Neurotropic Factor Research Articles

ROLE OF ACUTE EXERCISE-INDUCED BRAIN BDNF ON APP PROCESSING AND BACE1

Perturbations in metabolism results in the accumulation of beta-amyloid, which is a pathological feature of Alzheimer's Disease (AD) (1). Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate limiting enzyme in the pathway responsible for beta-amyloid production (2). Exercise has been shown to reduce BACE1 activity, although the exact neurobiological mechanisms responsible are unknown (3). Exercise has also been shown to increase brain-derived neurotropic factor (BDNF) content and signaling (4), however whether this neurotrophic factor mediates the effects of exercise on BACE1 regulation requires further investigation. C57BL6 male mice were placed on a low (LFD; n=24) or high fat diet (HFD; n=24) for 10-weeks. Following the intervention, the mice either remained sedentary (n=12) or underwent an acute bout of treadmill running (n=12), proceeded by glucose/insulin tolerance tests and a Barnes maze test (spatial memory). Mice were euthanized and the prefrontal cortex was collected for protein quantification. Markers of the amyloidogenic pathway, along with targets of the BDNF signaling pathway, were examined. The 10-week HFD intervention led to increased body mass, inguinal and epididymal white adipose tissue mass, and liver mass (p < 0.05). HFD groups had impairments in glucose and insulin tolerance, as well as spatial memory (time in incorrect zones) (p < 0.05). A HFD led to increases in Akt phosphorylation (insulin signalling) and decreases in ERK phosphorylation (downstream of BDNF) (p < 0.05). An acute bout of exercise was able to recover ERK phosphorylation in the HFD group (p < 0.05) and significantly increase BDNF protein content in both LFD and HFD groups (p < 0.05). However, there were no changes in BACE1 protein content with diet or exercise (p > 0.05). Results from this study suggest that exercise can increase BDNF protein content in an obesogenic rodent model. Furthermore, a HFD potentially contributes to memory impairments by aberrant insulin signalling and impairments in BDNF signalling, which can be recovered through exercise. Although BACE1 protein content did not change, future analysis will examine BACE1 activity. Through these mechanisms, we gain further insight into using BDNF, mediated through exercise, as a therapeutic intervention.

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Isolated Compounds from Turpinia formosana Nakai Induce Ossification.

Bone metabolism is a homeostatic process, imbalance in which leads to the onset of diseases such as osteoporosis and osteopenia. Although several drugs are currently available to treat such conditions, they are associated with severe side effects and do not enhance bone formation. Thus, identifying alternative treatment strategies that focus on enhancing bone formation is essential. Herein, we explored the osteogenic potential of Turpinia formosana Nakai using human osteoblast (HOb) cells. The plant extract was subjected to various chromatographic techniques to obtain six compounds, including one new compound: 3,3′-di-O-methylellagic acid-4-O-α-l-arabinofuranoside (1). Compounds 3,3′-di-O-methylellagic acid-4-O-α-l-arabinofuranoside (1), gentisic acid 5-O-β-d-(6′-O-galloyl) glucopyranoside (2), strictinin (3), and (-)-epicatechin-3-O-β-d-allopyranoside (6) displayed no significant cytotoxicity toward HOb cells, and thus their effects on various osteogenic markers were analyzed. Results showed that 1–3 and 6 significantly increased alkaline phosphatase (ALP) activity up to 120.0, 121.3, 116.4, and 125.1%, respectively. Furthermore, 1, 2, and 6 also markedly enhanced the mineralization process with respective values of up to 136.4, 118.9, and 134.6%. In addition, the new compound, 1, significantly increased expression levels of estrogen receptor-α (133.4%) and osteogenesis-related genes of Runt-related transcription factor 2 (Runx2), osteopontin (OPN), bone morphogenetic protein (BMP)-2, bone sialoprotein (BSP), type I collagen (Col-1), and brain-derived neurotropic factor (BDNF) by at least 1.5-fold. Our results demonstrated that compounds isolated from T. formosana possess robust osteogenic potential, with the new compound, 1, also exhibiting the potential to enhance the bone formation process. We suggest that T. formosana and its isolated active compounds deserve further evaluation for development as anti-osteoporotic agents.

Effect of nutrients and exhaustive exercise on brain function.

Epidemiological evidence suggests that health-oriented eating habits are associated with maintaining optimal cognitive ability. Nutrients are functional bioactive molecules promoting human health and essential components as well. Docosahexaenoic acid (DHA; 22:6n-3), one of polyunsaturated fatty acids (PUFAs) is synthesized through elongation pathway from linolenic acid (81:3n-3) which is recognized as important source of brain function. Endurance physical exercise and energy restriction was also recognized of cardiovascular stress adjustment by enhancing brainstem cholinergic activity as well as brain function. However, we even do not know the exact neuronal mechanisms about the nutrients, β-hydroxybutyrate (β-HB) and myokine impacts on brain-derived neurotropic factor (BDNF) activation. Therefore, this review focuses on recent evidence that explains how nutrients and prolonged exercise can affect nervous system pathways that are associated with improving brain function. The results revealed that frequent consumption of polyphenols and n-3 PUFAs could modify gastrointestinal environment with beneficial microorganisms. It may suggest a new hypothesis that gastrointestinal microbiome could influence cognitive function in addition to the traditional etiological pathway. And moreover, prolonged physical exercise includes open skill sports which is induced by β-oxidation of free fatty acids stimulate BDNF. And also β-HB production which is induced by carbohydrate depletion, hypoglycemia, or fasting stimulate BDNF production that acts an significantly important roles in cognitive function and acting on brain function with brain metabolism.

Adverse childhood experiences and neuroinflammatory biomarkers-The role of sex.

Despite the growing interest in adverse childhood experiences and biomarkers, less attention has been paid to multiple biomarkers as representing interrelated systems among college students. Guided by the neuroinflammatory pathway hypothesis, the current project takes the initial step in examining the link between three types of childhood adversity and biomarkers of neuroplasticity (brain-derived neurotropic factor [BDNF]) and low-grade inflammation (C-reactive protein [CRP]) in an overarching model and whether this link may differ in men and women. Undergraduate students (n=85) were recruited through multiple departments from a state university. The participants responded to the detailed online survey questionnaire on childhood adversity and provided one blood sample via venous blood draw. Given that CRP and BDNF represent two interrelated systems, structural equation models were considered the most suitable for the analyses. The findings partially support neural and inflammatory pathways, such that childhood adversity and particularly family dysfunction have a significant positive effect on BDNF (b=30.41, p<.01). The link between family dysfunction and CRP was stronger in female students (b=0.57, p<.05). Results suggest that interventions for college students with family dysfunctions may need to target different physiological and behavioral outcomes for male and female students.

Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans.

Time-restricted feeding (TRF) is a form of intermittent fasting that involves having a longer daily fasting period. Preliminary studies report that TRF improves cardiometabolic health in rodents and humans. Here, we performed the first study to determine how TRF affects gene expression, circulating hormones, and diurnal patterns in cardiometabolic risk factors in humans. Eleven overweight adults participated in a 4-day randomized crossover study where they ate between 8 am and 2 pm (early TRF (eTRF)) and between 8 am and 8 pm (control schedule). Participants underwent continuous glucose monitoring, and blood was drawn to assess cardiometabolic risk factors, hormones, and gene expression in whole blood cells. Relative to the control schedule, eTRF decreased mean 24-hour glucose levels by 4 ± 1 mg/dl (p = 0.0003) and glycemic excursions by 12 ± 3 mg/dl (p = 0.001). In the morning before breakfast, eTRF increased ketones, cholesterol, and the expression of the stress response and aging gene SIRT1 and the autophagy gene LC3A (all p < 0.04), while in the evening, it tended to increase brain-derived neurotropic factor (BNDF; p = 0.10) and also increased the expression of MTOR (p = 0.007), a major nutrient-sensing protein that regulates cell growth. eTRF also altered the diurnal patterns in cortisol and the expression of several circadian clock genes (p < 0.05). eTRF improves 24-hour glucose levels, alters lipid metabolism and circadian clock gene expression, and may also increase autophagy and have anti-aging effects in humans.

Crucial Role of Dopamine D2 Receptor Signaling in Nicotine-Induced Conditioned Place Preference.

Nicotine in tobacco causes psychological dependence through its rewarding effect in the central nervous system (CNS). Although nicotine dependence is explained by dopamine receptor (DR) signaling together with nicotinic acetylcholine receptors (nAChRs), the synaptic molecular mechanism underlying the interaction between dopamine receptor and nAChRs remains unclear. Since reward signaling is mediated by dopamine receptors, we hypothesized that the dopamine D2 receptor (D2R), in part, mediates the synaptic modulation of nicotine-induced conditioned place preference (CPP) in addition to dopamine D1 receptor. To investigate the involvement of D2R, wild-type (WT) and dopamine D2 receptor knockout (D2RKO) mice were assessed using the CPP task after induction of nicotine-induced CPP. As expected, D2RKO mice failed to induce CPP behaviors after repeated nicotine administration (0.5mg/kg). When kinase signaling was assessed in the nucleus accumbens and hippocampal CA1 region after repeated nicotine administration, both Ca2+/calmodulin-dependent protein kinase (CaMKII) and extracellular signal-regulated kinase (ERK) were upregulated in WT mice but not in D2RKO mice. Likewise, nicotine-induced CPP was associated with elevation of pro- brain-derived neurotropic factor (BDNF) and BDNF protein levels in WT mice, but not in D2RKO mice. Taken together, in addition to dopamine D1 receptor signaling, dopamine D2 receptor signaling is critical for induction of nicotine-induced CPP in mice.

Effects of Aerobic Exercise as Add-On Treatment for Inpatients With Moderate to Severe Depression on Depression Severity, Sleep, Cognition, Psychological Well-Being, and Biomarkers: Study Protocol, Description of Study Population, and Manipulation Check.

Background: Aerobic exercise (AE) may be a non-pharmacological strategy to improve depression treatment and lessen the burden of somatic comorbidity of depression. Only few studies have examined the effect of AE as an add-on treatment for moderate to severe depression in an inpatient setting, and most studies have focused on depression severity and cardiovascular parameters. The purpose of the present article is to present the study protocol, to provide information about the assessed study population, and to perform a manipulation check in order to examine whether the intervention program was properly implemented. Methods: We conducted a randomized controlled trial in two centers comparing 6 weeks of AE to a placebo control intervention (stretching) as an add-on to standardized inpatient treatment of moderate to severe depression. Besides depression severity, several other psychological and biological variables were measured such as salivary cortisol, brain-derived neurotropic factor, cognitive tests, and polysomnography. To evaluate long-term effects of the intervention, we also scheduled a follow-up 6 months after completion of the study intervention. Results: Forty-five patients were randomized to either AE (n = 23) or the placebo intervention (n = 22); 36 patients completed the 6-week intervention. In the AE group, 65% completed all 18 training sessions. Patients who were less physically active prior to admission were less likely to complete the study. With regard to energy expenditure, mean kcal/kg/week was 16.4 kcal/kg/week (range: 13.8–17.7), coming close to the targeted dose of 17.5 kcal/kg/week. Conclusions: Overall, patients showed good adherence to the intervention protocol despite at least moderate depression severity. However, the dropout rate suggests that depressed inpatients may need special support to adhere to a structured exercise intervention program. This study will add evidence on the effects of AE as an add-on to inpatient treatment of moderate to severe depression. Besides antidepressant effects, potentially beneficial effects of AE on a broad array of further variables associated with depression will be evaluated. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02679053.

Nanoscale imaging reveals miRNA-mediated control of functional states of dendritic spines

Dendritic spines are major loci of excitatory inputs and undergo activity-dependent structural changes that contribute to synaptic plasticity and memory formation. Despite the existence of various classification types of spines, how they arise and which molecular components trigger their structural plasticity remain elusive. microRNAs (miRNAs) have emerged as critical regulators of synapse development and plasticity via their control of gene expression. Brain-specific miR-134s likely regulate the morphological maturation of spines, but their subcellular distributions and functional impacts have rarely been assessed. Here, we exploited atomic force microscopy to visualize in situ miR-134s, which indicated that they are mainly distributed at nearby dendritic shafts and necks of spines. The abundance of miR-134s varied between morphologically and functionally distinct spine types, and their amounts were inversely correlated with their postulated maturation stages. Moreover, spines exhibited reduced contents of miR-134s when selectively stimulated with beads containing brain-derived neurotropic factor (BDNF). Taken together, in situ visualizations of miRNAs provided unprecedented insights into the "inverse synaptic-tagging" roles of miR-134s that are selective to inactive/irrelevant synapses and potentially a molecular means for modifying synaptic connectivity via structural alteration.

Theobromine Improves Working Memory by Activating the CaMKII/CREB/BDNF Pathway in Rats.

Theobromine (TB) is a primary methylxanthine found in cacao beans. cAMP-response element-binding protein (CREB) is a transcription factor, which is involved in different brain processes that bring about cellular changes in response to discrete sets of instructions, including the induction of brain-derived neurotropic factor (BDNF). Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been strongly implicated in the memory formation of different species as a key regulator of gene expression. Here we investigated whether TB acts on the CaMKII/CREB/BDNF pathway in a way that might improve the cognitive and learning function in rats. Male Wistar rats (5 weeks old) were divided into two groups. For 73 days, the control rats (CN rats) were fed a normal diet, while the TB-fed rats (TB rats) received the same food, but with a 0.05% TB supplement. To assess the effects of TB on cognitive and learning ability in rats: The radial arm maze task, novel object recognition test, and Y-maze test were used. Then, the brain was removed and the medial prefrontal cortex (mPFC) was isolated for Western Blot, real-time PCR and enzyme-linked immunosorbent assay. Phosphorylated CaMKII (p-CaMKII), phosphorylated CREB (p-CREB), and BDNF level in the mPFC were measured. In all the behavior tests, working memory seemed to be improved by TB ingestion. In addition, p-CaMKII and p-CREB levels were significantly elevated in the mPFC of TB rats in comparison to those of CN rats. We also found that cortical BDNF protein and mRNA levels in TB rats were significantly greater than those in CN rats. These results suggest that orally supplemented TB upregulates the CaMKII/CREB/BDNF pathway in the mPFC, which may then improve working memory in rats.

GHS-R1a Deficiency Alleviates Depression-Related Behaviors After Chronic Social Defeat Stress

Ghrelin is an important orexigenic hormone that regulates feeding, metabolism and glucose homeostasis in human and rodents. Ghrelin functions by binding to its receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), which is widely expressed inside and outside of the brain. Recent studies suggested that acyl-ghrelin, the active form of ghrelin, is a persistent biomarker for chronic stress exposure. However, how ghrelin/GHS-R1a signaling contributes to stress responses and mood regulation remains uncertain. In this study, we applied the chronic social defeat stress (CSDS) paradigm to both GHS-R1a knock-out (Ghsr-/-) mice and littermate control (Ghsr+/+) mice, and then measured their depression- and anxiety-related behaviors. We found that Ghsr+/+ mice, but not Ghsr-/- mice, displayed apparent anxiety and depression after CSDS, while two groups mice showed identical behaviors at baseline, non-stress state. By screening the central and peripheral responses of Ghsr-/- mice and Ghsr+/+ mice to chronic stress, we found similar elevations of total ghrelin and adrenocorticotropic hormone (ACTH) in the serum of Ghsr-/- mice and Ghsr+/+ mice after CSDS, but decreased interleukin-6 (IL-6) in the serum of defeated Ghsr-/- mice compared to defeated Ghsr+/+ mice. We also found increased concentration of brain derived neurotropic factor (BDNF) in the hippocampus of Ghsr-/- mice compared to Ghsr+/+ mice after CSDS. The basal levels of ghrelin, ACTH, IL-6, and BDNF were not different between Ghsr-/- mice and Ghsr+/+ mice. Our findings thus suggested that the differential expressions of BDNF and IL-6 after CSDS may contribute to less anxiety and less despair observed in GHS-R1a-deficient mice than in WT control mice. Therefore, ghrelin/GHS-R1a signaling may play a pro-anxiety and pro-depression effect in response to chronic stress, while GHS-R1a deficiency may provide resistance to depressive symptoms of CSDS.

SUN-535 Impact of Route of Estrogen Administration on Bone Turnover Markers in Oligoamenorrheic Athletes and Mediators of these Effects

Transdermal, but not oral, estrogen replacement improves bone mineral density (BMD) in athletes with oligo-amenorrhea (OA). Our objective was to determine mechanisms that may explain the impact of route of estrogen administration on bone outcomes. Whereas IGF-1 is bone anabolic, sclerostin, preadipocyte factor-1 (Pref-1) and brain derived neurotropic factor (BDNF) inhibit bone formation, and an effect of estrogen on these factors has been demonstrated in other populations. However, few studies have examined the impact of route of estrogen administration on these factors in adolescents and young adults. Further, it is unclear how the route of estrogen administration impacts bioavailable testosterone, which in turn may impact bone outcomes in young oligo-amenorrheic women. 73 OA 14-25 years old received (i) a 17β-estradiol transdermal patch continuously with cyclic oral micronized progesterone (PATCH), (ii) a combined ethinyl estradiol and desogestrel pill (PILL), or (iii) no estrogen/progesterone (NONE) for 12-months. We evaluated fasting morning levels of a marker of bone formation [N-terminal propeptide of type 1 procollagen (P1NP)], a marker of bone resorption [N-telopeptide (NTX)], IGF-1, insulin-like growth factor binding protein 3 (IGFBP3), total testosterone, estradiol, sex hormone-binding globulin (SHBG), sclerostin, Pref-1, BDNF, calcium, 25(OH) vitamin D, and parathyroid hormone (PTH) at baseline and 12-months. Groups did not differ for age, weight, exercise activity or markers of bone formation at baseline. We have previously reported increases in areal BMD Z-scores at the spine and femoral neck in the PATCH compared to PILL and NONE groups (Ackerman et al: BJSM Oct. 2018). Over 12 months, between group analysis showed greatest decreases of P1NP in the PILL group (p=0.03) associated with a decrease in IGF-1 and IGF1/IGFBP-3 ratio (r=0.33, p≤0.05), and an increase in SHBG (r=-0.28;p=0.02). Within group analysis showed that sclerostin, Pref-1 and BDNF decreased in the PATCH group over 12 months (p=0.01, 0.01 and 0.04 respectively). PATCH group had the greatest increases in estradiol (p=0.0009), and estradiol increases were associated with increases in BMD. Groups did not differ for changes in NTX. Transdermal 17β-estradiol does not cause the decrease in IGF-1 and SHBG observed with oral ethinyl estradiol. It leads to decreases in sclerostin, Pref-1 and BDNF. These effects may mediate the beneficial effects of transdermal estrogen on bone in young women.

MON-093 Myokine Levels after Resistance Exercise in Young Adults with Prader-Willi Syndrome (PWS)

Background: Individuals with PWS require marked caloric restriction and daily exercise to prevent morbid obesity. Lower energy expenditure compared to BMI-matched controls along with hypotonia, decreased muscle mass, and cognitive impairment make exercise particularly challenging for this population. Exercise guidelines include resistance training as an important component. Myokine responses to resistance exercise may have beneficial metabolic effects. Objectives: Determine if young PWS adults can perform a resistance exercise program. Evaluate myokine responses to acute resistance exercise in young adults with PWS and compare responses with age and BMI-matched controls. Methods: Each study group included 11 participants (7M/4F). Mean±SD ages were 30.7±4.6 and 30.1±4.3 years for PWS and controls (NS). BMI values were 28.3±4.3 and 28.2±4.2 kg/m2 for PWS and controls, respectively (NS). Blood samples for glucose, creatine kinase (CK), lactate, hemoglobin A1c (HbA1C) and myokines were obtained before performing a program of eight resistance exercises lasting 45-60 minutes. Additional blood samples were drawn immediately after, and 30 and 60 minutes after completing the exercises. Myokines were assayed using a multiplex myokine panel (Merck Millipore). Paired t-test was used for comparing results for PWS vs controls. The unpaired t-test was used for comparing peak laboratory values with basal levels. Results: Basal levels (mean±SEM) of glucose, hemoglobin A1c, and lactate were similar for PWS and controls but CK was lower in PWS vs controls (62±16 vs 322±100 U/L, p<0.04). Peak lactate was 3.7±0.7 in PWS vs 7.3±0.7 mmol/l in controls (p<0.001). Basal and peak levels of interleukin-6 (IL-6), brain-derived neurotropic factor (BDNF), irisin, osteonectin, myostatin, and fibroblast growth factor-21 varied widely and no statistically significant differences were found between the two groups. Post-exercise IL-6 increased by 41±16 % in PWS (p<0.03) and 35±10 % in controls (p<0.007). Post-exercise BDNF rose to 47±18% over baseline in control males (p<0.006) but not in PWS males, or in PWS and control females. Failure to increase BDNF and irisin levels following exercise was associated with significantly lower strength as determined by maximum weights used. Conclusions: PWS young adults are capable of performing resistance/strength-building exercise. The lower CK and peak lactate levels in PWS reflect decreased muscle mass in this population. IL-6 increased significantly in both PWS and control groups. Increases in BDNF and irisin were associated with greater exertion compared to non-responders. Resistance exercise should be part of the daily sports regimen for individuals with PWS. Further studies of myokine levels in PWS are needed to characterize the unique metabolic phenotype in this population and assist in prescribing appropriate personalized exercise programs.

Overexpression of BRCA1 in Neural Stem Cells Enhances Cell Survival and Functional Recovery after Transplantation into Experimental Ischemic Stroke.

Transplantation of neural stem cells (NSCs) is a promising therapy for ischemic stroke. However, the effectiveness of this approach is limited by grafted cell death. Breast cancer susceptibility protein 1 (BRCA1) could suppress apoptosis in neural progenitors and modulate oxidative stress in neurons. In this study, we found that BRCA1 was upregulated by oxygen-glucose deprivation/reoxygenation (OGD/R). Overexpression of BRCA1 in NSCs reduced cell apoptosis and oxidative stress after OGD/R insult. The molecule overexpression also stimulated cellular proliferation in OGD/R NSCs and increased the survival rate of grafted cells. Further, the transplantation of BRCA1-transfected NSCs into mice with ischemic stroke increased brain-derived neurotropic factor and nerve growth factor expression in the brain and elicited neurological function improvement. In addition, we found that RING finger domain and BRCT domain of BRCA1 could physically interact with p53 in NSCs. The cross talk between BRCA1 RING finger domain and p53 was responsible for p53 ubiquitination and degradation. Our findings indicate that modification with BRCA1 could enhance the efficacy of NSCs transplantation in ischemic stroke.

Neuroprotective Benefits of Antidepressants in Multiple Sclerosis: Are We Missing the Mark?

The potential of antidepressant medication to have a neuroprotective effect for people with multiple sclerosis (MS) has received increased interest in recent years. The possibility of antidepressants, particularly fluoxetine, for potential repurposing to treat primary progressive and secondary progressive MS is of interest as a result of the relative lack of disease-modifying medications for these subtypes. A number of animal studies have found positive results for a neuroprotective effect of antidepressant use in MS, with human studies showing mixed results. These human studies all have a significant limitation: they exclude people with moderate to severe depressive symptoms, a core symptom of MS beyond that of reactive depression. It is likely that reregulation of the common mechanisms in depression and MS, such as inflammation, serotonin, norepinephrine, glutamate and brain-derived neurotropic factor disruption, and hypothalamic-pituitary-thalamic axis dysregulation, are important to the neuroprotective value of antidepressant medication. Given that MS is known for its heterogeneity, the question might be less about whether antidepressant medication provides neuroprotective benefits to people with multiple sclerosis but for whom they provide benefits and whether we are designing studies that will detect a benefit. To answer these questions, studies must include people with MS and depressive symptoms as well as people with relapsing remitting and chronic subtypes.

Uncovering Caprin1's biological role to understand it's function in autism

Deregulation of various cellular pathways such as the immune, mRNA translation and cell cycle pathways have been linked to autism disorders, yet the cause of deregulation remains unclear. Here we study the Cytoplasmic Activation/Proliferation‐Associated Protein‐1 (Caprin1), an RNA binding protein implicated in autism. In neurons, Caprin1 binds and represses the translation of selective mRNAs at RNA granules. Upon various stimulations such as with brain derived neurotropic factor (BDNF), mRNAs dissociate from Caprin1 and shift into actively translating ribosomes. In addition, studies identified Caprin1 as a positive cell cycle regulator, allowing cells to transition between G1 and S phase by binding to upregulated cell cycle mRNAs. Yet, how Caprin1 mediates repression or promotion of different mRNAs is not well understood. To identify and understand the global mechanism of Caprin1 we conducted a series of high throughput assays including mass‐spectrometry‐based quantitative proteomics and RNAseq. We show that in the absence of Caprin1, cell cycle and cell metabolic genes were significantly decreased. On the other hand, absence of Caprin1 significantly increased genes involved in immune responses, including antigen processing. To further identify a mechanism we conducted a crosslinking‐immunoprecipitation (CLIP) assay to identify mRNAs bound directly to Caprin1. We find that Caprin1 mainly binds to mRNAs upstream of cytokine signaling and cell cycle pathways at the 3′UTR. We further show that Caprin1 degrades or stabilizes different bound mRNAs. Thus, we conclude that Caprin1 has a role in RNA stability, particularly in genes involved in cell cycle and immune response pathways, which are deregulated and implicated in autism.Support or Funding InformationRobertson Foundation, NIH R01AI090110 Supplement, Howard Hughes Medical Institute (HHMI)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

7,8-Dihydroxyflavone potentiates ongoing epileptiform activity in mice brain slices

In the central nervous system, Tropomyosin-receptor-kinase B (TrkB) signaling is involved in neuronal survival, differentiation as well as in regulation of synaptic transmission and excitability. As its powerful potential to modulate neuronal functions, TrkB pathway is an attractive target for novel drugs and treatment of common neurological disorders. 7,8-Dihydroxyflavone (DHF), a TrkB receptor agonist, has similar properties with neurotrophin Brain Derived Neurotropic Factor (BDNF). DHF is reported to have a number of beneficial effects in neuroprotection, against depression and improving learning and memory. However, the outcome of acute application of DHF on the excitability of neuronal circuits is not clear. Especially the effects of DHF on synchronized epileptiform activity are not known. In this study, we investigated whether DHF induces epileptiform activity in brain slices and DHF has any effect on already initiated epileptiform discharges. We used acute horizontal hippocampal-entorhinal cortex slices obtained from 30 to 35 days of mice. Extracellular field potential recordings were obtained from entorhinal cortex (EC) and hippocampus CA1 region. DHF did not initiate any epileptiform activity or abnormal discharges. However, DHF increased the frequency of 4 aminopyridine (4AP) induced ictal and interictal events in both EC and CA1. The duration of induced ictal charges were also prolonged upon DHF application. In a number of slices, both EC and CA1, DHF led to ictogenesis. These results suggest that the acute activation of TrkB by DHF has a powerful potential on synchronized neuronal discharges which should be considered in future therapeutical approaches.

Centella asiatica Prevents Increase of Hippocampal Tumor Necrosis Factor-α Independently of Its Effect on Brain-Derived Neurotrophic Factor in Rat Model of Chronic Stress.

Centella asiatica ameliorates memory impairment and induces expression of hippocampal brain-derived neurotropic factor (BDNF) in chronically stressed rats. The relationship between the anti-inflammatory effect of Centella asiatica on hippocampal BDNF and the involvement of sirtuin-1, a BDNF expression regulator, in neuroprotective mechanisms of Centella asiatica warrants an investigation. We investigated the effect of Centella asiatica ethanolic extracts (CA) on TNF-α, IL-10, and SIRT1 levels and whether these predicted BDNF expression in rat hippocampus after chronic stress. For the experiments, thirty male rats (Sprague Dawley) were divided into six groups: nonstressed-control, stressed-control, nonstressed +CA 300mg/kg/d, stressed +CA 150 mg/kg/d, stressed +CA 300 mg/kg/d, and stressed +CA 600 mg/kg/d. On day 28, rats were sacrificed and hippocampus was dissected out. Hippocampal TNF-α, IL-10, SIRT1, and BDNF were measured by enzyme-linked immunosorbent assay. Hippocampal TNF-α level was significantly higher in the stressed-control compared to nonstressed-control groups. Across all stress conditions, rats receiving the highest dose of CA had the lowest mean TNF-α and highest mean BDNF. There were no significant differences in IL-10 and SIRT1 levels between groups. Hippocampal TNF-α did not predict hippocampal BDNF in a regression analysis. In conclusion, lower TNF-α and higher BDNF in the hippocampus support the hypothesis that these factors independently contribute to Centella asiatica's neuroprotective effect in chronically stressed rats.

HIV-1 Tat protein promotes neuronal dysregulation by inhibiting E2F transcription factor 3 (E2F3)

Individuals who are infected with HIV-1 accumulate damage to cells and tissues (e.g. neurons) that are not directly infected by the virus. These include changes known as HIV-associated neurodegenerative disorder (HAND), leading to the loss of neuronal functions, including synaptic long-term potentiation (LTP). Several mechanisms have been proposed for HAND, including direct effects of viral proteins such as the Tat protein. Searching for the mechanisms involved, we found here that HIV-1 Tat inhibits E2F transcription factor 3 (E2F3), CAMP-responsive element-binding protein (CREB), and brain-derived neurotropic factor (BDNF) by up-regulating the microRNA miR-34a. These changes rendered murine neurons dysfunctional by promoting neurite retraction, and we also demonstrate that E2F3 is a specific target of miR-34a. Interestingly, bioinformatics analysis revealed the presence of an E2F3-binding site within the CREB promoter, which we validated with ChIP and transient transfection assays. Of note, luciferase reporter assays revealed that E2F3 up-regulates CREB expression and that Tat interferes with this up-regulation. Further, we show that miR-34a inhibition or E2F3 overexpression neutralizes Tat's effects and restores normal distribution of the synaptic protein synaptophysin, confirming that Tat alters these factors, leading to neurite retraction inhibition. Our results suggest that E2F3 is a key player in neuronal functions and may represent a good target for preventing the development of HAND.

An examination of genes, stress and suicidal behavior in two First Nations communities: The role of the brain-derived neurotropic factor gene

Suicide claims over 800,000 lives each year worldwide. Suicide rates in indigenous populations in Canada are about double that of the national average, making it a serious public health issue. Numerous factors are involved in suicide risk, including genetic factors, as well as various psychosocial stressors, such as historical experience with the Indian Residential School system for Indigenous populations, as well as protective variables such as social support. Here, we report the first genetic study of suicidal behaviors that includes multiple measures of stress and social supports. We investigated the role of the functional Val66Met marker (rs6265) in the Brain-Derived Neurotropic Factor (BDNF) gene in suicidal ideation and suicide attempt in a First Nations community sample (N = 278). We did not find a significant association between the BDNF rs6265 marker and suicidal behaviors. We found childhood adversities, recent life stress, chronic stress, perceived stress, difficulties, and hazardous alcohol use to be associated with both suicidal ideation and suicide attempt. Thus, while additional studies with larger samples are required to elucidate the genetic component of suicide, addressing environmental stressors may be important for suicide prevention.