Pairing of white wine made with shade-grown grapes and Japanese cuisine.

This study investigated the effect of pairing of wine vinified from shade-grown grapes before onset of ripening on the palatability of sashimi, a typical Japanese cuisine. GC-MS analyses of volatile chemicals revealed that shading reduced phenolic compounds and terpenoids, and added fatty acid ethyl esters which are also known to contribute to the flavor of Japanese sake. When the pairing of sashimi with wine was evaluated by individuals who regularly drink Japanese sake during meals, shade wine was more highly rated than wine made from normally-grown grapes.

Allyl isothiocyanate increases carbohydrate oxidation through enhancing insulin secretion by TRPV1.

The transient receptor potential (TRP) V1 is a cation channel belonging to the TRP channel family and it has been reported to be involved in energy metabolism, especially glucose metabolism. While, we have previously shown that intragastric administration of allyl isothiocyanate (AITC) enhanced glucose metabolism via TRPV1, the underlying mechanism has not been elucidated. In this study, we examined the relationship between insulin secretion and the increase in carbohydrate oxidation due to AITC. Intragastric administration of AITC elevated blood insulin levels in mice and AITC directly enhanced insulin secretion from isolated islets. These observations were not reproduced in TRPV1 knockout mice. Furthermore, AITC did not increase carbohydrate oxidation in streptozotocin-treated mice. These results suggest that intragastric administration of AITC could induce insulin secretion from islets via TRPV1 and that enhancement of insulin secretion was related to the increased carbohydrate oxidation due to AITC.

The Japan Society for Innovative Cuisine: Exploring New Visions of Japanese Cuisine.

Kyoto cuisine has a long history and its traditions have been practiced for hundreds of years. In Kyoto, a group of scientists and renowned chefs strives to better understand traditional Kyoto cuisine in order to foster culinary innovation within traditional Kyoto cuisine. We launched a research project in April 2009 using a specially equipped "laboratory-kitchen" located in Kyoto University. Chefs chose a variety of topics related to basic concepts and techniques for cooking. We conducted culinary experimentation, thorough analysis, and diligent discussion on each topic for approximately 6 mo. In the symposium, chefs will present the results of their experiments, discussing their techniques and bringing samples of final products.

Hyperoxia reverses glucotoxicity-induced inhibition of insulin secretion in rat INS-1 ß cells.

Chronic hyperglycemia has deleterious effects on pancreatic ß-cell function, a process known as glucotoxicity. This study examined whether chronic high glucose (CHG) induces cellular hypoxia in rat INS-1 ß 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 ß-cell hypoxia. Hyperoxia might prevent glucotoxicity-induced ß-cell dysfunction and improve insulin secretion.

Intragastric administration of allyl isothiocyanate reduces hyperglycemia in intraperitoneal glucose tolerance test (IPGTT) by enhancing blood glucose consumption in mice.

We investigated the effects of allyl isothiocyanate (AITC) on the blood glucose levels of mice using an intraperitoneal glucose tolerance test. The intragastric administration of 25 mg/kg body weight AITC reduced the increase in blood glucose level after 2 g/kg body weight glucose was given intraperitoneally, compared with that of control mice. To elucidate the mechanism responsible for the reduction, respiratory gas analysis employing (13)C-labeled glucose was performed. The intragastrically administering AITC increased (13)CO2 emission, compared to vehicle, after intraperitoneal administration of (13)C-labeled glucose. This indicated that AITC increased the utilization of exogenously administered glucose, which was excessive glucose in the blood. To examine whether transient receptor potential (TRP) channels mediated this reduction in the blood glucose levels, we used TRPA1 and TRPV1 knockout (KO) mice. Intragastrically administering AITC reduced the increase in the blood glucose level in TRPA1 KO mice but not in TRPV1 KO mice. These findings suggest that dietary AITC might reduce the increases in blood glucose levels by increasing the utilization of excessive glucose in the blood by activating TRPV1.

γ-Tocotrienol attenuates TNF-α-induced changes in secretion and gene expression of MCP-1, IL-6 and adiponectin in 3T3-L1 adipocytes.

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.

Physiologic implications of phosphoinositides and phospholipase C in the regulation of insulin secretion.

The secretion of insulin from the pancreatic beta-cell must be commensurate to satisfy the insulin requirements of the organism. This cell has a great flexibility to meet these requirements which are increased not only by the ingestion of nutrients (increase of plasma glucose) but also by the sensitivity of target tissues to insulin as well. The insulin secretion is a complex biochemical event regulated by a host of potential second messenger molecules acting alone or in concert. These events include the cation calcium, which gains access to the beta-cell via the opening of voltage-regulated channels, cAMP and phosphoinositide-derived second messenger molecules, generated as a consequence of phospholipase C (PLC) activation. In this review, we focused on phosphoinositides, PLC/Phosphokinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) cascade in the regulation of insulin secretion. We also described our studies on the mechanism of the beta-cell desensitization using perifused islets. It is suggested that a failure of the signaling events contribute to the pathogenesis of diabetes in which the beta-cell can no longer secrete the required amounts of insulin. It has been observed that chronic exposure to high glucose desensitizes the beta-cells to subsequent stimulation. We suggested that the failure of PLC activation can be attributed in the impairment of insulin secretion by chronic sustained glucose exposure. It may contribute to the vicious circle of impaired insulin secretion leading up to diabetes.

Association of estrogen receptor-alpha gene polymorphisms with cardiac autonomic nervous activity in healthy young Japanese males.

BACKGROUND: Estrogens exert beneficial effects on the cardiovascular system that are mediated by estrogen receptors. We examined the association between the estrogen receptor alpha gene (ESR1) PvuII and XbaI polymorphisms and cardiac autonomic nervous function in Japanese males. METHODS: We examined 252 young healthy males for association of ESR1 PvuII and XbaI polymorphisms and short-term heart rate variability (HRV) during supine rest and in a standing position. The very low frequency (VLF), low frequency (LF), and high frequency (HF) components of HRV were quantified by frequency domain analysis. RESULTS: Carriers of the ESR1 PvuII C allele had higher mean blood pressure (BP), while the XbaI GG genotype was significantly associated with higher diastolic and mean BP, but lower HR. In the haplotype analysis, carriers of the ESR1 haplotype 2 (PvuII C and XbaI A) allele had a higher systolic and mean BP, and lower HRV spectral powers (total power, VLF, LF, and HF components) in a supine rest compared with those of non-carriers. CONCLUSIONS: The ESR1 PvuII and XbaI haplotype is associated with BP variation and the reduction in cardiac autonomic nervous activity in young Japanese males, which may be precursors of future pathological episodes of cardiovascular diseases.

Association of UCP2 and UCP3 polymorphisms with heart rate variability in Japanese men.

OBJECTIVES: The mitochondrial uncoupling proteins UCP2 and UCP3 are implicated in energy metabolism and regulation of reactive oxygen species, which are closely involved in autonomic nervous system function. Heart rate variability (HRV) reflects cardiac autonomic regulation and has been used to evaluate dysfunction of the autonomic nervous system in hypertension and cardiovascular diseases. We examined the association between polymorphisms in the UCP2 and UCP3 genes and HRV in healthy young Japanese men. METHODS: The 45 bp insertion/deletion polymorphism in exon8 of UCP2 and the -55C/T polymorphism in the UCP3 promoter region were genotyped (n = 255). Cardiac autonomic function was evaluated by power spectral analysis of HRV during supine rest and in a standing position. Low-frequency (<0.15 Hz) and high-frequency (>0.15 Hz) components of HRV were quantified by frequency domain analysis. RESULTS: The I/I genotype of the UCP2 45 bp insertion/deletion polymorphism was associated with relatively higher blood pressure and HRV sympathetic indices (low frequency percentage and low frequency:high frequency ratio) at supine rest. For the -55C/T polymorphism of UCP3, individuals carrying the -55T allele had significantly lower HRV sympathetic indices, but higher HRV parasympathetic indices (high frequency and high frequency percentage), than carriers of the C/C genotype at standing. Both UCP2 and UCP3 polymorphisms were significantly associated with a third-degree family history of hypertension, diabetes, and obesity. Additionally, carriers of the UCP2 45 bp I allele -UCP3 -55C/C combined genotype had the lowest HRV sympathetic and the highest HRV parasympathetic indices at standing among the combined genotypes. CONCLUSION: UCP2 and UCP3 polymorphisms were associated with HRV in young and healthy states, suggesting a significant relationship between autonomic cardiovascular regulation and UCP2/UCP3 polymorphisms.

Biphasic insulin secretion from freshly isolated or cultured, perifused rodent islets: comparative studies with rats and mice.

In the present report, we compared the insulin secretory responses of freshly isolated, perifused rat and mouse islets to glucose. Prestimulatory glucose levels were changed to assess their influence on the subsequent secretory responses. Additional studies included experiments with the incretin factor glucagon-like peptide-1 (GLP-1), the cholinergic agonist carbachol, and the alpha2 agonist epinephrine. Our findings demonstrate that under conditions where glucose (8.5-11.1 mmol/L) evokes a dramatic biphasic insulin secretory response from perifused rat islets, mouse islets exhibit little response. Increasing the prestimulatory glucose level to 8.5 mmol/L dramatically distorts subsequently measured glucose-induced insulin secretion from rat islets but allows the evocation of a modest but clear biphasic response from mouse islets in response to 30 mmol/L, but not 11.1 or 16.7 mmol/L, glucose. In the presence of a minimally effective glucose level (10 mmol/L), mouse islets remain exquisitely sensitive to the combined stimulatory effects of GLP-1 (2.5 nmol/L) plus carbachol (0.5 micromol/L) and to the inhibitory influence of epinephrine (10 nmol/L). Short-term culture of rat islets in CMRL 1066 containing 5.6 mmol/L glucose resulted in a significant decrease in the secretory response to 11.1 mmol/L glucose, whereas the same manipulation improved mouse islet responses. It is concluded that the process of collagenase isolating islets does not alter mouse islet sensitivity in any adverse way and that increasing the prestimulatory glucose level can indeed alter the pattern of insulin secretion in either a positive or negative manner depending upon the species being investigated. Prior short-term culture of rodent islets differentially affects secretion from these 2 species.

Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration.

Uncoupling protein 3 (UCP3) expression increases dramatically in skeletal muscle under metabolic states associated with elevated lipid metabolism, yet the function of UCP3 in a physiological context remains controversial. Here, in situ mitochondrial H(2)O(2) emission and respiration were measured in permeabilized fiber bundles prepared from both rat and mouse (wild-type) gastrocnemius muscle after a single bout of exercise plus 18 h of recovery (Ex/R) that induced a approximately 2-4-fold increase in UCP3 protein. Elevated uncoupling activity (i.e. GDP inhibitable) was evident in Ex/R fibers only upon the addition of palmitate (known activator of UCP3) or under substrate conditions eliciting substantial rates of H(2)O(2) production (i.e. respiration supported by succinate or palmitoyl-L-carnitine/malate but not pyruvate/malate), indicative of UCP3 activation by endogenous reactive oxygen species. In mice completely lacking UCP3 (ucp3(-/-)), Ex/R failed to induce uncoupling activity. Surprisingly, when UCP3 activity was inhibited by GDP (rats) or in the absence of UCP3 (ucp3(-/-)), H(2)O(2) emission was significantly (p < 0.05) higher in Ex/R versus non-exercised control fibers. Collectively, these findings demonstrate that the oxidant emitting potential of mitochondria is increased in skeletal muscle during recovery from exercise, possibly as a consequence of prolonged reliance on lipid metabolism and/or altered mitochondrial biochemistry/morphology and that induction of UCP3 in vivo mediates an increase in uncoupling activity that restores mitochondrial H(2)O(2) emission to non-exercised, control levels.

Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII.

Insulin regulates blood glucose by promoting uptake by fat and muscle, and inhibiting production by liver. Insulin-stimulated glucose uptake is mediated by GLUT4, which translocates from an intracellular compartment to the plasma membrane. GLUT4 traffic and insulin secretion both rely on calcium-dependent, regulated exocytosis. Deletion of the voltage-gated potassium channel Kv1.3 results in constitutive expression of GLUT4 at the plasma membrane. Inhibition of channel activity stimulated GLUT4 translocation through a calcium dependent mechanism. The synaptotagmins (Syt) are calcium sensors for vesicular traffic, and Syt VII mediates lysosomal and secretory granule exocytosis. We asked if Syt VII regulates insulin secretion by pancreatic beta cells, and GLUT4 translocation in insulin-sensitive tissues mouse model. Syt VII deletion (Syt VII -/-) results in glucose intolerance and a marked decrease in glucose-stimulated insulin secretion in vivo. Pancreatic islet cells isolated from Syt VII -/- cells secreted significantly less insulin than islets of littermate controls. Syt VII deletion disrupted GLUT4 traffic as evidenced by constitutive expression of GLUT4 present at the plasma membrane of fat and skeletal muscle cells and unresponsiveness to insulin. These data document a key role for Syt VII in peripheral glucose homeostasis through its action on both insulin secretion and GLUT4 traffic.

Divergent effects of epinephrine and prostaglandin E2 on glucose-induced insulin secretion from perifused rat islets.

The impact of the catecholamine epinephrine and the postulated inhibitory second messenger prostaglandin E(2) (PGE(2)) on the kinetics and magnitude of glucose-induced insulin secretion were compared and contrasted. In agreement with a number of studies, epinephrine was a most effective antagonist of glucose-induced insulin secretion. Dose-response studies using 8 to 10 mmol/L glucose as stimulant established that levels as low as 1 to 10 nmol/L of the catecholamine were effective at inhibiting release. Glucose (20 mmol/L) caused an approximately 25-fold increase in insulin secretion, an effect that was completely abolished by 1 micromol/L epinephrine. Under conditions where it completely abolished 20 mmol/L glucose-induced insulin release, epinephrine (1 micromol/L) reduced, but did not abolish, the stimulatory effect of glucose on phospholipase C activation. Chronic 3-hour exposure to 10 mmol/L glucose alone desensitized the islet to subsequent stimulation by glucose. Despite its ability to completely suppress secretion to 10 mmol/L glucose, epinephrine failed to protect the islet from hyperglycemia-induced desensitization. In sharp contrast to epinephrine, PGE(2) at levels ranging from 1 to 10 micromol/L had no discernible adverse effect on 10 mmol/L glucose-induced secretion. These findings suggest that multiple mechanisms contribute to the inhibitory impact of epinephrine on release and, in conjunction with other studies, cast serious doubt on the concept that PGE(2) plays any significant inhibitory role in the regulation of glucose-induced secretion.

Desensitization of the pancreatic beta-cell: effects of sustained physiological hyperglycemia and potassium.

The impact of modest but prolonged (3 h) exposure to high physiological glucose concentrations and hyperkalemia on the insulin secretory and phospholipase C (PLC) responses of rat pancreatic islets was determined. In acute studies, glucose (5-20 mM) caused a dose-dependent increase in secretion with maximal release rates 25-fold above basal secretion. When measured after 3 h of exposure to 5-10 mM glucose, subsequent stimulation of islets with 10-20 mM glucose during a dynamic perifusion resulted in dose-dependent decrements in secretion and PLC activation. Acute hyperkalemia (15-30 mM) stimulated calcium-dependent increases in both insulin secretion and PLC activation; however, prolonged hyperkalemia resulted in a biochemical and secretory lesion similar to that induced by sustained modest hyperglycemia. Glucose- (8 mM) desensitized islets retained significant sensitivity to stimulation by either carbachol or glucagon-like peptide-1. These findings emphasize the vulnerability of the beta-cell to even moderate sustained hyperglycemia and provide a biochemical rationale for achieving tight glucose control in diabetic patients. They also suggest that PLC activation plays a critically important role in the physiological regulation of glucose-induced secretion and in the desensitization of release that follows chronic hyperglycemia or hyperkalemia.

Acute and chronic effects of glucose and carbachol on insulin secretion and phospholipase C activation: studies with diazoxide and atropine.

The acute and chronic effects of 20 mM glucose and 10 microM carbachol on beta-cell responses were investigated. Acute exposure of rat islets to 20 mM glucose increased glucose usage rates and resulted in a large insulin-secretory response during a dynamic perifusion. The secretory, but not the metabolic, effect of 20 mM glucose was abolished by simultaneous exposure to 100 microM diazoxide. Glucose (20 mM) significantly increased inositol phosphate (IP) accumulation, an index of phospholipase C (PLC) activation, from [(3)H]inositol-prelabeled islets. Diazoxide, but not atropine, abolished this effect as well. Unlike 20 mM glucose, 10 microM carbachol (in the presence of 5 mM glucose) increased IP accumulation but had no effect on insulin secretion or glucose (5 mM) metabolism. The IP effect was abolished by 50 microM atropine but not by diazoxide. Chronic 3-h exposure of islets to 20 mM glucose or 10 microM carbachol profoundly reduced both the insulin-secretory and PLC responses to a subsequent 20 mM glucose stimulus. The adverse effects of chronic glucose exposure were abolished by diazoxide but not by atropine. In contrast, the adverse effects of carbachol were abolished by atropine but not by diazoxide. Prior 3 h of exposure to 20 mM glucose or carbachol had no inhibitory effect on glucose metabolism. Significant secretory responses could be evoked from 20 mM glucose- or carbachol-pretreated islets by the inclusion of forskolin. These findings support the concept that an early event in the evolution of beta-cell desensitization is the impaired activation of islet PLC.

Dexamethasone suppresses phospholipase C activation and insulin secretion from isolated rat islets.

Dexamethasone inhibits insulin secretion from isolated islets. In the present experiments, possible underlying biochemical mechanisms responsible for defective secretion were explored. Dexamethasone (1 micromol/L) had no immediate deleterious effect on 15 mmol/L glucose-induced insulin release from perifused rat islets. However, a 3-hour preincubation period with 1 micromol/L dexamethasone resulted in parallel reductions in both the first (64%) and second phases (74%) of 15 mmol/L glucose-induced insulin secretion monitored during a dynamic perifusion. When measured after the perifusion, there were no differences in insulin content or in the capacity of control or dexamethasone-treated islets to use glucose. Dexamethasone (1 micromol/L) preexposure also reduced phorbol ester- and potassium-induced secretion. In additional experiments, islets were labeled for 3 hours with 3H-inositol in the presence or absence of 1 micromol/L dexamethasone. The steroid did not affect total 3H-inositol incorporation during the labeling period. However, the capacity of 15 mmol/L glucose, 30 mmol/L KCl, and 100 micromol/L carbachol to activate phospholipase C (PLC), monitored by the accumulation of labeled inositol phosphates, was significantly reduced in dexamethasone-pretreated islets. Inclusion of the nuclear glucocorticoid receptor antagonist RU486 (mifepristone, 10 micromol/L) abolished the adverse effects of dexamethasone on both glucose-induced inositol phosphate accumulation and insulin secretion. Quantitative Western blot analyses revealed that the islet contents of PLCdelta1, PLCbeta1, beta2, beta3, and protein kinase C alpha were unaffected by dexamethasone pretreatment. These findings demonstrate that dexamethasone pretreatment impairs insulin secretion via a genomic action and that impaired activation of the PLC/protein kinase C signaling system is involved in the evolution of its inhibitory effect on secretion.

Inhibitory effects of antipsychotics on carbachol-enhanced insulin secretion from perifused rat islets: role of muscarinic antagonism in antipsychotic-induced diabetes and hyperglycemia.

Treatment with the atypical antipsychotics olanzapine and clozapine has been associated with an increased risk for deterioration of glucose homeostasis, leading to hyperglycemia, ketoacidosis, and diabetes, in some cases independent of weight gain. Because these events may be a consequence of their ability to directly alter insulin secretion from pancreatic beta-cells, we determined the effects of several antipsychotics on cholinergic- and glucose-stimulated insulin secretion from isolated rat islets. At concentrations encompassing therapeutically relevant levels, olanzapine and clozapine reduced insulin secretion stimulated by 10 micromol/l carbachol plus 7 mmol/l glucose. This inhibition of insulin secretion was paralleled by significant reductions in carbachol-potentiated inositol phosphate accumulation. In contrast, risperidone or ziprasidone had no adverse effect on cholinergic-induced insulin secretion or inositol phosphate accumulation. None of the compounds tested impaired the islet secretory responses to 8 mmol/l glucose alone. Finally, in vitro binding and functional data show that olanzapine and clozapine (unlike risperidone, ziprasidone, and haloperidol) are potent muscarinic M3 antagonists. These findings demonstrate that low concentrations of olanzapine and clozapine can markedly and selectively impair cholinergic-stimulated insulin secretion by blocking muscarinic M3 receptors, which could be one of the contributing factors to their higher risk for producing hyperglycemia and diabetes in humans.

Intracranial administration of transforming growth factor-beta3 increases fat oxidation in rats.

The effects of intracranial transforming growth factor (TGF)-beta3 on spontaneous motor activity and energy metabolism were examined in rats. After injection of TGF-beta3 into the cisterna magna of the rat, spontaneous motor activity decreased significantly for 1 h. The intracranial injection of TGF-beta3 produced an immediate decrease in respiratory exchange ratio (RER). No significant changes were observed in energy expenditure. TGF-beta3 induced a significant increase in total fat oxidation and a decrease in total carbohydrate oxidation. Furthermore, the serum substrates associated with fat metabolism were significantly altered in rats injected with TGF-beta3. Both lipoprotein lipase activity in skeletal muscle and the concentration of serum ketone bodies increased, suggesting that the increase in fat oxidation caused by TGF-beta3 may have occurred in the liver and muscle. Intracranial injection of TGF-beta3 appeared to evoke a switch in the energy substrates accessed in energy expenditure. These results suggest that the release of TGF-beta3 in the brain by exercise is a signal for regulating energy consumption.

Effects of intracranial injection of transforming growth factor-beta relevant to central fatigue on the waking electroencephalogram of rats: comparison with effects of exercise.

To investigate the detailed actions of transforming growth factor-beta (TGF-beta) in the brain, which increase accompanied with continuity of exercise, the authors performed electroencephalogram (EEG) spectral analysis for 2 h after intracranial injection of TGF-beta in rats and compared with the effects of swimming exercise. Relative power values (power percent) of the theta frequency band (4-7 Hz) increased and power percent of the alpha frequency band (7-13 Hz) decreased after intracranial injection of TGF-beta. The directions of these changes of EEG after intracranial injection of TGF-beta were consistent with those after exercise. The EEG pattern produced by leucine-enkephalin (Leu-enk), a typical brain peptide related to exercise, was completely different from that after exercise. The results suggested that the increase in TGF-beta concentration in the brain is, at least partly, relevant to the change of neuronal activity after exercise.