Neurotropic Factor Research Articles

A self-selected 16:8 time-restricted eating quasi-experimental intervention improves various markers of cardiovascular health in middle-age male cyclists

ObjectivesTime-restricted eating (TRE) is a dietary intervention that may offer some protection against cardiovascular disease (CVD), while also preserving performance in athletes. To date however, research on TRE in an active population has only been conducted in college-age cohorts and the effects of TRE in an older, trained population are less understood. Therefore, the aim of this study was to compare the effects of a 4-wk, 16:8 TRE intervention on markers of CVD risk in middle-age, male cyclists. MethodsParticipants (N = 12; age, 51.9 ± 8.6 y; training duration/wk, 375 ± 140 min; peak aerobic capacity, 41.8 ± 5.6 mL/kg/min) reported to the laboratory for two sessions (i.e., at baseline and post-TRE) where blood was drawn from an antecubital vein after an 8-h overnight fast. Dependent variables measured at baseline and post-TRE included insulin, cortisol, brain-derived neurotropic factor, free testosterone, thyroxine, triiodothyronine, C-reactive protein, advanced oxidative protein products, glutathione, tumor necrosis factor (TNF)-α, glucose, and a full lipid profile. ResultsCompared with baseline, TRE significantly lowered TNF-α (12.3 ± 3.4 versus 9.2 ± 2.4 pg/mL; P = 0.02) and glucose concentrations (93.4 ± 9.7 versus 87.5 ± 7.9 mg/dL; P = 0.01), as well as significantly elevated high-density lipoprotein cholesterol levels (45.7 ± 13.7 versus 49.2 ± 12.3 mg/dL; P = 0.04), respectively. No further significant changes were observed between the remaining variables (all P > 0.05). ConclusionOverall, these data suggest that incorporating a 4-wk TRE intervention with habitual endurance training can significantly improve some markers of CVD risk and may compliment the robust health benefits derived from a regular exercise regimen.

Homocysteine Modulates Social Isolation-Induced Depressive-Like Behaviors Through BDNF in Aged Mice.

Social isolation is an unpleasant experience associated with an increased risk of mental disorders. Exploring whether these experiences affect behaviors in aged people is particularly important, as the elderly is very likely to suffer from periods of social isolation during their late-life. In this study, we analyzed the depressive-like behaviors, plasma concentrations of homocysteine (Hcy), and brain-derived neurotropic factor (BDNF) levels in aged mice undergoing social isolation. Results showed that depressive-like behavioral performance and decreased BDNF level were correlated with increased Hcy levels that were detected in 2-month isolated mice. Elevated Hcy induced by high methionine diet mimicked the depressive-like behaviors and BDNF downregulation in the same manner as social isolation, while administration of vitamin B complex supplements to reduce Hcy alleviated the depressive-like behaviors and BDNF reduction in socially isolated mice. Altogether, our results indicated that Hcy played a critical role in social isolation-induced depressive-like behaviors and BDNF reduction, suggesting the possibility of Hcy as a potential therapeutic target and vitamin B intake as a potential value in the prevention of stress-induced depression.

Disinhibition of Mesolimbic Dopamine Circuit by the Lateral Hypothalamus Regulates Pain Sensation.

Our recent study demonstrated the critical role of the mesolimbic dopamine (DA) circuit and its brain-derived neurotropic factor (BDNF) signaling in mediating neuropathic pain. The present study aims to investigate the functional role of GABAergic inputs from the lateral hypothalamus (LH) to the ventral tegmental area (VTA; LHGABA→VTA) in regulating the mesolimbic DA circuit and its BDNF signaling underlying physiological and pathologic pain. We demonstrated that optogenetic manipulation of the LHGABA→VTA projection bidirectionally regulated pain sensation in naive male mice. Optogenetic inhibition of this projection generated an analgesic effect in mice with pathologic pain induced by chronic constrictive injury (CCI) of the sciatic nerve and persistent inflammatory pain by complete Freund's adjuvant (CFA). Trans-synaptic viral tracing revealed a monosynaptic connection between LH GABAergic neurons and VTA GABAergic neurons. Functionally, in vivo calcium/neurotransmitter imaging showed an increased DA neuronal activity, decreased GABAergic neuronal activity in the VTA, and increased dopamine release in the NAc, in response to optogenetic activation of the LHGABA→VTA projection. Furthermore, repeated activation of the LHGABA→VTA projection was sufficient to increase the expression of mesolimbic BDNF protein, an effect seen in mice with neuropathic pain. Inhibition of this circuit induced a decrease in mesolimbic BDNF expression in CCI mice. Interestingly, the pain behaviors induced by activation of the LHGABA→VTA projection could be prevented by pretreatment with intra-NAc administration of ANA-12, a TrkB receptor antagonist. These results demonstrated that LHGABA→VTA projection regulated pain sensation by targeting local GABAergic interneurons to disinhibit the mesolimbic DA circuit and regulating accumbal BDNF release.SIGNIFICANCE STATEMENT The mesolimbic dopamine (DA) system and its brain-derived neurotropic factor (BDNF) signaling have been implicated in pain regulation, however, underlying mechanisms remain poorly understood. The lateral hypothalamus (LH) sends different afferent fibers into and strongly influences the function of mesolimbic DA system. Here, utilizing cell type- and projection-specific viral tracing, optogenetics, in vivo calcium and neurotransmitter imaging, our current study identified the LHGABA→VTA projection as a novel neural circuit for pain regulation, possibly by targeting the VTA GABA-ergic neurons to disinhibit mesolimbic pathway-specific DA release and BDNF signaling. This study provides a better understanding of the role of the LH and mesolimbic DA system in physiological and pathological pain.

Gut microbiota indole-3-propionic acid mediates neuroprotective effect of probiotic consumption in healthy elderly: A randomized, double-blind, placebo-controlled, multicenter trial and in vitro study

The beneficial effects of probiotic consumption on age-related decline in cerebral function have been previously reported in the literature; however, the mechanistic link between gut and brain interactions has not yet been fully elucidated. Therefore, this study aimed to identify the role of gut microbiota-derived metabolites in gut-brain interactions via blood metabolomic profiling analysis in clinical trials and invitro mechanistic studies. A randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted in 63 healthy elderly individuals (≥65 years of age). Participants were administered either placebo (placebo group, N=31) or probiotic capsules (Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI; probiotics group, N=32) for 12 weeks. Global and targeted metabolomic profiling analyses of their blood samples were then performed using 1H nuclear magnetic resonance and liquid chromatography-mass spectrometry methods, both at baseline and at the end of the trial. Gut microbial analysis was conducted using the 16S ribosomal ribonucleic acid gene sequencing method. Subsequently, microglial BV2 cells were treated invitro with indole-3-propionic acid (IPA) following lipopolysaccharide stimulation, and neuronal SH-SY5Y cells were treated with conditioned media from the BV2 cells. Finally, the levels of pro-inflammatory cytokines in BV2 cells and neurotrophins in SH-SY5Y cells were quantified using a real-time polymerase chain reaction or enzyme-linked immunosorbent assay. The metabolomic profiling analyses showed that probiotic consumption significantly altered the levels of metabolites involved in tryptophan metabolism (P<0.01). Among these metabolites, gut microbiota-produced IPA had a 1.91-fold increase in the probiotics group (P<0.05) and showed a significant relation to gut bacterial profiles (P<0.01). Elevated IPA levels were also positively associated with the level of serum brain-derived neurotropic factor (BDNF) in the probiotics group (r=0.28, P<0.05), showing an inverse trend compared to the placebo group. In addition, invitro treatment with IPA (5μM) significantly reduced the concentration of proinflammatory TNF-α in activated microglia (P<0.05), and neuronal cells cultured with conditioned media from IPA-treated microglia showed a significant increase in BDNF and nerve growth factor production (P<0.05). These results show that gut microbiota-produced IPA plays a role in protecting the microglia from inflammation, thus promoting neuronal function. Therefore, this suggests that IPA is a significant mediator linking the interaction between the gut and the brain in the elderly with probiotic supplementation.

Influence of functional-assembled-FGL polypeptide timbering material on expression of glial cell line-derived neurotropic growth factor mRNA in damaged rat’s spinal cord

Spinal cord injury is one of most serious complications when there is spine injury in patients. Spinal cord injury clinically involves anesthesia and mobility loss in leg in most of patients. Rats were herein molded and divided into groups, and Basso-Beattie-Bresnahan (BBB) method was adopted to assess the motor function of rats. The quantities of cassyl aspartic acid-specified protease (Caspase-3), neurofilament protein-200 (NF-200) and Glial Fibrillary Acidic Protein (GFAP)-positive cell were detected by immunohistochemical staining method. The expression of Glial cell line-derived neurotropic growth factor (GDNF) mRNA in spinal cord tissue was detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) method. The quantity of Caspase-3 positive cell and area of glial scar in the fiber grating laser-National Security (FGL-NS) group were significantly reduced compared with those from the other two groups. The quantities of NF-200 positive cell, graded result of Basso-Beattie-Bresnahan method and content of GDNF mRNA in the FGL-NS group were increased compared to those from the other two groups. The FGL-NS improved the expression of GDNF mRNA so as to repair the damaged neuronal cells.

BACKGROUND EEG ACTIVITY MEDIATES ASSOCIATIONS BETWEEN BDNF-VAL66MET POLYMORPHISM AND MEMORY DURING AGING

Significant heterogeneity in cognitive aging is explained by the influence of both genetic and environmental factors. BDNF (brain-derived neurotrophic factor) is a neurotropic factor involved in the processes of plasticity in the mature brain. Val66Met polymorphism is a functional polymorphism of the BDNF gene, which determines its association with the architectonics and functions of the brain and the efficiency of cognitive functions. The aim of this study was to identify the aging-related features of the relationship between Val66Met polymorphism and the efficiency of verbal memory processes, determined in the dichotic test, as well as with the background oscillatory activity of the brain, recorded with eyes closed in 52 EEG leads. The study involved 235 right-handed young Caucasians (YA, mean age 21.65 years, SD = 3.18) and 141 older (OA, 64.37 years, SD = 6.04). Genetic differences in memory parameters and endophenotypes of EEG activity were found only in OA individuals. In dichotic testing, subjects with the Val/Val genotype reproduced fewer words from the right ear compared to carriers of the Met allele. When analyzing the EEG, genetic differences were found in the focal indicators of asymmetry in the power of the delta, theta, beta 1 and 2 rhythms, and were due to the greater power of the rhythms in the central temporal sections of the right hemisphere compared to the left hemisphere in Val/Val, with the opposite ratio in carriers of the Met allele. For the beta 2 rhythm, similar differences in asymmetry were also characteristic of the parietal-occipital regions of the hemispheres. It was found that indicators of central temporal asymmetry are mediators in the association between BDNF gene polymorphism and memory efficiency. The data obtained for the first time show age-related differences in the effects of the Val/Met BDNF polymorphism on the efficiency of verbal memory and EEG power and suggest possible relationships between these genotype-associated parameters.

Skeletal muscle derived pro-brain derived neurotropic factor promotes ischemia-reperfusion induced inflammation

Skeletal muscle ischemia-reperfusion (IR) injury is prevalent in trauma, peripheral vascular diseases, and following surgical procedures, however, effective prevention and treatment for skeletal muscle IR injury are lacking. Brain-derived neurotrophic factor (BDNF), originally discovered in the brain, is expressed and released from skeletal muscle as a myokine. However, the transcription splice variants, posttranslational modifications, and functions of BDNF in skeletal muscle are poorly defined. In this study, we first showed that skeletal muscle expressed unique splice variants of BDNF compared to the brain. At the protein level, Western blot comparing BDNF in brain and skeletal muscle revealed that skeletal muscle expresses significantly more proBDNF than mature BDNF under basal conditions, opposite to brain tissue. Consistent with this, the levels of the major protein convertases in skeletal muscle were significantly lower compared to the brain, suggesting that the high level of proBDNF is at least partially due to the low cleavage activity in skeletal muscle. The potential function of the proBDNF in disease conditions was then examined in mice with skeletal muscle IR injury. IR injury was induced in 3-month-old male and female C57BL/6 mice by placing a tourniquet on one hind limb for 1 hour, then removing it, allowing reperfusion for 1-14 days, with the contralateral hind limb serving as a control. We hypothesize that proBDNF may be necessary for facilitating the inflammatory response, while mature BDNF may be necessary for promoting inflammation resolution and myogenesis following IR injury. Remarkably, the level of proBDNF, but not mature BDNF, was increased significantly in IR muscle compared to the contralateral control (p=0.013). This was accompanied by increased proinflammatory cytokines and macrophage infiltration in the injured muscle. Mice with skeletal muscle-specific knockout of BDNF showed a significant reduction in proinflammatory cytokine production and macrophage infiltration following IR injury compared to wild-type animals. To confirm the role of proBDNF in this finding, the receptor for proBDNF, p75NTR, was blocked using the small molecule LM11A-31. In IR injured muscle, LM11A-31 treatment significantly reduced the proinflammatory response and macrophage infiltration compared to control animals, similar to what is seen in BDNF knockout animals. Collectively, these results indicate that myokine proBDNF promotes inflammation and macrophage recruitment in the IR-injured muscle, and therefore is a potential target for the treatment of skeletal muscle injury. This work was funded by NIH grant R01HL147105 and NIH Training Grant T32-GM136503. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of stressogenic factors on the course of metabolic-associated fatty liver disease. Review

Metabolic‑associated fatty liver disease (MAFLD) is one of the most widespread diseases worldwide, including Ukraine. The complex pathophysiological MAFLD mechanisms include the disturbances of various processes (insulin resistance, lipotoxicity, pro‑inflammatory activation, changes in intestinal microbiota (IM), etc.). MAFLD is closely associated with the mental disorders, and they potentiate the course of each other. Stress induces both behavioral and biological reactions, which activate all the hypothalamic–pituitary–adrenal axis, thus resulting in the rise in the levels of cortisol and proinflammatory biomarkers that may be involved in the MAFLD development. There is a lack of data related to the effects of the stressogenic factors of the wartime and postwar state on the formation and progression of MAFLD. Knowledge about the role of chronic stress biomarkers (dehydroepiandrosterone, prolactin, brain neurotropic factor (BDNF)) in the MAFLD pathogenesis is insufficient. The literature data regarding changes in the qualitative and quantitative composition of the intestinal microbiota at the level of the main phyla in MAFLD patients are contradictory. The dynamics of intestinal microbiota under the influence of stress factors of war and post‑war times is not investigated. Complex determination of the degree of violation of the intestinal epithelial barrier integrity, the state of the IM, the level of stress hormones and pro‑inflammatory factors in patients with MAFLD in the stressful conditions of war and post‑war state will make it possible to clarify the pathophysiological links of MAFLD formation and progression and to work out pathogenetically based prophylactic and therapeutic interventions to inhibit the development of inflammation and fibrosis processes in liver tissue in MAFLD patients by means of correction of the microbiota and modification of the stress factors of the war and post‑war state. Moreover, it will enable investigations of the effects of the developed therapy on the clinical manifestations, metabolic profile, IM composition, inflammation, and the level of neurotropic hormones in MAFLD patients. Thus, scientific research of the effects of stressogenic factors on the course of metabolic‑associated fatty liver disease and determination of its pathogenetic mechanisms is relevant and appropriate.

The effects of oral supplementation of Japanese sake yeast on anxiety, depressive-like symptoms, oxidative stress, and BDNF changes in chronically stressed adolescent rats

Chronic stress during the pre-pubertal period has adverse effects in developing neuropsychiatric disorders such as depression and anxiety. The administration of supplements with antioxidant properties may alleviate depression and anxiety behavior. This study investigated the effects of oral supplementation of Japanese sake yeast on anxiety, depressive-like symptoms, oxidative stress, and changes in brain-derived neurotropic factor (BDNF) in adolescence rats subjected to chronic stress. In order to assess the effects of chronic stress, adolescent rats were grouped into one non-stressed control group (non-stress) and four different experimental groups. The other animals were subjected to stress and orally received normal saline (Control-stress), 15 mg/kg yeast (Stress-15), 30 mg/kg yeast (Stress-30) and 45 mg/kg yeast (Stress-45). Anxiety and depression-like behavior, BDNF levels, and oxidative stress markers were evaluated. The rats exposed to stress exhibited anxiogenic and depression-like behavior as well as lower levels of BDNF and higher levels of oxidative markers compared with non-stressed rats (P&lt;0.05). However, the oral supplementation of sake yeast decreased anxiogenic and depression-like behavior and oxidative indices, and also increased BDNF levels compared to stressed rats treated with saline in a dose-dependent manner (P&lt;0.05). In sum, stress caused anxiety and depression behavior, increased oxidative indices, and reduced BDNF levels while sake yeast alleviated adverse effects of stress on anxiety and depression behaviors, decreased oxidative markers, and increased BDNF levels.

Aerobic exercise improves executive functions in females, but not males, without the BDNF Val66Met polymorphism

BackgroundAerobic exercise promotes cognitive function in older adults; however, variability exists in the degree of benefit. The brain-derived neurotropic factor (BDNF) Val66Met polymorphism and biological sex are biological factors that have been proposed as important modifiers of exercise efficacy. Therefore, we assessed whether the effect of aerobic exercise on executive functions was dependent on the BDNFval66met genotype and biological sex.MethodsWe used data from a single-blind randomized controlled trial in older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Fifty-eight older adults were randomly assigned to either the 6 months, three times per week progressive aerobic training (AT) group or the usual care plus education control (CON) group. The secondary aim of the parent study included executive functions which were assessed with the Trail Making Test (B–A) and the Digit Symbol Substitution Test at baseline and trial completion at 6 months.ResultsAnalysis of covariance, controlling for baseline global cognition and baseline executive functions performance (Trail Making Test or Digit Symbol Substitution Test), tested the three-way interaction between experimental group (AT, CON), BDNFval66met genotype (Val/Val carrier, Met carrier), and biological sex (female, male). Significant three-way interactions were found for the Trail Making Test (F(1,48) = 4.412, p < 0.04) and Digit Symbol Substitution Test (F(1,47) = 10.833, p < 0.002). Posthoc analyses showed female Val/Val carriers benefited the most from 6 months of AT compared with CON for Trail Making Test and Digit Symbol Substitution Test performance. Compared with CON, AT did not improve Trail Making Test performance in male Val/Val carriers or Digit Symbol Substitution Test performance in female Met carriers.ConclusionsThese results suggest that future randomized controlled trials should take into consideration BDNF genotype and biological sex to better understand the beneficial effects of AT on cognitive function in vascular cognitive impairment to maximize the beneficial effects of exercise and help establish exercise as medicine for cognitive health.

BDNF expression in brain regions of Anorexia Nervosa mouse model, a biomarker of diagnostic and prognostic?

IntroductionAnorexia nervosa (AN) is a complex mental disorder mainly characterized by a voluntary food restriction and excessive physical activity resulting in dramatic weight loss. Changes in the brain-derived neurotropic factor (BDNF) have been reported in AN patients compared to controls. According to meta-analysis, functional variant rs6265 Val66Met of the BDNF gene has been found genetically associated to AN. We also reported an association of this functional variant and electrodermal response to images of thinness suggesting an association between rs6265 and a reward effect of weight loss in AN. In animal models, BDNF modulates negatively the central control of food intake and its injection in rodents induces weight loss and anorexia. Thus, besides its function on neuronal survival, synaptic plasticity and mood, BDNF was also reported to have a metabolic effect via both central nervous system and peripheral organs, which makes BDNF a good candidate for AN diagnosis biomarker.ObjectivesOur study investigates the levels of expression of Bdnf, gene and protein, taking advantage of the mouse AN-like model by measuring Bdnf levels in specific brain areas and blood in food-restricted and refeed animals.MethodsWe used a mouse AN-like model combining a phase of chronic food restriction (50%) during 15 days followed by an ad libitum refeeding period of one week. Female mice have or not access to a running with wheel to create a similar metabolic environment that those patients suffering from AN during restriction and recovery once hospitalised. The Bdnf mRNA and protein levels were measured in samples of blood and brain regions (prefrontal cortex, hippocampus, hypothalamus, dorsal striatum, nucleus Accumbens, ventral tegmental area and amygdala) using quantitative PCR and ELISA methods in the different groups of mice (ad libitum, ad libitum with wheel, food restriction and food restriction with wheel). Statistical analysis will compare the measures for different samples by one-way or two-way ANOVAs depending the group of animals or brain regions and blood.ResultsTo date, no difference of the level of transcription for Bdnf was observed between the different groups of mice (ad libitum, ad libitum with wheel, food restriction and food restriction with wheel) in the prefrontal cortex, hippocampus and hypothalamus. We expect significant differences of Bdnf expression in the other brain regions of interest for the food restricted animals with or without the wheel compared to ad libitum animals. We expect also differences in the level of expression of Bdnf in fasted animals compared to the refeed animals.ConclusionsThe BDNF could represent a potential biomarker of AN for the diagnostic and the prognosis in the evolution to the remission when weight recover and thus will allow a better understanding of the aetiology of AN. This study is supported by Fédération pour la Recherche sur le Cerveau.Disclosure of InterestNone Declared

Maternal vitamin D status and attention deficit hyperactivity disorder (ADHD), an under diagnosed risk factor; A review

Vitamin D is important to mediate several brain processes such as proliferation, apoptosis, and neurotransmission in early stages of life. Vitamin D deficiency during critical periods of development can lead to persistent brain alterations. Vitamin D homeostasis during pregnancy is affected by two factors which includes an increase in mother’s calcitriol levels and an increase in mother’s Vitamin D Binding protein concentrations. Attention deficient hyperactivity disorder (ADHD) is an outcome of a complicated interaction between genetic, environmental, and developmental traits, and genetic factors cover about 80% of the cases. The efficiency of the immune system can be altered by a deficiency of Vitamin D in maternal body and maternal stress during gestation such as perinatal depression. Studies have proved that during gestation if there is a deficiency of vitamin D in maternal body, it can influence the brain development of the fetus and can also alter the synthesis of the brain-derived neurotropic factor. The current manuscript has been compiled to elaborate different factors which are associated with ADHD particularly focusing on the relationship of vitamin D deficiency in mothers. References material was selected from NCBI (PUBMED), Science direct, Google scholar, Publons etc. Using the terms ADHD, Vitamin D and Maternal nutritional status. Although, controversial relationship was found between the deficiency of Vitamin D level in pregnant women and development of ADHD in children but more controlled trials are required for future direction as well as to rule out other associated causes.

Effects of a variable light intensity lighting program on the welfare and performance of commercial broiler chickens.

Our previous variable-light intensity lighting program studies indicate the light intensity preference behavior of broilers for their daily activity including eating and resting. To evaluate the effects of variable-light intensity lighting program on performance and welfare of broilers, four commercial trials were conducted for looking at behaviors, mortality, leg-health, performance, and brain welfare indicator genes including tryptophan hydroxylase 2 and tyrosine hydroxylase (TH), glucocorticoid receptor (GR), brain-derived neurotropic factor (BDNF), and melanopsin (Opn4) gene expression. One-day-old broilers were housed in four commercial broiler houses. Each quadrant (section) of the house was placed with 4,800 chicks. A total of four lighting programs began on day 7 with 5 lux (lx), 20 lx, natural light (NL, 480 lx), and variable light (2-5/40 lx) using LED lights on a 16L:8D photoperiod. In the variable-light house, the number of dustbathing holes was significantly higher than that in natural-light houses and 5-lx and 20-lx houses. Daily physical activities, footpad condition, fear response to novel objects, body weight, feed conversion ratio, and the number of leg-problem induced culled birds were affected by the variable-light intensity lighting program. Expression of tryptophan hydroxylase 2 in the DRN and VTA of variable-light treated birds was lower than that of 5-lx- and 20-lx-treated birds on day 42 (p < 0.05). Higher expression of VTA-TH in 5-lx-treated birds than that in 20-lx-, NL-, and variable-light-treated birds suggests the high stress-susceptibility of 5-lx treated birds. Lower VTA-GR expression in 20-lx- and variable-light-treated birds indicates lower stress than that in NL- and 5-lx-treated birds (p < 0.05). The VTA-BDNF expression of NL-treated birds was 2.5 fold higher than that of 5-lx-, 20-lx-, and variable-light-treated birds (p < 0.05), and variable-light-treated birds showed the lowest level of BDNF expression (p < 0.05), suggesting the chronic social defeat stress in NL-treated birds. The result of VTA-Opn4 expression on day 42 suggests the possible role of VTA-Opn4 in broiler welfare through central light perception. Taken together, the variable-light intensity lighting program increased volunteer natural behaviors and physical activity, which may improve footpad condition and leg health of birds, consequently. Performance data including the increased daily weight gain and the lowered feed conversion ratio and results of brain welfare indicator gene expression showed the beneficial effect of the variable-light intensity lighting program on the performance and welfare of commercial broilers.

Childhood adverse events and BDNF promoter methylation in later-life.

Studies have shown that the effects of early-life stress and trauma can be enduring, with long-term negative effects on health. Epigenetics, including DNA methylation, have been implicated as a potential mechanism for these effects. Brain-derived neurotropic factor (BDNF) is a neurotransmitter involved in learning and memory, and altered BDNF promoter methylation measured in peripheral tissue has been found with early-life stress. However, whether such methylation differences remain stable into later life, is unknown. This study aimed to investigate the association between childhood adversity and BDNF promoter methylation in adults aged 65 years and over. Data came from a large study of older community-dwelling individuals in France (ESPRIT). Information on three major childhood adverse events, namely abuse/maltreatment, war/natural disaster, and financial difficulties/poverty, was obtained by retrospective reporting from participants of ESPRIT study. BDNF promoter I and IV methylation was assessed in blood and buccal tissue. Linear regression analysis was performed, adjusting for age, sex, education, depression, and morbidity. Among 927 participants, there was no strong evidence that childhood abuse/maltreatment or financial difficulties/poverty were associated with BDNF methylation in older individuals. For war/natural disaster, differential methylation at four of twenty-nine CpG sites was observed, however, these would not have remained significant after correction for multiple testing. Together, these findings do not support a long-term association between adverse childhood events and BDNF methylation in older age, but further large prospective studies are needed, which do not target specific genes, but consider DNA methylation across the genome.

Erythropoietin in Glaucoma: From Mechanism to Therapy.

Glaucoma can cause irreversible vision loss and is the second leading cause of blindness worldwide. The disease mechanism is complex and various factors have been implicated in its pathogenesis, including ischemia, excessive oxidative stress, neurotropic factor deprivation, and neuron excitotoxicity. Erythropoietin (EPO) is a hormone that induces erythropoiesis in response to hypoxia. However, studies have shown that EPO also has neuroprotective effects and may be useful for rescuing apoptotic retinal ganglion cells in glaucoma. This article explores the relationship between EPO and glaucoma and summarizes preclinical experiments that have used EPO to treat glaucoma, with an aim to provide a different perspective from the current view that glaucoma is incurable.

Levels of Neurospecific Peptides, Neurotransmitters and Neuroreceptor Markers in the Serum of Children with Various Sensory Disorders, Mild Cognitive Impairments and Other Neuropathology

Background. The role of recently discovered neurospecific peptides in the pathogenesis of acute and progressive neurologic disorders, their neuroprotective features, and possibilities to use them as markers for the course and prognosis of certain diseases have been actively studied in recent decades. However, neurospecific peptides are almost not studied in chronic residual diseases. In our study we measured the levels of neurospecific peptides and some other markers to achieve understanding of general neurophysiological trends in congenital and acquired chronic non-progressive brain pathology with reference to the selection of relevant groups — study objects. Objective. The aim of the study is to study patterns of neurospecific peptides, neurotransmitters and neuroreceptor markers distribution in the serum of children with various pathogenetic variants of chronic neuropathology. Methods. The study included children from 3 to 16 years old with different pathologies. The sample was divided into groups by pathology type: no sensory and neurological disorders, congenital sensory deficit due to mutation of genes expressed and not expressed in the brain, early acquired sensory deficit of multifactorial nature, congenital mild and severe organic disorders of central nervous system (CNS) in residual stage without baseline sensory deficit, acquired functional CNS disorders without baseline organic defect and sensory deficit. The following laboratory data (neurophysiological components) was studied: nerve growth factor, brain-derived neurotropic factor, neurotrophin-3, neurotrophin-4, neuregulin-1-beta-1, beta-secretase, sirtuin-1, synaptophysin, neuronal nitric oxide synthase, and anti-NR2 glutamate receptor antibodies. The parameters of cognitive activity, sense of vision, sense of smell, and acoustic sense were also evaluated. Results. The study included 274 participants. Neuropeptides and markers have shown a variable degree and range in the group spectrum of differences from normal levels. The most variable in the examined sample was NO-synthase, as well as levels of both neurotrophins, beta-secretase, and glutamate receptor marker. All visual deficits were associated with increased NO-synthase levels (p &lt; 0.001). Neuroplasticity peptides (beta-secretase, neurotrophin-3 and 4) have been activated in all pathological conditions. Nerve growth factor and brain-derived neurotropic factor were specifically activated in mild organic CNS lesions (mild cognitive impairments), while neuregulin — in congenital genetically determined visual deficits. There was no specific activation of neuropeptides and NO-synthase level tended to decrease in cases of severe CNS lesions. Conclusion. The study results suggest that all types of early visual impairment are associated with increased physiological neuronal activity, and non-organic neurological functional disorders — mainly with increased physiological synaptic activity. General neuroplasticity processes were activated in all cases of visual deficits but more specific. However, more specific and well-studied processes were activated in mild organic CNS lesions, and neuroplasticity processes did not activate adequately in severe organic CNS lesions probably due to the limited neuronal and synaptic resources.

ADVANCES IN TREATMENT OF MOOD DISORDERS

In the last many decades psychotropics have mostly focused on Serotonin, Norepinephrine, and Dopamine for depression, and dopamine blockers for psychosis. Researchers started working diligently and explored new targets like Glutamate in treating depressive disorder and schizophrenia. The antagonist effect of Ketamine on N-methyl-D-aspartate (NMDA) receptors was investigated, which can result in a faster antidepressant response as compared to conventional treatment . GABA receptors were also explored to develop novel compounds, which resulted in the discovery of brexanalone, a neuroactive steroid-positive allosteric modulator of GABAA approved in March 2019 by the FDA for the treatment of postpartum depression. It is administered as an intravenous infusion over 60 hours and results in a rapid antidepressant response in` postpartum depression lasting for more than one week. Another neuroactive steroid Zuranolone effectively treats postpartum depression and major depressive disorder (MDD) . The antidepressant also modulates neuronal plasticity by enhancing the Brain-derived neurotropic factor BDNF levels.

STAT3 signaling induced by the IL-6 family of cytokines modulates angiogenesis.

Aberrant angiogenesis is a hallmark of cardiovascular and retinal neovascular disease. The STAT3 signaling pathway represents a potential pharmacological target for these diseases due to its impact on angiogenesis. Surprisingly, some STAT3 activators, such as the IL-6 cytokine family member oncostatin M (OSM), enhance angiogenesis, whereas others, such as ciliary neurotropic factor (CNTF), reduce it. This study aimed to clarify these conflicting effects. In contrast to the anti-angiogenic cytokine CNTF, the pro-angiogenic cytokine OSM was able to activate intracellular signaling pathways beyond the STAT3 pathway, including the ERK and AKT pathways. These differences translated into transcriptomic and metabolic shifts. siRNA-mediated STAT3 knockdown experiments showed a decrease in VEGF-induced endothelial migration and sprouting, enhancing the pro-angiogenic drive of OSM and switching the CNTF response from anti-angiogenic to pro-angiogenic. These effects correlated with a transcriptomic shift representing enhanced STAT1 and ERK activity following STAT3 knockdown, including a compensatory prolonged phosphorylated STAT1 activity. In conclusion, the angiogenic effect of STAT3 appears to be determined by cytokine-induced STAT3 specificity and simultaneous activity of other intracellular signaling pathways, whereas the STAT3 pathway, predominantly recognized for its pro-angiogenic phenotypes, reveals novel anti-angiogenic potential.

Abstract 119

Background: Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. In patients with CHH, the genetic profile is heterogeneous, and more than 40 genes are involved either alone or in combination with one another. Mutations in the FN3 (fibronectin-3) superfamily of genes encode proteins involved in GnRH neuron ontogeny. One such gene is the NDNF (neuron derived neurotropic factor) gene which has been established in mouse and zebrafish knockout models to manifest with altered GnRH migration and also in humans recently as CHH with anosmia or hyposmia. Case Report: A male child aged seven years and three months, born of second-degree consanguinity, presented with complaints of small sized penis and bilateral undescended testes since birth. There was no significant antenatal history nor any history suggestive of salt wasting, virilization or failure to thrive in infancy. At nine months of age, he underwent diagnostic laparoscopy &amp; bilateral orchidopexy. Child had normal developmental milestones and was cheerful and attentive in class. The child on examination had facial dysmorphism with triangular facies and prominent ears, normal vital signs and no midline defects. Anthropometry was essentially normal and SMR was notable for micropenis, 1cc right inguinoscrotal testis and non-palpable left testis with hypoplastic scrotum and an EMS of 6.5. He also had synkinesia with normosmia. Rest of the systemic examination was normal. Clinical diagnosis of congenital hypogonadotropic hypogonadism was considered. Review of prior investigations showed low gonadotropins recorded at mini-puberty, XY karyotype and an hCG stimulation test with non-stimulable testosterone (59.6 ng/dL). Prior USG showed right inguinal canal and left intra-abdominal testes with normal adrenals. The thyroid, GH and cortisol axes tested normal. Genetic analysis with whole exome sequencing showed heterozygous pathogenic mutation of exon 4 of NDNF gene. Conclusion: This case highlights thephenotypeofanovelmutation involving the NDNF gene that has been recently implicated in CHH in humans. This patient had clinical and biochemical features of hypogonadotropic hypogonadism with normosmia and synkinesia, along with facial dysmorphism. This phenotypic combination has not been described previously with this gene mutation.

S-nitrosoglutathione modulates HDAC2 and BDNF levels in the brain and improves cognitive deficits in experimental model of Alzheimer’s disease in rats

Aim Alzheimer’s disease (AD) is a neurodegenerative disorder which is characterized by cognitive deficits and abnormal memory formation. Histone acetylation is essential for hippocampal memory formation and improving the cognitive deficits, and histone deacetylase 2 (HDAC2) is increased in the hippocampus of AD patients. The present study evaluated the effects of the nitric oxide (NO) mimetics, L-arginine and the nitrosothiol NO donor, s-nitrosoglutathione (GSNO), on memory and brain HDAC2 levels in experimental animal model of sporadic Alzheimer’s disease (sAD). Methods AD was induced experimentally in rats by intracerebroventricular injection of streptozotocin (STZ, 3mg/kg). The effects of NO mimetics, GSNO and L-arginine, were assessed on STZ induced cognitive deficits in the Morris water maze (MWM) test, and, following this, the hippocampal homogenates were assayed for amyloid-β, brain derived neurotropic factor (BDNF) and HDAC2 levels. The neurobehavioral and biochemical data of the drug treated groups were compared with those of experimental control group. Results The results showed that icv-STZ induced cognitive deficits were differentially attenuated by GSNO (50µg/kg) and, to a lesser extent, L-arginine (100mg/kg) with improvement in the spatial learning tasks in MWM test. These behavioral changes were associated with decreased levels of biochemical markers viz. amyloid β, BDNF and HDAC2 levels in hippocampus. Conclusions It is inferred that NO donors like GSNO could influence AD pathophysiology via epigenetic modification of HDAC2 inhibition.