored solution (conditioned stimulus; CS+) paired with IG infusion of nutrient solution and another flavored solution (CS-) with IG distilled water infusion on alternate days. The nutrient solution was 60mM monosodium L-glutamate, sodium chloride or glucose. Before and after conditioning, rats received 30min two-bottle choice tests for CS+ and CS- solution. All groups exhibited no significant preference for CS+ in pre-test period. By the last half of conditioning period, intake of CS+ solution was significantly higher than that of CS- in MSG group, but not in NaCl and glucose groups. After conditioned, the MSG group showed significantly higher intake and preference for CS+ solution (69.9%), while the NaCl and glucose group did not show any significant intake and preference for CS+ solution (50.9%, 43.5%, respectively). These results indicate that the amino acid L-glutamate at a preferable concentration has a positive postingestive effect as demonstrated by its ability to condition a flavor preference. The mechanism(s) for this positive effect could be through a direct effect on gut Glu receptors rather than the provision of calories or glucose from metabolized Glu; Further studies are needed to test these hypotheses.

Recent studies have demonstrated the existence of receptors for L-glutamate (GLU) and their transduction molecules in the gut mucosa as well as in the oral cavity. Among 20 amino acids, gastric vagal afferent fibers respond only to intragastric administration of GLU. Functional magnetic resonance imaging revealed activation of several fore-brain regions in response to intragastric infusion of taste solutions (D-glucose [sweet], monosodium L-glutamate [MSG; umami], and NaCl [salty] at 60 mM) in rats. Glucose activated the nucleus accumbens. MSG activated the medial preoptic area, dorsomedial nucleus of the hypothalamus, and habenular nucleus. Both glucose and MSG activated the amygdala. Some areas, such as the insular cortex, anterior cingulate cortex, hippocampus, and caudate-putamen were activated by all three substances. Glucose-induced brain activation developed slowly and persisted for a long time, whereas activation by MSG developed rapidly during infusion and reduced rapidly after cessation of infusion. NaCl induced only small and transient activation. Thus, both activated areas and temporal response patterns in the brain were distinct between sweet and umami substances delivered in the stomach. Postoral taste substances may activate the brain via neural (vagal) and/or humoral pathways.

Monosodium L-glutamate (MSG) elicits a unique taste termed umami and is widely used as a flavor enhancer in a variety of cuisines. Recent studies suggest the existence of L-glutamate (GLU) receptors and its transduction molecules in the gut mucosa as well as in the oral cavity. The vagal gastric afferent fibers respond specifically to the luminal stimulation of GLU in the stomach. GLU administration in the stomach also activates several brain areas (insular cortex, basal ganglia, limbic system, and hypothalamus). Ingestion of MSG enhanced secretion of digestive juices and insulin. Spontaneous ingestion of an MSG solution at the most preferred concentration (1% (w/v)) reduced weight gain, fat deposition, and plasma leptin levels without affecting food intake, naso-anal length (an index of somatic development), and lean mass in rats. These results suggest that umami signaling via gustatory and visceral pathways may play an important role in the process of digestion, absorption, metabolism, and other physiological functions via activation of the brain.

Monosodium l-glutamate (MSG), an umami taste substance, may be a key molecule coupled to a food intake signaling pathway, possibly mediated through a specific l-glutamate (GLU) sensing mechanism in the gastrointestinal tract. Here we investigated the effect of the spontaneous ingestion of a 1% MSG solution and water on food intake and body weight in male Sprague-Dawley rats fed diets of varying caloric density, fat and carbohydrate contents. Fat mass and lean mass in the abdomen, blood pressure, and several blood metabolic markers were also measured. Rats given free access to MSG and water showed a high preference (93-97%) for the MSG solution, regardless of the diet they consumed. Rats ingesting MSG had a significantly smaller weight gain, reduced abdominal fat mass, and lower plasma leptin levels, compared to rats ingesting water alone. Naso-anal length, lean mass, food and energy intakes, blood pressure, blood glucose, and plasma levels of insulin, triglyceride, total cholesterol, albumin, and GLU were not influenced by the ingestion of the MSG solution. These same effects were observed in a study of adult rats. Together, these results suggest that MSG ingestion reduces weight gain, body fat mass, and plasma leptin levels. Moreover, these changes are likely to be mediated by increased energy expenditure, not reduced energy intake or delayed development. Conceivably, these effects of MSG might be mediated via gut GLU receptors functionally linked to afferent branches of the vagus nerve in the gut, or the afferent sensory nerves in the oral cavity.

Recent studies have shown the nutrient-sensing systems transmitting nutritive information from the gut to the brain. However neural activity evoked by ingested dietary nutrients has not been investigated adequately. Using functional magnetic resonance imaging, we demonstrated that rat forebrain responded to intragastric administration of glucose, L-glutamate, and NaCl. These dietary nutrients led to a significant activation in the forebrain regions including nucleus accumbens, hypothalamic area, and limbic system with different timings. These data indicate that several forebrain regions have important roles on perception and process of postingestive nutrient information.

Injection with 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway results in loss of nigrostriatal dopaminergic neurons, which has been used widely as an animal model of Parkinson's disease. In the present study, location and extent of lesions 1 day after 6-OHDA injections (2, 4, 8, or 16 microg as a free base) in the substantia nigra (SN) were evaluated in rats by T(2)-weighted magnetic resonance imaging (MRI). The changes in MRI were also compared to immunohistochemical and behavioral changes. Hyperintense area in MRI was found at the region corresponding to 6-OHDA injection in a dose-dependent manner and was accompanied by a loss of tyrosine hydroxylase (TH)-positive cells. The shape of hyperintense area in the SN appeared to be composed of two components (i.e., circular and longitudinal regions). Administration of a larger dose of 6-OHDA (8-16 microg) was accompanied by an increase in hyperintense area and loss of TH-positive cells beyond the SN. The hyperintense area was observed on the first and third days after 6-OHDA injection, but the size and intensity declined to near normal levels on the ninth day. Rotational behavior induced by methamphetamine reached maximal levels at 4 microg 6-OHDA, and the behavior was maintained with doses up to 16 microg of 6-OHDA. Intrastriatal injection with 6-OHDA was less effective. These results suggest that MRI provides highly valuable information for verifying the size and location of intended lesions as well as for determining the optimal dose of neurotoxins in individual animals.

カオリン誘発性ラット水頭症におけるアクアポリン(AQP)-1および4の発現について調べた.カオリン注射の2,4および9週後の時点でAQP-1 mRNAの誘導が認められ,脳室拡張の進展に伴い徐々に増大した.AQP-1蛋白の発現も同じ場所で同じ時間経過で発現したが,徐々に増加することはなかった.遺伝子および蛋白の発現は共に,CSFシャント後ダウンレギュレーションされた.AQP-4のmRNAまたは蛋白の発現はどの時間で見ても,脳組織のどの部分でも増大しなかった.本研究は,カオリンで誘導したラットの実験的水頭症においてアクアポリンAQP-1の遺伝子および蛋白は発現するが,AQP-4については発現しないことを示した.AQP-1の発現は,CSF循環障害により生じたうっ血に対処するために起こるものと考えられる.以上,AQP-1の調節が水頭症治療のために,有用であることが示唆された

Melatonin, a pineal secretory product synthesized from tryptophan, has been found to be effective against neurotoxicity. The present study was aimed at demonstrating the effectiveness of melatonin in vivo in reducing ischemia-induced cerebral edema using magnetic resonance imaging (MRI). Rats were subjected to middle cerebral artery (MCA) occlusion/reperfusion surgery. Melatonin was administered twice (6.0 mg/kg, p.o.) just prior to 1 hr of MCA occlusion and 1 day after the surgery. T2-weighted multislice spin-echo images were acquired 1 day after the surgery. In the saline-treated control rats, increases in T2-weighted signals (water content) were clearly observed in the striatum and in the cerebral cortex. In the melatonin-treated group, total volume of edema was reduced by 51.6% compared with control group (P < 0.01). The protective effect of melatonin against edema was more clearly observed in the cerebral cortex (reduced by 59.8%, P < 0.01) than in the striatum (reduced by 34.2%, P < 0.05). Edema volume in a coronal slice was the greatest at the level of the bregma. Suppression of cerebral edema by melatonin was more effective posterior than anterior to the bregma. Melatonin appeared to reduce the volume of the edematous sites rather than to shift the signal intensity distribution. The present MRI study clearly demonstrates the effectiveness of melatonin against cerebral edema formation in ischemic animals in vivo, especially in the cerebral cortex. Melatonin may be highly useful in preventing cortical dysfunctions such as motor, sensory, memory, and psychological impairments associated with ischemic stroke.

Reduction of cerebral edema, an early symptom of ischemia, is one of the most important remedies for reducing subsequent chronic neural damage in stroke. Melatonin, a metabolite of tryptophan released from the pineal gland, has been found to be effective against neurotoxicity in vitro. The present study was aimed to demonstrate the effectiveness of melatonin in vivo in reducing ischemia-induced edema using magnetic resonance imaging (MRI). Rats were subjected to middle cerebral artery (MCA) occlusion/reperfusion surgery. Melatonin was administered twice (6.0 mg/kg, p.o.): just prior to 1 h MCA occlusion and 1 day after the surgery. T2-weighted multislice spin-echo images were acquired 1 day after the surgery. Increases in T2-weighted signals in ischemic sites of the brain were clearly observed after MCA occlusion. The signal increase was found mainly in the striatum and in the cerebral cortex in saline-treated control rats. In the melatonin-treated group, the total volume of cerebral edema was reduced by 45.3% compared to control group (P < 0.01). The protective effect of melatonin against cerebral edema was more clearly observed in the cerebral cortex (reduced by 56.1%, P < 0.01), while the reduction of edema volume in the striatum was weak (reduced by 23.0%). The present MRI study clearly demonstrated that melatonin is effective in reducing edema formation in ischemic animals in vivo, especially in the cerebral cortex. Melatonin may be highly useful in preventing cortical dysfunctions such as motor, sensory, memory, and psychological impairments.

Spatio-temporal dynamics of activated brain areas induced by drinking were investigated and visualized in behaving rats using functional magnetic resonance imaging (fMRI). The rats were trained to drink in the magnet bore, and the images were taken during and after drinking glucose and distilled water. During glucose ingestion, the signal intensity was increased continuously and maximally in the lateral hypothalamic area (LHA) and the ventromedial hypothalamus (VMH). Somewhat less intense activation in the central nucleus of the amygdala (AMc), and transient activation in the piriform cortex and the mediodorsal nucleus of the thalamus were observed. The signal intensities of other regions measured were largely unchanged. During post-ingestive periods, the signals re-increased in the hypothalamic areas and AMc. When water was given, LHA and VMH were similarly activated, however, the signal intensity in the amygdala was not significantly increased. The results indicate that these brain regions are activated differentially during drinking behavior, and that LHA and VMH play a central role in the control of not only feeding but also drinking. The regional activities in LHA and VMH are not principally related to the gustatory sensation, and the reactivation after drinking may be related to satisfaction or post-ingestive nutritional information. Also, the responses of AMc are probably due to reward value difference. To the best of our knowledge, this is the first report of mapping of brain areas using fMRI in behaving rats. The improved method described in this study for collecting fMRI data in behaving animals will be useful for studying functional network during animal behavior.

Rats were given free access to a running wheel, food, water, and a solution composed of branched-chain amino acids plus glutamine and arginine (the "BCAA-based" solution). A positive relationship between dark-period running distance and preference for the BCAA-based solution was observed. Serotonin release in the lateral hypothalamus, the central nucleus of amygdala and the medial nucleus raphe in overnight fluid-deprived rats during their first subsequent free drinking was also measured. A lowered serotonin release in the lateral hypothalamus characterized the rats that consumed the BCAA-based solution. No drink-related changes were observed in the amygdala. A separate group of rats was trained on a treadmill. Following the training period, plasma amino acids and brain serotonin release were measured during running. The BCAA-based solution infused before running elevated the branched chain amino acids/tryptophan plasma ratio at the end of, and after, running. Additionally, a decreased lateral hypothalamus serotonin release was seen 80 min after running, when compared with water-infused rats. No fluid-related changes in the amygdala were observed. The exercise-related shift in the fluid preference towards a BCAA-based solution suggests an ergogenic benefit. The forced-running study shows the lateral hypothalamus as a critical region in the effects of a BCAA-based solution.

The present study investigated the effects of repeated cold stress on single neuron activity in the lateral hypothalamic area (LHA) and medial hypothalamic area (MHA) of behaving rats. The rats were trained to lick a protruding spout in response to one of several cue-tone stimuli (CTSs) to ingest water, or amino acid, NaCl or glucose solution. Following this training, the rats were raised under either stressed (repeated temperature changes between −3 and 24°C) or control (24°C) condition for 2 mo. During this period, neuronal activity was recorded in the LHA and MHA. For rats raised under the stressed condition, mean spontaneous firing rate of LHA neurons was significantly greater than for rats under the control condition. More LHA neurons in the stressed rats responded, with an accompanying decrease in activity (inhibitory response), to CTSs than in the control rats. During extinction learning, some LHA neurons enhanced or reversed the responses to CTSs in the stressed rats, whereas no LHA neurons showed such response changes in the control rats. In contrast to the effects of the stressed condition on LHA neuron activity, mean spontaneous firing rate of MHA neurons in the stressed rats was significantly smaller than in the control rats. Fewer MHA neurons in the stressed rats responded to CTSs and/or ingestion of sapid solutions. The preceding results suggested that repeated cold stress produces a specific pattern of changes in spontaneous activity and responses to sensory stimuli in LHA and MHA neurons; this could underlie the behavioral changes induced by repeated cold stress such as hyperphagia and hyper-reactivity to sensory stimuli.

近年ますます複雑化する社会のなかで、子供の心の健康の発達と維持の重要性が改めて重要視されている。そのなかで心の健康を増進する上での日々の食の重要性、特に伝統的な食材の価値が見直されている。我々は最近、マウスを実験モデル動物として用いた行動科学的・組織形態学的アプローチによる研究によって、日本の代表的な伝統食の一つ、かつおだしの成長・発達期における摂取が、その後の情動行動の発達に大きな影響を与えることを示した。今回の発表では、情動に関連した脳領域において、その異常が統合失調症をはじめとする様々な精神疾患の病態と深く関わっていると考えられているパルブアルブミン陽性ニューロンの成熟と情動発達に対するかつおだし摂取の効果を紹介する。

和食の基本は「だし」である。だしの代表格であるかつおだしを用いて嗜好性の調節機構を調べた結果、少なくとも3つの因子(遺伝因子、高脂肪食摂取、かつおだしの摂取体験/学習)が関与することが明らになった。とくに、だしの摂取体験がだしの嗜好性増加に大きく影響したことから、味や香りや食感以外の因子が強く関与することが示唆された。だしは嗜好濃度が低いため、カロリー摂取はほとんど期待できない。従って、だしの摂取によって何らかの生理的変化(健康機能)が生じることが予想された。本稿では、かつおだしの嗜好性を決める因子とかつおだしの健康機能について解説する。

コーヒーは胃運動と自律神経活動を亢進させることが示唆された。

味覚変調作用とは、ある化合物/食品の味が、他の化合物/食品を味わうことによって異なる味へと変化する現象をいう。餅は甘いが、ある甘い市販飲料（アクエリアスなど）と一緒に食べると強い苦味を発生する。しかしそのメカニズムは不明である。われわれは、餅に含まれる成分（中性では苦くない；水やお茶では苦味を発生しない）が、酸性飲料を一緒に摂ることによって強い苦味を発生することを見出した。そこで、本研究では、1）いろいろな穀物、でんぷん、あるいは再加工餅などを用いて苦味を発生する食糧を特定し、2）苦味物質の存在形態を調べることにより、味覚変調（苦味発生）のメカニズムを総合的に解明する。食べ合わせにより不快な味に変わる現象のメカニズムを解明することができれば、よりおいしい食べ方の提案/啓発、さらには苦味を発生させないおいしい食品の開発につながると期待できる。ホットかつ斬新な話題であるため、マスメディアの興味を引く内容であり、一般消費者へのインパクトも大きい。

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