Brain-derived Neurotrophic Factor Expression Research Articles

The Role of BDNF in the Antidepressant Effects of Electroconvulsive Therapy.

Electroconvulsive therapy (ECT) is an effective treatment method for depression therapy. It produces a number of biological effects, including neurotrophic factors regulation. In the present paper, we investigated the ECT response in depressed rats subjected to the variable frequency ultrasound (20-45 kHz) and examined the contribution of brain-derived neurotrophic factor (BDNF) expression changes to the observed effects. The obtained results reflect the therapeutic potential of ECT for the treatment of depressive-like state in rodents and indicate the role of BDNF in these processes. In future research, it is necessary to investigate the relationship between neurotrophin and structural changes and to study other neurotrophic biomarkers that may be associated with the development of depression-like state and the therapy response.

Stress-mediated Activation of Ferroptosis, Pyroptosis, and Apoptosis Following Mild Traumatic Brain Injury Exacerbates Neurological Dysfunctions.

Nearly half of mild traumatic brain injury (mTBI) patients continue to experience residual neurological dysfunction, which may be attributed to exposure to stress. Ferroptosis, a newly discovered form of cell death, is increasingly recognized for its involvement in the pathophysiology of TBI. Understanding the mechanisms by which stress influences mTBI, particularly through ferroptosis, is crucial for the effective treatment and prevention of mTBI patients who are sensitive to stressful events. In our study, a mouse mTBI model was established. An acute restraint stress (RS) and a chronic unpredictable mild stress (CUMS) model then were applied to make acute and chronic stress, respectively. We found acute RS significantly delayed the recovery of reduced body weight and short-term motor dysfunctions and exacerbated cell insults and blood-brain barrier leakage caused by mTBI. Further studies revealed that acute RS exacerbates neuronal ferroptosis, pyroptosis, and apoptosis by promoting iron overloading in the neocortex following mTBI. Interestingly, the inhibition of ferroptosis with iron chelators, including deferoxamine and ciclopirox, reversed pyroptosis and apoptosis. Moreover, CUMS aggravated neurological dysfunctions (motor function, cognitive function, and anxiety-like behavior) and exacerbated brain lesion volume. CUMS also exacerbates ferroptosis, pyroptosis, and apoptosis by intensifying iron deposition, along with decreasing the expression of neuronal brain-derived neurotrophic factor and glucocorticoid receptor in the neocortex post mTBI. These effects were also mitigated by iron chelators. Our findings suggest that alleviating ferroptosis induced by iron deposition may represent a promising therapeutic approach for mTBI patients who have experienced stressful events.

Mannose-Functionalized Chitosan-Coated PLGA Nanoparticles for Brain-Targeted Codelivery of CBD and BDNF for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a common neurodegenerative disease causing cognitive and memory decline. AD is characterized by the deposition of amyloid-β and hypophosphorylated forms of tau protein. AD brains are found to be associated with neurodegeneration, oxidative stress, and inflammation. Cannabidiol (CBD) shows neuroprotective, antioxidant, and anti-inflammatory properties and simultaneously reduces amyloid-β production and tau hyperphosphorylation. The brain-derived neurotrophic factor (BDNF) plays a vital role in the development and maintenance of the plasticity of the central nervous system. A decline of BDNF levels in AD patients results in reduced plasticity and neuronal cell death. Current therapeutics against AD are limited to only symptomatic relief, necessitating a therapeutic strategy that reverses cognitive decline. In this scenario, combination therapy of CBD and BDNF could be a fruitful strategy for the treatment of AD. We designed mannose-conjugated chitosan-coated poly(d,l-lactide-co-glycolide (PLGA) (CHTMAN-PLGA) nanoparticles for the codelivery of CBD and BDNF to the brain. Chitosan is modified with mannose to specifically target the glucose transporter-1 (GLUT-1) receptor abundantly present in the blood-brain barrier for selectively delivering therapeutics to the brain. The CBD-encapsulated nanoparticles showed an average hydrodynamic diameter of 306 ± 8.12 nm and a zeta potential of 31.7 ± 1.53 mV. The coated nanoparticles prolonged encapsulated CBD release from the PLGA matrix. The coated nanoparticles exhibited sustained release of CBD for up to 22 days with 91.68 ± 2.91% release of the encapsulated drug. The coated nanoparticles, which had a high positive zeta potential (31.7 ± 1.53 mV), encapsulated the plasmid DNA. The qualitative transfection efficiency was investigated using CHTMAN-PLGA-CBD/pGFP in bEND.3, primary astrocytes, and primary neurons, while the quantitative transfection efficiency of the delivery system was determined using CHTMAN-PLGA-CBD/pBDNF. In vitro, the pBDNF transfection study revealed that the BDNF expression was 4-fold higher for CHTMAN-PLGA-CBD/pBDNF than for naked pBDNF in all of the cell lines. The cytotoxicity and hemocompatibility of the designed nanoparticles were tested in bEND.3 cells and red blood cells, respectively, and the nanoparticles were found to be nontoxic and hemocompatible. Hence, mannose-conjugated chitosan-coated PLGA nanoparticles could be useful as brain-targeting delivery vehicles for the codelivery of CBD and BDNF for possible AD treatment.

8245 Estradiol Interacts with the Val66Met Single Nucleotide Polymorphism in the Brain-Derived Neurotrophic Factor Gene to Alter Endometrial Thickness in a Rat Model

Abstract Disclosure: S. Moosa: None. E. Kohlmeir: None. S. Kujawa: None. D. Korol: None. A. Prakapenka: None. Brain derived neurotrophic factor (BDNF) is most known for its involvement in cell development, survival, and plasticity in the nervous system. BDNF and its cognate receptors can also be found in non-neural tissue including the ovary and uterus in humans and in animal models, suggesting that BDNF signaling may regulate reproductive functions. Indeed, disruptions in BDNF signaling are associated with health conditions related to the reproductive system, such as endometriosis. Studies show that treatment with estradiol increases expression of uterine BDNF and its cognate receptors, suggesting that estradiol can modulate BDNF signaling and its effects in the reproductive system. A common human functional single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met (rs6265), is thought to decrease activity-dependent release of BDNF, altering BDNF signaling. Using a CRISPR/cas9 rat model of the human Val66Met BDNF SNP, we investigated the interacting role of estradiol and this variation in the BDNF gene on female uterine structure. Middle-aged (11-14-months-old) female rats were either homozygous for the Val allele (Val/Val; control) or the Met allele (Met/Met; BDNF SNP). All rats were ovariectomized and after three weeks randomly assigned to receive subcutaneous treatment of vehicle (sesame oil) or estradiol (17beta-estradiol benzoate) for two consecutive days. Twenty-four hours after the second injection, rats were euthanized and tissue collected, weighed, and placed in fixative. Uterine tissue weights differed significantly by treatment and by genotype such that uterine horns were heavier in estradiol-treated compared to vehicle-treated rats within each genotype and uterine horns were heavier in Met/Met compared to Val/Val rats within each treatment condition. To determine which uterine layer contributed to the weight differences, uterine horns were sectioned and stained with hematoxylin and eosin. Thickness of myometrium, endometrium, and lumen were individually measured. Although there were no treatment and no genotype effects on myometrial thickness, there were significant treatment and genotype effects on endometrial thickness. Of note, the endometrium of estradiol-treated Met/Met rats was thicker compared to vehicle-treated Met/Met rats and compared to estradiol-treated Val/Val rats, suggesting that estradiol and the BDNF gene variation interact to modulate endometrial size. Lumen circumference did not differ between genotypes but did increase with estradiol compared to vehicle treatment within each genotype. Altogether, findings suggest that BDNF genotype affects uterine structure, notably the endometrium. Differences with BDNF gene variation emerged with estradiol exposure, implicating the hormone’s role in modulating BDNF signaling and warranting future research on the interactive effects of estradiol and BDNF genotype on the endometrium. Presentation: 6/2/2024

8245 Estradiol Interacts with the Val66Met Single Nucleotide Polymorphism in the Brain-Derived Neurotrophic Factor Gene to Alter Endometrial Thickness in a Rat Model

Abstract Disclosure: S. Moosa: None. E. Kohlmeir: None. S. Kujawa: None. D. Korol: None. A. Prakapenka: None. Brain derived neurotrophic factor (BDNF) is most known for its involvement in cell development, survival, and plasticity in the nervous system. BDNF and its cognate receptors can also be found in non-neural tissue including the ovary and uterus in humans and in animal models, suggesting that BDNF signaling may regulate reproductive functions. Indeed, disruptions in BDNF signaling are associated with health conditions related to the reproductive system, such as endometriosis. Studies show that treatment with estradiol increases expression of uterine BDNF and its cognate receptors, suggesting that estradiol can modulate BDNF signaling and its effects in the reproductive system. A common human functional single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met (rs6265), is thought to decrease activity-dependent release of BDNF, altering BDNF signaling. Using a CRISPR/cas9 rat model of the human Val66Met BDNF SNP, we investigated the interacting role of estradiol and this variation in the BDNF gene on female uterine structure. Middle-aged (11-14-months-old) female rats were either homozygous for the Val allele (Val/Val; control) or the Met allele (Met/Met; BDNF SNP). All rats were ovariectomized and after three weeks randomly assigned to receive subcutaneous treatment of vehicle (sesame oil) or estradiol (17beta-estradiol benzoate) for two consecutive days. Twenty-four hours after the second injection, rats were euthanized and tissue collected, weighed, and placed in fixative. Uterine tissue weights differed significantly by treatment and by genotype such that uterine horns were heavier in estradiol-treated compared to vehicle-treated rats within each genotype and uterine horns were heavier in Met/Met compared to Val/Val rats within each treatment condition. To determine which uterine layer contributed to the weight differences, uterine horns were sectioned and stained with hematoxylin and eosin. Thickness of myometrium, endometrium, and lumen were individually measured. Although there were no treatment and no genotype effects on myometrial thickness, there were significant treatment and genotype effects on endometrial thickness. Of note, the endometrium of estradiol-treated Met/Met rats was thicker compared to vehicle-treated Met/Met rats and compared to estradiol-treated Val/Val rats, suggesting that estradiol and the BDNF gene variation interact to modulate endometrial size. Lumen circumference did not differ between genotypes but did increase with estradiol compared to vehicle treatment within each genotype. Altogether, findings suggest that BDNF genotype affects uterine structure, notably the endometrium. Differences with BDNF gene variation emerged with estradiol exposure, implicating the hormone’s role in modulating BDNF signaling and warranting future research on the interactive effects of estradiol and BDNF genotype on the endometrium. Presentation: 6/2/2024

New insights into individual differences in response to chronic unpredictable mild stress (CUMS) in rats with respect to hippocampal BDNF and GSK3-β expression levels

Preclinical and clinical studies have shown a wide-range of individual differences in response to stressors or novel environments which can affect the susceptibility to develop abnormal behaviors and neuropsychiatric disorders. Both vulnerability and resiliency have been observed in animals and humans experiencing stressful events. Chronic unpredictable mild stress (CUMS) is a rodent depression model consisting of various stressors. This protocol leads to depressive- and anhedonic-like behaviors in rodents. The present study aimed to evaluate potential individual differences in response to CUMS in rats, with respect to the expression level of brain-derived neurotrophic factor (BDNF) and glycogen synthase kinases 3-beta (GSK3-β) (proteins involved in the modulation of mood, neuroplasticity, and cognition) in the hippocampus. CUMS was performed for four consecutive weeks. Depressive-like behavior, locomotor activity, anxiety-like behavior, and pain threshold were also evaluated using forced swim test (FST), open field test (OFT), and the hot plate (HP), respectively. Real-time PCR was used to evaluate BDNF and GSK3-β expression levels. The results showed that CUMS rats can be classified as two clusters: affected and non-affected (depressed and non-depressed). Affected rats showed depressive- and anxiety-like behaviors, decreased locomotor activity, and increased pain threshold. However, non-affected rats were similar to controls. In addition, there was a downregulation of BDNF and upregulation of GSK3-β in affected rats. Spearman correlation analysis also showed a relationship between BDNF and GSK3-β expression levels with individual differences. In conclusion, the present study showed that BDNF and GSK3-β may be involved in individual differences in CUMS rats.

Corrigendum: Sorl1 knockout inhibits expression of brain-derived neurotrophic factor: involvement in the development of late-onset Alzheimer's disease.

Corrigendum: Sorl1 knockout inhibits expression of brain-derived neurotrophic factor: involvement in the development of late-onset Alzheimer's disease.

Hypocretin-1/Hypocretin Receptor 1 Regulates Neuroplasticity and Cognitive Function through Hippocampal Lactate Homeostasis in Depressed Model.

Cognitive dysfunction is not only a common symptom of major depressive disorder, but also a more common residual symptom after antidepressant treatment and a risk factor for chronic and recurrent disease. The disruption of hypocretin regulation is known to be associated with depression, however, their exact correlation is remains to be elucidated. Hypocretin-1 levels are increased in the plasma and hypothalamus from chronic unpredictable mild stress (CUMS) model mice. Excessive hypocretin-1 conducted with hypocretin receptor 1 (HCRTR1) reduced lactate production and brain-derived neurotrophic factor (BDNF) expression by hypoxia-inducible factor-1α (HIF-1α), thus impairing adult hippocampal neuroplasticity, and cognitive impairment in CUMS model. Subsequently, it is found that HCRTR1 antagonists can reverse these changes. The direct effect of hypocretin-1 on hippocampal lactate production and cognitive behavior is further confirmed by intraventricular injection of hypocretin-1 and microPET-CT in rats. In addition, these mechanisms are further validated in astrocytes and neurons in vitro. Moreover, these phenotypes and changes in molecules of lactate transport pathway can be duplicated by specifically knockdown of HCRTR1 in hippocampal astrocytes. In summary, the results provide molecular and functional insights for involvement of hypocretin-1-HCRTR1 in altered cognitive function in depression.

Deep brain stimulation mitigates memory deficits in a rodent model of traumatic brain injury

BackgroundTraumatic brain injury (TBI) is a major life-threatening event. In addition to neurological deficits, it can lead to long-term impairments in attention and memory. Deep brain stimulation (DBS) is an established therapy for movement disorders that has been recently investigated for memory improvement in various disorders. In models of TBI, stimulation delivered to different brain targets has been administered to rodents long after the injury with the objective of treating motor deficits, coordination and memory impairment. ObjectiveTo test the hypothesis that DBS administered soon after TBI may prevent the development of memory deficits and exert neuroprotective effects. MethodsMale rats were implanted with DBS electrodes in the anterior nucleus of the thalamus (ANT) one week prior to lateral fluid percussion injury (FPI). Immediately after TBI, animals received active or sham stimulation for 6 h. Four days later, they were assessed in a novel object/novel location recognition test (NOR/NLR) and a Barnes maze paradigm. After the experiments, hippocampal cells were counted. Separate groups of animals were sacrificed at different timepoints after TBI to measure cytokines and brain derived neurotrophic factor (BDNF). In a second set of experiments, TBI-exposed animals receiving active or sham stimulation were injected with the tropomyosin receptor kinase B (TrkB) antagonist ANA-12, followed by behavioural testing. ResultsRats exposed to TBI given DBS had an improvement in several variables of the Barnes maze, but no significant improvements in NOR/NLR compared to Sham DBS TBI animals or non-implanted controls. Animals receiving stimulation had a significant increase in BDNF levels, as well as in hippocampal cell counts in the hilus, CA3 and CA1 regions. DBS failed to normalize the increased levels of TNFα and the proinflammatory cytokine IL1β in the perilesional cortex and the hippocampus of the TBI-exposed animals. Pharmacological experiments revealed that ANA-12 administered alongside DBS did not counter the memory improvement observed in ANT stimulated animals. ConclusionsDBS delivered immediately after TBI mitigated memory deficits, increased the expression of BDNF and the number of hippocampal cells in rats. Mechanisms for these effects were not related to an anti-inflammatory effect or mediated via TrkB receptors.

Brain Derived Neurotrophic Factor Stimulates Hypothalamic and Gonadal Reproductive Hormones and Oocyte Maturation in Zebrafish.

Brain-derived neurotrophic factor (BDNF) is a peptide widely known for its role in neurogenesis and synaptic plasticity. Its expression in non-neuronal tissues has been reported. In mammals, it is involved in ovarian development, follicle growth, oocyte maturation, and early embryonic development. In zebrafish, it was demonstrated that BDNF increases food intake and regulates metabolism. Reproduction and metabolism are tightly linked. We hypothesized that BDNF modulates reproductive hormones and reproductive functions in zebrafish. This study aimed to determine BDNF expression in the zebrafish reproductive axis and whether it modulates the reproductive endocrine milieu and oocyte biology in zebrafish. Our results show that bdnf and its receptor trkb, and BDNF-like immunoreactivity are detected in zebrafish gonads and liver cells. This suggests BDNF local production and possible actions within the gonads and liver. Intraperitoneal administration of 1, 10, or 100 ng/g bodyweight BDNF significantly (ANOVA, p<0.05) increased sgnrh/cgnrh-II, kiss1, and cyp19a1b mRNAs in the zebrafish brain; steroidogenic enzymes (star and cyp19a1a) and key receptors in the zebrafish gonads. In vitro incubation of zebrafish liver cells with BDNF significantly (ANOVA, p<0.05) increased estrogen receptor mRNAs and vitellogenin concentrations (ELISA) in the cells. BDNF (100 ng/mL) induced (ANOVA, p<0.05) oocyte maturation in vitro at 24 hours post-incubation and significantly upregulated cumulus-expansion related genes (ANOVA, p<0.05). Overall, our findings indicate a stimulatory role for BDNF in the reproductive axis of zebrafish. This provides impetus for future research on its mechanism of action and potential practical applications to enhance reproduction in aquaculture.

Expression of brain-derived neurotrophic factor and neurotrophic tyrosine receptor kinase-2 in bovine testes

Expression of brain-derived neurotrophic factor and neurotrophic tyrosine receptor kinase-2 in bovine testes

Expression of Neurotrophic Factors and Their Receptors in the Rat Spinal Trigeminal Nucleus

The spinal trigeminal nucleus as part of the trigeminal sensory nuclear complex is associated with the transmission of discriminative tactile sensations, primarily pain, and temperature, from the orofacial region. It is divided into three parts – caudal, interpolar, and oral subnucleus which process pain and temperature stimulate. Our previous experiments have revealed the presence of certain neurotrophic factors such as the nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) in this nucleus. These neurotrophins facilitate neuronal differentiation, survival, and plasticity by signalling through high-affinity transmembrane receptors. By using primary antibodies against NGF, BDNF, NT-3, and glial-derived neurotrophic factor (GDNF), and their corresponding receptors of the tyrosine receptor kinase (Trk) proto-oncogene family and GFRα1, we found immunoreactive cells scattered along the whole length of the nucleus in rats in all three subnuclei. In particular, we observed that the majority of spinal trigeminal neurons were intensely immunostained for all the neurotrophic factors examined and that they were richly endowed with their Trk receptors. Our results also showed that NGF, NT-3, TrkC and GFRα1 expression did not differ between different topographic regions of the nucleus, while BDNF, GDNF, and TrkA expression was highest in the SpVo, and TrkB expression was highest in the SpVi and SpVc. Given that these neurotrophic factors are involved in mechanisms of central sensitization in trigeminal nociceptive pathways, it can be inferred that neurotrophins may contribute to a better understanding of the fundamental mechanisms of orofacial pain.

Akkermansia muciniphila improve cognitive dysfunction by regulating BDNF and serotonin pathway in gut-liver-brain axis

BackrgroundAkkermansia muciniphila, a next-generation probiotic, is known as a cornerstone regulating the gut-organ axis in various diseases, but the underlying mechanism remains poorly understood. Here, we revealed the neuronal and antifibrotic effects of A. muciniphila on the gut-liver-brain axis in liver injury.ResultsTo investigate neurologic dysfunction and characteristic gut microbiotas, we performed a cirrhosis cohort (154 patients with or without hepatic encephalopathy) and a community cognition cohort (80 participants in one region for three years) and validated the existence of cognitive impairment in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic injury mouse model. The effects of the candidate strain on cognition were evaluated in animal models of liver injury. The expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors was accessed in patients with fibrosis (100 patients) according to the fibrosis grade and hepatic venous pressure gradient. The proportion of A. muciniphila decreased in populations with hepatic encephalopathy and cognitive dysfunction. Tissue staining techniques confirmed gut-liver-brain damage in liver injury, with drastic expression of BDNF and serotonin in the gut and brain. The administration of A. muciniphila significantly reduced tissue damage and improved cognitive dysfunction and the expression of BDNF and serotonin. Isolated vagus nerve staining showed a recovery of serotonin expression without affecting the dopamine pathway. Conversely, in liver tissue, the inhibition of injury through the suppression of serotonin receptor (5-hydroxytryptamine 2A and 2B) expression was confirmed. The severity of liver injury was correlated with the abundance of serotonin, BDNF, and A. muciniphila.ConclusionsA. muciniphila, a next-generation probiotic, is a therapeutic candidate for alleviating the symptoms of liver fibrosis and cognitive impairment.Graphical

Antistress Effects of Terpinen-4-ol and Compounds of Mimicked Yuzu Synthetic Fragrance in Humans and Mice.

This study investigated the antistress effects of yuzu synthetic fragrances by employing three experiments on humans and mice using two yuzu synthetic fragrances and five single compounds. We prepared two synthetic fragrances based on the component analysis of two natural yuzu essential oils extracted by cold-pressed and steam-distilled extraction methods. Chromogranin A (CgA) and heart rate (HR) were used as stress indices in human experiments. Immobility time during the forced swim test was used as a stress index in mice experiments. We analyzed brain mechanisms by measuring the expression of neurotrophic factors, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in the mice experiments. Synthetic yuzu fragrance mimicked steam-distilled oil (SD) significantly reduced participants' heart rate in experiment 1. In the forced swim test conducted in experiment 2, SD significantly reduced immobility time, and increased the expression of neurotrophic factors BDNF, NGF, and NT-3 in the hippocampus of mice. In experiment 3, focusing on single compounds, terpinen-4-ol significantly reduced immobility time in the forced swim test. These findings indicate that inhalation of SD and terpinen-4-ol has antistress effects. Terpinen-4-ol is a strong candidate for further investigation as a potential stress-reducing agent.

Comparing the effect of high-intensity interval exercise and voluntary exercise training on cognitive functions in rats

It is known that exercise increases brain-derived neurotrophic factor (BDNF) levels in the hippocampus, the brain region responsible for learning and memory, resulting in improved cognitive functions and learning processes. However, it is claimed that different types of exercise cause different responses in the brain. It is thought that lactate and osteocalcin secreted in response to exercise are associated with an increase in BDNF levels. However, there are not enough studies on this subject. This study aimed to compare the effects of high-intensity interval training (HIIT) and voluntary exercise training on cognitive performance and molecular connections. Male rats were randomly divided into control, voluntary exercise training and HIIT groups. The voluntary exercise group had free access to the voluntary wheel for 8 weeks. The HIIT group performed HIIT on the treadmill 3 days a week for 8 weeks. The rats underwent open field (OF), elevated plus maze (EPM) and Morris water maze (MWM) tests 24 h after the last exercise training. Then, after blood was drawn under anesthesia, the rats were sacrificed and their hippocampus tissues were separated. Glucocorticoid and BDNF levels in the blood were evaluated by enzyme-linked immunosorbent assay (ELISA), and osteocalcin and BDNF expressions in the hippocampus were evaluated by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Neither voluntary exercise training nor HIIT had any significant effect on behavioral parameters assessed by OF, EPM and MWM tests. However, BDNF expression in hippocampus tissue was higher in the HIIT group than in the control group. In addition, osteocalcin expression in hippocampus tissue was higher in the HIIT and voluntary exercise groups than in the control group. In conclusion, according to the findings we obtained from this study, although it does not have a significant effect on cognitive functions, the effect of HIIT on brain functions seems to be more effective than voluntary exercise.

Investigating the influence of estrous cycle-dependent hormonal changes on neurogenesis in adult mice

ObjectiveNeurogenesis is the process of generating new neurons from neural stem cells (NSCs) in the adult brain. Sex hormones play an essential role in the development of the brain. The aim of this study was to evaluate the neurogenic changes in the brain at different phases of the estrous cycle in adult mice. Materials and methodsFemale NMRI mice were divided into four groups: 1- Estrous, 2- Proestrous, 3- Metestrous, and 4- Diestrous. Different stages of the estrous cycle were determined by staining of vaginal smears. The level of estrogen, progesterone, prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) hormones was evaluated by the enzyme-linked immunosorbent assay (ELISA) method. The expression of brain-derived neurotrophic factor) BDNF), nerve growth factor (NGF), ciliary neurotrophic factor(CNTF)) genes in hippocampal and the expression of glial fibrillary acidic protein (GFAP) in subventricular zone (SVZ) tissue were evaluated. ResultsThe serum estrogen and FSH increased significantly in Proestrous group (p < 0.001). Also, progesterone and prolactin hormones were significantly increased in the Diaestrus group (p < 0.001). The expression levels of BDNF, NGF, and CNTF significantly increased in the hippocampal tissue of Proestrous and Diaestrus groups (p < 0.001). The number of GFAP+ cells in SVZ of the Proestrous and Diestrous groups had a significant increase (p < 0.05, p < 0.01, p < 0.001). ConclusionOur data showed that Changes in sex hormones, especially estrogen in the estrous cycle, can cause the production of new neurons and astrocytes in the hippocampus and SVZ. Therefore, the increase in neurotrophic factors in the Proestrus and Diestrus leads to neurogenesis in adult mice brains.

Functional neurological disorder and gut microbiome: Casual or causal relationship?

Functional neurological disorder (FND), or conversion disorder, is a psychosomatic condition that affects the voluntary motor and/or sensory functions of the patient. Its origin is not yet fully understood, but the main risk factors related to this disorder include exposure to recent psychological stressors and previous experience of aversive episodes during childhood, such as abuse, family dysfunction, and neglect. The symptoms of FND result from complex interactions involving the central nervous system and also the endocrine and immune systems. In this work, we hypothesized the relationship between the gut microbiome and the pathophysiology of FND because both share several common features, such as the effects of neurotransmitters, the hippocampal expression of brain-derived neurotrophic factor, and the inflammatory responses. Based on these common aspects, we suggested that stress, gut microbiome, and inflammation factors induce chronic and systemic inflammation of the brain causing neurological disorders, including FND. More specific studies are warranted to validate the casual or causal relationship between FND and the gut microbiome.

Accelerated BDNF expression in visceral white adipose tissues following high-fat diet feeding in mice.

Brain-derived neurotrophic factor (BDNF) is expressed in the white adipose tissues (WATs), and the expression increases during high-fat diet (HFD) feeding, implicating its role in obesity. Here, we focused on BDNF expression in epididymal WAT (eWAT), a visceral adipose tissue, in mice. During 2 weeks of HFD feeding, Bdnf mRNA expression in eWAT slightly increased, but a robust increase was observed after 8 weeks of HFD feeding. This upregulation of Bdnf mRNA was correlated with significant induction of hypoxia-inducible factor 1α (Hif1α) and platelet-derived growth factor subunit B (Pdgfb) mRNA in eWAT following 8 weeks of HFD feeding. Furthermore, the increased expression of the M1 macrophage markers was strongly correlated with the elevation of Bdnf mRNA in the eWAT. Notably, 8 weeks of HFD feeding significantly elevated Tnfα mRNA expression in eWAT, while no such induction was observed in inguinal WAT (iWAT). In contrast, the expression of Adipoq (adiponectin), implicated in improved insulin sensitivity and anti-inflammatory effects, was significantly upregulated in iWAT, but not in eWAT. Thus, our study may show the role of BDNF in eWAT in obesity models, potentially contributing to the pathological state of visceral adipose tissues.

The extracellular vesicle of depressive patient-derived Escherichia fergusonii induces vagus nerve-mediated neuroinflammation in mice

BackgroundGut microbiota dysbiosis is closely associated with psychiatric disorders such as depression and anxiety (DA). In our preliminary study, fecal microbiota transplantation from volunteers with psychological stress and subclinical symptoms of depression (Vsd) induced DA-like behaviors in mice. Escherichia fergusonii (Esf) was found to be more abundant in the feces of Vsd compared to healthy volunteers. Therefore, we investigated the effect of Esf on DA-like behavior and neuroinflammation in mice with and without celiac vagotomy.Methods and resultsOrally gavaged Esf increased DA-like behaviors, tumor necrosis factor (TNF)-α, and toll-like receptor-4 (TLR4) expression, and NF-κB+Iba1+ and lipopolysaccharide (LPS)+Iba1+ cell populations, while decreasing serotonin, 5-HT1A receptor, and brain-derived neurotrophic factor (BDNF) expression in the hippocampus and prefrontal cortex. However, celiac vagotomy attenuated Esf-induced DA-like behavior and neuroinflammation. Orally gavaged extracellular vesicle (EV) from Vsd feces (vfEV) or Esf culture (esEV) induced DA-like behavior and inflammation in hippocampus, prefrontal cortex and colon. However, celiac vagotomy attenuated vfEV- or esEV-induced DA-like behaviors and inflammation in the brain alone, while vfEV- or esEV-induced blood LPS and TNF-α levels, colonic TNF-α expression and NF-κB-positive cell number, and fecal LPS level were not. Although orally gavaged fluorescence isothiocyanate-labeled esEV was translocated into the blood and hippocampus, celiac vagotomy decreased its translocation into the hippocampus alone.ConclusionsesEVs may be translocated into the brain via the vagus nerve and bloodstream, subsequently inducing TNF-α expression and suppressing serotonin, its receptor, and BDNF expression through the activation of TLR4-mediated NF-κB signaling, thereby contributing to DA pathogenesis.

Zeaxanthin and Lutein Ameliorate Alzheimer's Disease-like Pathology: Modulation of Insulin Resistance, Neuroinflammation, and Acetylcholinesterase Activity in an Amyloid-β Rat Model.

Alzheimer's disease (AD) is characterized by impaired insulin/insulin-like growth factor-1 signaling in the hippocampus. Zeaxanthin and lutein, known for their antioxidant and anti-inflammatory properties, have been reported to protect against brain damage and cognitive decline. However, their mechanisms related to insulin signaling in AD remain unclear. This study investigated the efficacy and mechanisms of zeaxanthin, lutein, and resveratrol in modulating an AD-like pathology in an amyloid-β rat model. Rats were administered hippocampal infusions of 3.6 nmol/day amyloid-β (Aβ)(25-35) for 14 days to induce AD-like memory deficits (AD-CON). Normal control rats received Aβ(35-25) (Normal-CON). All rats had a high-fat diet. Daily, AD rats consumed 200 mg/kg body weight of zeaxanthin (AD-ZXT), lutein (AD-LTN), and resveratrol (AD-RVT; positive-control) or resistant dextrin as a placebo (AD-CON) for eight weeks. The AD-CON rats exhibited a higher Aβ deposition, attenuated hippocampal insulin signaling (reduced phosphorylation of protein kinase B [pAkt] and glycogen synthase kinase-3β [pGSK-3β]), increased neuroinflammation, elevated acetylcholinesterase activity, and memory deficits compared to the Normal-CON group. They also showed systemic insulin resistance and high hepatic glucose output. Zeaxanthin and lutein prevented memory impairment more effectively than the positive-control resveratrol by suppressing acetylcholinesterase activity, lipid peroxidation, and pro-inflammatory cytokines (TNF-α, IL-1β). They also potentiated hippocampal insulin signaling and increased brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CTNF) mRNA expression to levels comparable to the Normal-CON rats. Additionally, zeaxanthin and lutein improved glucose disposal, reduced hepatic glucose output, and normalized insulin secretion patterns. In conclusion, zeaxanthin and lutein supplementation at doses equivalent to 1.5-2.0 g daily in humans may have practical implications for preventing or slowing human AD progression by reducing neuroinflammation and maintaining systemic and central glucose homeostasis, showing promise even when compared to the established neuroprotective compound resveratrol. However, further clinical trials are needed to evaluate their efficacy and safety in human populations.