In Vivo Measurement of Brain GABA Concentrations by Magnetic Resonance Spectroscopy in Smelters Occupationally Exposed to Manganese

Background

Exposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable.

Objectives

Our goal was to determine whether in vivo brain levels of γ-aminobutyric acid (GABA), N-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure.

Methods

We used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)].

Results

Seven of 10 exposed subjects showed clear T₁-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = −0.93; p < 0.001).

Conclusions

We demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity.     

谷氨酰胺对应激大鼠学习记忆的影响及其机制的研究

目的　观察谷氨酰胺 (Gln)对应激大鼠学习记忆的影响 ,并对其机制进行探讨。方法　Wistar大鼠 30只 ,随机分为三组 : 组为对照组 , 组为应激组 , 组为应激 +Gln组。其中 、 组饲以普通饲料 , 组给予补充 2 % Gln的饲料。以光电刺激作为应激条件 ,在 组和 组大鼠建立应激模型 ,用 Y-迷宫法对大鼠的学习记忆能力进行测定 ,并分别用放射性配基结合法、放射免疫法、荧光分光光度计法测定大鼠小脑中 γ-氨基丁酸 (GABA)受体、脑中胆囊收缩素 (CCK)、还原型谷胱甘肽 (GSH)的含量。结果　与 组相比 , 组大鼠在 Y-迷宫实验中的逃避时间延长 ,而 组与 组则无显著差异 ; 组大鼠小脑中 GABA受体水平、CCK含量均升高 ,而 GSH含量则降低 ,给予 Gln后可从一定程度上逆转上述改变。结论　心理应激可影响大鼠的学习记忆能力 ,而 Gln则有一定的改善作用 ,其机制可能是通过减轻应激所致的脑中GABA受体水平、CCK和 GSH含量的异常改变而发挥此作用     

Jasmine Tea Attenuates Chronic Unpredictable Mild Stress-Induced Depressive-like Behavior in Rats via the Gut-Brain Axis

The number of depressed people has increased worldwide. Dysfunction of the gut microbiota has been closely related to depression. The mechanism by which jasmine tea ameliorates depression via the brain-gut-microbiome (BGM) axis remains unclear. Here, the effects of jasmine tea on rats with depressive-like symptoms via the gut microbiome were investigated. We first established a chronic unpredictable mild stress (CUMS) rat model to induce depressive symptoms and measured the changes in depression-related indicators. Simultaneously, the changes in gut microbiota were investigated by 16S rRNA sequencing. Jasmine tea treatment improved depressive-like behaviors and neurotransmitters in CUMS rats. Jasmine tea increased the gut microbiota diversity and richness of depressed rats induced by CUMS. Spearman’s analysis showed correlations between the differential microbiota (Patescibacteria, Firmicutes, Bacteroidetes, Spirochaetes, Elusimicrobia, and Proteobacteria) and depressive-related indicators (BDNF, GLP-1, and 5-HT in the hippocampus and cerebral cortex). Combined with the correlation analysis of gut microbiota, the result indicated that jasmine tea could attenuate depression in rats via the brain- gut-microbiome axis.     

Tualang honey improves memory performance and decreases depressive-like behavior in rats exposed to loud noise stress

Recent evidence has exhibited dietary influence on the manifestation of different types of behavior induced by stressor tasks. The present study examined the effects of Tualang honey supplement administered with the goal of preventing or attenuating the occurrence of stress-related behaviors in male rats subjected to noise stress. Forty-eight adult male rats were randomly divided into the following four groups: i) nonstressed with vehicle, ii) nonstressed with Tualang honey, iii) stressed with vehicle, and iv) stressed with honey. The supplement was given once daily via oral gavage at 0.2 g/kg body weight. Two types of behavioral tests were performed, namely, the novel object recognition test to evaluate working memory and the forced swimming test to evaluate depressive-like behavior. Data were analyzed by a two-way analysis of variance (ANOVA) using IBM SPSS 18.0. It was observed that the rats subjected to noise stress expressed higher levels of depressive-like behavior and lower memory functions compared to the unexposed control rats. In addition, our results indicated that the supplementation regimen successfully counteracted the effects of noise stress. The forced swimming test indicated that climbing and swimming times were significantly increased and immobility times significantly decreased in honey-supplemented rats, thereby demonstrating an antidepressant-like effect. Furthermore, cognitive function was shown to be intensely affected by noise stress, but the effects were counteracted by the honey supplement. These findings suggest that subchronic exposure to noise stress induces depressive-like behavior and reduces cognitive functions, and that these effects can be attenuated by Tualang honey supplementation. This warrants further studies to examine the role of Tulang honey in mediating such effects.     

注意缺陷多动障碍模型大鼠谷氨酸和谷氨酰胺检测结果分析

目的:观察ADHD模型大鼠血清和脑内谷氨酸、谷氨酰胺含量变化,为研究ADHD的发病机制提供依据。方法:采用丹酰氯柱前衍生化-高效液相色谱法测定自发性高血压大鼠和正常大鼠血清和脑内谷氨酸、谷氨酰胺含量。结果:模型组血清谷氨酸低于对照组(P0.05),模型组脑组织谷氨酸显著高于对照组(P0.05),谷氨酰胺显著低于对照组(P0.05)。结论:谷氨酸、谷氨酰胺在ADHD的发病中可能起到一定的作用。     

Overlapping Mechanisms of Action of Brain-Active Bacteria and Bacterial Metabolites in the Pathogenesis of Common Brain Diseases

The involvement of the gut microbiota and the metabolites of colon-residing bacteria in brain disease pathogenesis has been covered in a growing number of studies, but comparative literature is scarce. To fill this gap, we explored the contribution of the microbiota–gut–brain axis to the pathophysiology of seven brain-related diseases (attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, Alzheimer’s disease, Parkinson’s disease, major depressive disorder, and bipolar disorder). In this article, we discussed changes in bacterial abundance and the metabolic implications of these changes on disease development and progression. Our central findings indicate that, mechanistically, all seven diseases are associated with a leaky gut, neuroinflammation, and over-activated microglial cells, to which gut-residing bacteria and their metabolites are important contributors. Patients show a pro-inflammatory shift in their colon microbiota, harbouring more Gram-negative bacteria containing immune-triggering lipopolysaccharides (LPS) in their cell walls. In addition, bacteria with pro-inflammatory properties (Alistipes, Eggerthella, Flavonifractor) are found in higher abundances, whereas lower abundances of anti-inflammatory bacteria (Bifidobacterium, Coprococcus, Eucbacterium, Eubacterium rectale, Faecalibacterium, Faecalibacterium prasunitzii, Lactobacillus, Prevotella, Roseburia) are reported, when compared to healthy controls. On the metabolite level, aberrant levels of short-chain fatty acids (SCFAs) are involved in disease pathogenesis and are mostly found in lower quantities. Moreover, bacterial metabolites such as neurotransmitters (acetylcholine, dopamine, noradrenaline, GABA, glutamate, serotonin) or amino acids (phenylalanine, tryptophan) also play an important role. In the future, defined aberrations in the abundance of bacteria strains and altered bacterial metabolite levels could likely be possible markers for disease diagnostics and follow-ups. Moreover, they could help to identify novel treatment options, underlining the necessity for a deeper understanding of the microbiota–gut–brain axis.     

Neurochemical Effects of Chronic Administration of Calcitriol in Rats

Despite accumulating data showing the various neurological actions of vitamin D (VD), its effects on brain neurochemistry are still far from fully understood. To further investigate the neurochemical influence of VD, we assessed neurotransmitter systems in the brain of rats following 6-week calcitriol (1,25-dihydroxyvitamin D) administration (50 ng/kg/day or 100 ng/kg/day). Both the two doses of calcitriol enhanced VDR protein level without affecting serum calcium and phosphate status. Rats treated with calcitriol, especially with the higher dose, exhibited elevated γ-aminobutyric acid (GABA) status. Correspondingly, the mRNA expression of glutamate decarboxylase (GAD) 67 was increased. 100 ng/kg of calcitriol administration also increased glutamate and glutamine levels in the prefrontal cortex, but did not alter glutamine synthetase (GS) expression. Additionally, calcitriol treatment promoted tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2) expression without changing dopamine and serotonin status. However, the concentrations of the metabolites of dopamine and serotonin were increased and the drug use also resulted in a significant rise of monoamine oxidase A (MAO_A) expression, which might be responsible to maintain the homeostasis of dopaminergic and serotonergic neurotransmission. Collectively, the present study firstly showed the effects of calcitriol in the major neurotransmitter systems, providing new evidence for the role of VD in brain function.     

Ammonia toxicity mechanism in fish: Studies on rainbow trout (Salmo gairdneri Rich.)

Salmo gairdneri specimens were exposed for 4–48 hr to various environmental un-ionized ammonia (UIA) concentrations. In the brain of NH₃-treated trout glutamate, GABA, total sugars, ATP, NADH, and succinate decrease, while tissue NH₃ content, glutamine, and lactate increase. In the liver total sugars, succinate, and lactate decrease, while tissue NH₃, glutamine, and the taurine/glycine ratio increase. Such variations depend upon exposure time and environmental UIA level. Ammonia toxicity mechanism in fish is discussed and compared with the one proposed in mammals. Further data obtained from overturned specimens suggest that in these animals a cerebral hypoxic phenomenon also occurs.     

Supplementation of Antipsychotic Treatment with the Amino Acid Sarcosine Influences Proton Magnetic Resonance Spectroscopy Parameters in Left Frontal White Matter in Patients with Schizophrenia

Dysfunction of the glutamatergic system, the main stimulating system in the brain, has a major role in pathogenesis of schizophrenia. The frontal white matter (WM) is partially composed of axons from glutamatergic pyramidal neurons and glia with glutamatergic receptors. The natural amino acid sarcosine, a component of a normal diet, inhibits the glycine type 1 transporter, increasing the glycine level. Thus, it modulates glutamatergic transmission through the glutamatergic ionotropic NMDA (N-methyl-d-aspartate) receptor, which requires glycine as a co-agonist. To evaluate the concentrations of brain metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine, and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left frontal WM, Proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy was used. Twenty-five patients randomly chosen from a group of fifty with stable schizophrenia (DSM-IV-TR) and dominant negative symptoms, who were receiving antipsychotic therapy, were administered 2 g of sarcosine daily for six months. The remaining 25 patients received placebo. Assignment was double blinded. ¹H-NMR spectroscopy (1.5 T) was performed twice: before and after the intervention. NAA, Glx and mI were evaluated as Cr and Cho ratios. All patients were also assessed twice with the Positive and Negative Syndrome Scale (PANSS). Results were compared between groups and in two time points in each group. The sarcosine group demonstrated a significant decrease in WM Glx/Cr and Glx/Cho ratios compared to controls after six months of therapy. In the experimental group, the final NAA/Cr ratio significantly increased and Glx/Cr ratio significantly decreased compared to baseline values. Improvement in the PANSS scores was significant only in the sarcosine group. In patients with schizophrenia, sarcosine augmentation can reverse the negative effect of glutamatergic system overstimulation, with a simultaneous beneficial increase of NAA/Cr ratio in the WM of the left frontal lobe. Our results further support the glutamatergic hypothesis of schizophrenia.     

Sulfur amino acid-free diet results in increased glutamate in human midbrain: a pilot magnetic resonance spectroscopic study

ObjectiveThis pilot study was designed to determine if metabolic effects in different brain regions (left and right parietal lobes, midbrain) caused by 3 d of food consumption without methionine or cysteine could be detected by proton magnetic resonance spectroscopy.MethodsHealthy individuals 18 to 36 y old (n = 8) were studied by magnetic resonance spectroscopy after receiving a diet with adequate sulfur amino acids (SAAs) or with zero SAA for 3 d. Pulse sequences were used to selectively measure glutathione (GSH), and linear combination modeling of spectra was used to measure other high-abundance brain metabolites and expressed relative to creatine (Cr).ResultsAlthough dietary SAAs are required to maintain GSH, the 3-d SAA insufficiency resulted in no significant change in GSH/Cr in the three brain regions. Principal component analysis of 16 metabolites measured by linear combination modeling showed that the metabolic pattern in the midbrain, but not in the parietal lobes, was distinguished according to the dietary SAAs. Multivariate statistical analysis showed that the major discriminating factors were signals of glutamate/Cr, (glutamate + glutamine)/Cr, and myoinositol/Cr. Correlation analyses between midbrain metabolites and GSH-related metabolites in plasma showed that midbrain glutamate/Cr had an inverse correlation with plasma cystine.ConclusionThe data show that magnetic resonance spectroscopy is a non-invasive tool suitable for nutritional assessment and suggest that nutritional imbalance caused by 3 d of SAA-free food more selectively affects the midbrain than the parietal lobes.     

Effects of poly-��-glutamic acid on serum and brain concentrations of glutamate and GABA in diet-induced obese rats

Poly-gamma-glutamic acid (γ-PGA) is a mucilaginous and biodegradable compound produced by Bacillus subtilis from fermented soybeans, and is found in the traditional Korean soy product, cheongkukjang. This study was carried out to evaluate the effects of γ-PGA from a food source on the concentration of the neurotransmitter GABA and its metabolic precursor glutamate in diet-induced obese rats. Eight-week old male Sprague-Dawley rats (n=60) were used. The rats were divided into two groups and obesity was induced by providing either a 10% control fat or 45% high fat diet for 5 weeks. The rats were then blocked into 6 groups and supplemented with a 0.1% γ-PGA diet for 4 weeks. After sacrifice, brain and serum GABA and glutamate concentrations were analyzed by high performance liquid chromatography with fluorometric detection. The rats fed the high fat diet had significantly increased body weights. γ-PGA supplementation significantly increased serum concentrations of glutamate and GABA in the control fat diet groups while this effect was not found in the high fat groups. In the brain, glutamate concentrations were significantly higher in the γ-PGA supplemented groups both in rats fed the normal and high fat diets than in the no γ-PGA controls. GABA concentrations showed the same tendency. The results indicated that γ-PGA intake increased GABA concentrations in the serum and brain. However, the effects were not shown in obese rats.     

^1H MRS在足月新生儿缺氧缺血性脑病中的应用

目的 通过探讨氢质子磁共振波谱与足月新生儿缺氧缺血性脑病代谢变化的关系,以评估氢质子磁共振波谱在诊断足月新生儿缺氧缺血性脑病及预后的作用.方法 研究对象为30例在临床诊断为新生儿缺氧缺血性脑病的足月新生儿与7例足月正常对照儿.所有研究对象于出生13天内进行头颅氢质子磁共振波谱检查,测量右侧基底节和右侧额叶代谢产物波峰下面积值,同时记录研究对象的胎龄、性别、分娩方式、出生体重、头颅氢质子磁共振波谱检查时的日龄、新生儿缺氧缺血性脑病临床分度等资料,于其生后第3天、第7天、第14天、第28天进行新生儿行为神经评分,并对上述资料进行统计学分析.结果 ①新生儿缺氧缺血性脑病组与对照组比较,右侧基底节和右侧额叶乳酸/肌酸、N-乙酰天门冬氨酸/肌酸、谷氨酸盐和谷氨酰胺/肌酸的比值均有统计学意义（均P〈0.05）;而右侧基底节和右侧额叶肌醇/肌酸、胆碱/肌酸的比值均无统计学意义（均P〉0.05）;②新生儿缺氧缺血性脑病轻度与中重度比较,右侧基底节和右侧额叶乳酸/肌酸、N-乙酰天门冬氨酸/肌酸、谷氨酸盐和谷氨酰胺/肌酸的比值均有统计学意义（均P〈0.05）;③新生儿缺氧缺血性脑病组右侧基底节和右侧额叶乳酸/肌酸、N-乙酰天门冬氨酸/肌酸、谷氨酸盐和谷氨酰胺/肌酸的比值与临床分度有显著相关性（均P〈0.01）;④新生儿缺氧缺血性脑病组右侧基底节和右侧额叶乳酸/肌酸、N-乙酰天门冬氨酸/肌酸、谷氨酸盐和谷氨酰胺/肌酸的比值与患儿第14天新生儿行为神经评分具有显著相关性（均P〈0.01）.结论 氢质子磁共振波谱对新生儿缺氧缺血性脑病的临床诊断及短期预后评估具有重要临床意义,值得深入研究及推广.     

Proton magnetic resonance spectroscopy in adults with childhood lead exposure

Background

Childhood lead exposure adversely affects neurodevelopment. However, few studies have examined changes in human brain metabolism that may underlie known adverse cognitive and behavioral outcomes.

Objective

We examined the association between mean childhood blood lead levels and in vivo brain metabolite concentrations as adults, determined by proton magnetic resonance spectroscopy (MRS) in a birth cohort with documented low-to-moderate lead exposure.

Methods

Adult participants from the Cincinnati Lead Study [n = 159; mean age (± SD), 20.8 ± 0.9 years] completed a quantitative, short-echo proton MRS protocol evaluating seven regions to determine brain concentrations of N-acetyl aspartate (NAA), creatine and phosphocreatine (Cr), cholines (Cho), myo-inositol, and a composite of glutamate and glutamine (GLX). Correlation and multiple linear regression analyses were conducted.

Results

Mean childhood blood lead levels were associated with regionally specific brain metabolite concentrations adjusted for age at imaging and Full-Scale intelligence quotient. Adjusted analyses estimated for a unit (micrograms per deciliter) increase in mean childhood blood lead concentrations, a decrease of NAA and Cr concentration levels in the basal ganglia, a decrease of NAA and a decrease of Cho concentration levels in the cerebellar hemisphere, a decrease of GLX concentration levels in vermis, a decrease of Cho and a decrease of GLX concentration levels in parietal white matter, and a decrease of Cho concentration levels in frontal white matter.

Conclusions

Gray-matter NAA reductions associated with increasing childhood blood lead levels suggest that sustained childhood lead exposure produces an irreversible pattern of neuronal dysfunction, whereas associated white-matter choline declines indicate a permanent alteration to myelin architecture.     

Maternal High-Fat Diet Modulates Cnr1 Gene Expression in Male Rat Offspring

In recent years, strong evidence has emerged that exposure to a maternal high-fat diet (HFD) provokes changes in the structure, function, and development of the offspring’s brain and may induce several neurodevelopmental and psychiatric illnesses. The aims of this study were to evaluate the effects of a maternal HFD during pregnancy and lactation on depressive-like behavior and Cnr1 gene expression (encoding the CB1 receptor) in brain structures of rat offspring and to investigate the epigenetic mechanism involved in this gene expression. We found that a maternal HFD during pregnancy and lactation induced a depressive-like phenotype at postnatal days (PNDs) 28 and 63. We found that a maternal HFD decreased the Cnr1 mRNA levels in the prefrontal cortex with the increased levels of miR-212-5p and methylation of CpG islands at the Cnr1 promoter and reduced the level of Cnr1 gene expression in the dorsal striatum with an increased level of miR-154-3p in adolescent male offspring. A contrasting effect of a maternal HFD was observed in the hippocampus, where upregulation of Cnr1 gene expression was accompanied by a decrease of miR-154-3p (at PNDs 28 and 63) and miR-212-5p (at PND 63) expression and methylation of CpG islands at the Cnr1 promoter in male offspring. In summary, we showed that a maternal HFD during pregnancy and lactation triggered several epigenetic mechanisms in the brains of rat offspring, which may be related to long-lasting alterations in the next generation and produce behavioral changes in offspring, including a depressive-like phenotype.     

Dietary variation of protein–carbohydrate: Effect on hypothalamic and hippocampal GABA–glutamate in relation to aging

Abstract

Dietary protein variation has been found to alter brain regional neurochemistry with aging. In the present investigation, we studied the effect of short-term treatment of protein–carbohydrate variable diet to rat on hypothalamic and hippocampal γ-amino butyric acid (GABA)–glutamate metabolism with increase of age. Exposure of male albino rats with diet containing normal protein (20%)–normal carbohydrate (68%) increased GABA metabolism and decreased glutamate metabolism in both hypothalamus and hippocampus with the increase of age. GABA–glutamate metabolism of rats having low protein (8%)–high carbohydrate (80%) diet for short-term period (STP), was activated in young age (3 months) and decreased in old age (18 months) in both the brain regions. On the contrary, intake of high protein (50%)–low carbohydrate (38%) diet under similar condition decreased GABA–glutamate metabolism in both hypothalamus and hippocampus of young brain and increased only in hypothalamus of aged brain. In hippocampus of aged brain the same diet decreased glutamate metabolism without changing its GABA metabolism. These results suggest that an age-associated change in GABA–glutamate metabolism depends on the amount of dietary protein and carbohydrate and also on the brain region.     

Glutamine administration during total parenteral nutrition protects liver adenosine nucleotides during and after subsequent hemorrhagic shock

BACKGROUND: Glutamine supplementation of total parenteral nutrition (TPN) in stressed patients has been advocated. To determine whether glutamine supplementation affects the host response to conditions of stress, animals were given TPN with or without glutamine for 7 days. They were then subjected to the acute stress of hemorrhagic shock, which results in marked loss of hepatic adenosine triphosphate (ATP) and adenosine diphosphate (ADP), with accumulation of adenosine monophosphate (AMP) and the metabolites adenosine, inosine, hypoxanthine, and xanthine. This loss of ATP and accumulation of metabolites contributes to subsequent tissue damage. The hypothesis of the study was that glutamine supplementation would significantly improve restoration of hepatic adenosine nucleotides before and after hemorrhagic shock. METHODS: Sprague-Dawley rats were given TPN for 7 days. One half of the animals (n = 8) received TPN supplemented with glutamine, while one half received TPN with an isonitrogenous mixture of alanine and glycine. Animals were subjected to hemorrhagic shock for 30 minutes and then resuscitated using only heparinized shed blood. Liver biopsies were taken pre- and post-shock, and at 30 and 60 minutes after resuscitation. ATP, ADP, AMP, and their metabolites were measured using gradient high-performance liquid chromatography. RESULTS: After 7 days of TPN, baseline values of ATP, ADP, AMP, and metabolites were similar between the 2 groups before the initiation of shock. Glutamine-treated animals manifested a 40% decrease in ATP level immediately after shock and recovered to 90% of baseline within 60 minutes. By contrast, the control animals manifested a 66% decrease in ATP level after the shock period and recovered only to 60% of baseline at 1 hour postresuscitation. Similar changes were observed in ADP levels and were accompanied by corresponding changes in AMP and adenosine metabolites, all of which rose during shock and fell after resuscitation. CONCLUSIONS: Glutamine supplementation significantly protected the liver from tissue damage caused by hemorrhagic shock. ATP levels remained higher during shock and recovered more rapidly after resuscitation. Glutamine supplementation may help to protect cellular energy stores in the stressed organism and may offer opportunities for therapeutic intervention during and after stress.     

Short-Chain Fatty Acids Ameliorate Depressive-like Behaviors of High Fructose-Fed Mice by Rescuing Hippocampal Neurogenesis Decline and Blood–Brain Barrier Damage

Excessive fructose intake is associated with the increased risk of mental illness, such as depression, but the underlying mechanisms are poorly understood. Our previous study found that high fructose diet (FruD)-fed mice exhibited neuroinflammation, hippocampal neurogenesis decline and blood–brain barrier (BBB) damage, accompanied by the reduction of gut microbiome-derived short-chain fatty acids (SCFAs). Here, we found that chronic stress aggravated these pathological changes and promoted the development of depressive-like behaviors in FruD mice. In detail, the decreased number of newborn neurons, mature neurons and neural stem cells (NSCs) in the hippocampus of FruD mice was worsened by chronic stress. Furthermore, chronic stress exacerbated the damage of BBB integrity with the decreased expression of zonula occludens-1 (ZO-1), claudin-5 and occludin in brain vasculature, overactivated microglia and increased neuroinflammation in FruD mice. These results suggest that high fructose intake combined with chronic stress leads to cumulative negative effects that promote the development of depressive-like behaviors in mice. Of note, SCFAs could rescue hippocampal neurogenesis decline, improve BBB damage and suppress microglia activation and neuroinflammation, thereby ameliorate depressive-like behaviors of FruD mice exposed to chronic stress. These results could be used to develop dietary interventions to prevent depression.     

Effects of oral supplementation with glutamine and alanyl-glutamine on glutamine,glutamate, and glutathione status in trained rats and subjected to long-duration exercise

ObjectiveWe investigated the effect of supplementation with the dipeptide L-alanyl-L-glutamine (DIP) and a solution containing L-glutamine and L-alanine, both in the free form, on the plasma and tissue concentrations of glutamine, glutamate, and glutathione (GSH) in rats subjected to long-duration exercise.MethodsRats were subjected to sessions of swim training. Twenty-one days before sacrifice, the animals were supplemented with DIP (1.5 g/kg, n = 6), a solution of free L-glutamine (1 g/kg) and free L-alanine (0.61 g/kg; GLN + ALA, n = 6), or water (CON, n = 6). Animals were sacrificed before (TR, n = 6) or after (LD, n = 6) long-duration exercise. Plasma concentrations of glutamine, glutamate, glucose, and ammonia and liver and muscle concentrations of glutamine, glutamate, and reduced and oxidized (GSSG) GSH were measured.ResultsHigher concentrations of plasma glutamine were found in the DIP-TR and GLN + ALA-TR groups. The CON-LD group showed hyperammonemia, whereas the DIP-LD and GLN + ALA-LD groups exhibited lower concentrations of ammonia. Higher concentrations of glutamine, glutamate, and GSH/GSSG in the soleus muscle and GSH and GSH/GSSG in the liver were observed in the DIP-TR and GLN + ALA-TR groups. The DIP-LD and GLN + ALA-LD groups exhibited higher concentrations of GSH and GSH/GSSG in the soleus muscle and liver compared with the CON-LD group.ConclusionChronic oral administration of DIP and free GLN + ALA before long-duration exercise represents an effective source of glutamine and glutamate, which may increase muscle and liver stores of GSH and improve the redox state of the cell.     

Brain glutamate and gamma-aminobutyrate (GABA) metabolism in thiamin-deficient rats

The brain metabolism of glutamate and gamma-aminobutyrate (GABA) was investigated in thiamin-deficient and pair-fed control rats, in order to determine whether the GABA shunt may provide an important alternative to 2-oxo-glutarate dehydrogenase (EC 1.2.4.2) in energy-yielding metabolism in thiamin deficiency. Brains from thiamin-deficient animals contained less glutamate, 2-oxo-glutarate and GABA than those from control animals. The brain content of ATP was unaffected by thiamin deficiency. After intracerebroventricular injection of [14C]glutamate, the specific radioactivity of GABA in the brains from deficient animals was 45-50% higher than that in controls, suggesting a considerable increase in the metabolic flux through the GABA shunt in thiamin deficiency. Brain GABA showed a marked circumannual variation, with a peak in mid-summer and a minimum value in mid-winter.     

青春期雌性小鼠抑郁模型的建立及其意义

目的 建立青春期雌性小鼠抑郁模型,为女性青春期抑郁症高发机制研究奠定基础。方法 C57BL/6J 18天雌性、雄性小鼠各16只分别随机分为雌性对照组和雌性组,雄性对照组和雄性组 （n=8）。4组小鼠适应2 d后于第20天测试行为学。雌性组和雄性组自第21天制备3周慢性轻度不可预知应激 （chronic unpredictable mild stress,CUMS） 模型,3周后再对4组进行行为学测试。结果 造模前4组行为学均无统计学差异 （均有P> 0.05）。造模后雌性组较雌性对照组体质量变化、糖水消耗百分比、旷场运动距离及中央区时间、高架十字迷宫开放臂时间减少 （均有P<0.05）,悬尾和强迫游泳不动时间增加（均有P<0.05） ;雄性组较雄性对照组体质量变化、糖水消耗百分比、旷场运动距离及中央区时间减少,强迫游泳不动时间增加 （均有P<0.05）。与造模前比较,雌性组糖水消耗百分比和中央区时间均减少 （均有P<0.05）,悬尾和强迫游泳不动时间均增加（均有P<0.05）;雄性组较造模前糖水消耗百分比减少（t=6.02,P<0.001）,强迫游泳不动时间增加 （t=2.91,P=0.013）。造模后雌性组较雄性组运动距离和开放臂时间均减少 （均有P<0.05）,悬尾和强迫游泳不动时间均增加（均有P<0.05）。结论 成功造模后雌性组较雄性组抑郁样行为更加明显,表明青春期雌性小鼠比雄性小鼠对CUMS更加易感。