Bdnf Transcription Research Articles

Screening inducers of neuronal BDNF gene transcription using primary cortical cell cultures from BDNF-luciferase transgenic mice

Brain-derived neurotrophic factor (BDNF) is a key player in synaptic plasticity, and consequently, learning and memory. Because of its fundamental role in numerous neurological functions in the central nervous system, BDNF has utility as a biomarker and drug target for neurodegenerative and neuropsychiatric disorders. Here, we generated a screening assay to mine inducers of Bdnf transcription in neuronal cells, using primary cultures of cortical cells prepared from a transgenic mouse strain, specifically, Bdnf-Luciferase transgenic (Bdnf-Luc) mice. We identified several active extracts from a library consisting of 120 herbal extracts. In particular, we focused on an active extract prepared from Ginseng Radix (GIN), and found that GIN activated endogenous Bdnf expression via cAMP-response element-binding protein-dependent transcription. Taken together, our current screening assay can be used for validating herbal extracts, food-derived agents, and chemical compounds for their ability to induce Bdnf expression in neurons. This method will be beneficial for screening of candidate drugs for ameliorating symptoms of neurological diseases associated with reduced Bdnf expression in the brain, as well as candidate inhibitors of aging-related cognitive decline.

Diurnal rhythms in gene expression in the prefrontal cortex in schizophrenia

Schizophrenia is associated with disrupted cognitive control and sleep-wake cycles. Here we identify diurnal rhythms in gene expression in the human dorsolateral prefrontal cortex (dlPFC), in schizophrenia and control subjects. We find significant diurnal (24 h) rhythms in control subjects, however, most of these transcripts are not rhythmic in subjects with schizophrenia. Instead, subjects with schizophrenia have a different set of rhythmic transcripts. The top pathways identified in transcripts rhythmic only in subjects with schizophrenia are associated with mitochondrial function. Importantly, these rhythms drive differential expression patterns of these and several other genes that have long been implicated in schizophrenia (including BDNF and GABAergic-related transcripts). Indeed, differential expression of these transcripts is only seen in subjects that died during the night, with no change in subjects that died during the day. These data provide insights into a potential mechanism that underlies changes in gene expression in the dlPFC with schizophrenia.

Manipulation of a genetically and spatially defined sub-population of BDNF-expressing neurons potentiates learned fear and decreases hippocampal-prefrontal synchrony in mice.

Brain-derived neurotrophic factor (BDNF) signaling regulates synaptic plasticity in the hippocampus (HC) and prefrontal cortex (PFC), and has been extensively linked with fear memory expression in rodents. Notably, disrupting BDNF production from promoter IV-derived transcripts enhances fear expression in mice, and decreases fear-associated HC-PFC synchrony, suggesting that Bdnf transcription from promoter IV plays a key role in HC-PFC function during fear memory retrieval. To better understand how promoter IV-derived BDNF controls HC-PFC connectivity and fear expression, we generated a viral construct that selectively targets cells expressing promoter IV-derived Bdnf transcripts ("p4-cells") for tamoxifen-inducible Cre-mediated recombination (AAV8-p4Bdnf-ERT2CreERT2-PEST). Using this construct, we found that ventral hippocampal(vHC) p4-cells are recruited during fear expression, and that activation of these cells causes exaggerated fear expression that co-occurs with disrupted vHC-PFC synchrony in mice. Our data highlight how this novel construct can be used to interrogate genetically defined cell types that selectively contribute to BDNF-dependent behaviors.

Chronological Molecular Changes in Neuronal Communication in Androgen-Deficient Rats.

We investigated the early onset of molecular changes in the hippocampus of orchidectomy (ODX)-induced androgen-deficient rats. Transcript levels of the genes associated with loss of synaptic plasticity (Bdnf, Syn, GluN1, α7-nAChR, and M1-mAChR), formation of neurofibrillary tangles (Tau4 and Tau3), and amyloid plaques (App, Adam10, and Bace1), in the hippocampus of rats at 0, 1, 3, 6, and 9days after ODX (D0, D1, D3, D6 and D9, respectively) were determined. Primarily, the sudden loss of androgen, as confirmed by the decreased serum testosterone levels and accessory sex organ weights, induced a chronological reduction in Syn (at D1), and increase in GluN1 (at D3), α7-nAChR, and M1-mAChR (at D6) and a decrease in Bdnf (at D9) transcript levels. Tau4 and Tau3 mRNA levels were increased at D6 and D9, respectively. No changes in App, Adam10, and Bace1 mRNA levels were detected within the 9-day study period. To confirm those changes were caused by androgen deprivation and not increasing age, the mRNA expression levels of those genes in 9-day orchidectomized rats (ODX-D9) were compared with age-matched intact rats. All changes of mRNA expression levels of the ODX-D9 rats were aligned with the D9 rats, except for GluN1 that was decreased in the ODX-D9 rats. Moreover, the total and phosphorylated tau protein levels were increased in the ODX-D9 rats. These results denote that androgen deficiency induces the early onset of neurodegeneration, while the loss of synaptic plasticity together with the formation of neurofibrillary tangles could be used as markers for neurodegenerative prediction.

Enriched gestation activates the IGF pathway to evoke embryo-adult benefits to prevent Alzheimer\u2019s disease

BackgroundBuilding brain reserves before dementia onset could represent a promising strategy to prevent Alzheimer’s disease (AD), while how to initiate early cognitive stimulation is unclear. Given that the immature brain is more sensitive to environmental stimuli and that brain dynamics decrease with ageing, we reasoned that it would be effective to initiate cognitive stimulation against AD as early as the fetal period.MethodsAfter conception, maternal AD transgenic mice (3 × Tg AD) were exposed to gestational environment enrichment (GEE) until the day of delivery. The cognitive capacity of the offspring was assessed by the Morris water maze and contextual fear-conditioning tests when the offspring were raised in a standard environment to 7 months of age. Western blotting, immunohistochemistry, real-time PCR, immunoprecipitation, chromatin immunoprecipitation (ChIP) assay, electrophysiology, Golgi staining, activity assays and sandwich ELISA were employed to gain insight into the mechanisms underlying the beneficial effects of GEE on embryos and 7–10-month-old adult offspring.ResultsWe found that GEE markedly preserved synaptic plasticity and memory capacity with amelioration of hallmark pathologies in 7–10-m-old AD offspring. The beneficial effects of GEE were accompanied by global histone hyperacetylation, including those at bdnf promoter-binding regions, with robust BDNF mRNA and protein expression in both embryo and progeny hippocampus. GEE increased insulin-like growth factor 1 (IGF1) and activated its receptor (IGF1R), which phosphorylates Ca2+/calmodulin-dependent kinase IV (CaMKIV) at tyrosine sites and triggers its nuclear translocation, subsequently upregulating histone acetyltransferase (HAT) and BDNF transcription. The upregulation of IGF1 mimicked the effects of GEE, while IGF1R or HAT inhibition during pregnancy abolished the GEE-induced CaMKIV-dependent histone hyperacetylation and BDNF upregulation.ConclusionsThese findings suggest that activation of IGF1R/CaMKIV/HAT/BDNF signaling by gestational environment enrichment may serve as a promising strategy to delay AD progression.

Dimethyl fumarate up-regulates expression of major neurotrophic factors in the epidermal neural crest stem cells.

There is an agreement that combining treatments can lead to substantial improvement, therefore the present study assessed the effects of different concentrations of dimethyl fumarate (DMF) on viability of epidermal neural crest stem cells (EPI-NCSCs). In addition, this investigation was designed to evaluate the effects of DMF on relative expression of major trophic factors mainly the ones with neurotrophic effects, expressed in EPI-NCSCs in order to enhance their therapeutic potential. To determine the appropriate concentration of DMF for EPI-NCSCs treatment, the MTT assay was employed and based on the obtained data, EPI-NCSCs treated with 10μM DMF for 6, 24, 72 or 168 h. In each time point, quantitative RT-PCR technique was used to evaluate NGF, NT-3, BDNF, GDNF and VEGF transcripts. The acquired data showed that 10μM DMF significantly increased the mRNA expression of NGF, NT-3 and BDNF, 72 h following treatment; however, DMF inhibitory effect on GDNF mRNA expression was observed in various time points. No significant changes were detected for VEGF transcript. Our findings reveled that expression of major neurotrophic factors were up-regulated by dimethyl fumarate treatment. Therefore, combining EPI-NCSCs with DMF treatment might be a valuable strategy to improve their therapeutic functions in vivo.

Human UCB-MSCs treatment upon intraventricular hemorrhage contributes to attenuate hippocampal neuron loss and circuit damage through BDNF-CREB signaling

BackgroundHuman umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have been shown to prevent brain damage and improve neurocognition following intraventricular hemorrhage (IVH). However, the molecular mechanisms underlying the effects of hUCB-MSCs are still elusive. Thus, as the hippocampus is essential for learning, memory, and cognitive functions and is intimately involved in the ventricular system, making it a potential site of IVH-induced injury, we determined the molecular basis of the effects of hUCB-derived MSCs on hippocampal neurogenesis and the recovery of hippocampal neural circuits after IVH in a rodent model.MethodsWe inflicted severe IVH injury on postnatal day 4 (P4) in rats. After confirmation of successful induction of IVH using MRI (P5), intracerebroventricular administration of MSCs (ICV-MSC) was performed at 2 days post-injury (P6). For hippocampal synaptic determination, a rat entorhinal-hippocampus (EH) organotypic slice co-culture (OSC) was performed using day 3 post-IVH brains (P7) with or without ICV-MSCs. A similar strategy of experiments was applied to those rats receiving hUCB-MSC transfected with BDNF-Si-RNA for knockdown of BDNF or scrambled siRNA controls after IVH. The molecular mechanism of the MSCs effects on neurogenesis and the attenuation of neuron death was determined by evaluation of BDNF-TrkB-Akt-CREB signaling axis.ResultsWe showed that treatment with hUCB-MSCs attenuated neuronal loss and promoted neurogenesis in the hippocampus, an area highly vulnerable to IVH-induced brain injury. hUCB-MSCs activate BDNF-TrkB receptor signaling, eliciting intracellular activation of Akt and/or Erk and subsequent phosphorylation of CREB, which is responsible for promoting rat BDNF transcription. In addition to the beneficial effects of neuroprotection and neurogenesis, hUCB-MSCs also contribute to the restoration of impaired synaptic circuits in the hippocampus and improve neurocognitive functions in IVH-injured neonatal rat through BDNF-TrkB-CREB signaling axis activation.ConclusionsOur data suggest that hUCB-MSCs possess therapeutic potential for treating neuronal loss and neurocognitive dysfunction in IVH through the activation of intracellular TrkB-CREB signaling that is invoked by hUCB-MSC-secreted BDNF.

The Role of Dendritic Brain-Derived Neurotrophic Factor Transcripts on Altered Inhibitory Circuitry in Depression

BackgroundA parallel downregulation of brain-derived neurotrophic factor (BDNF) and somatostatin (SST), a marker of inhibitory gamma-aminobutyric acid interneurons that target pyramidal cell dendrites, has been reported in several brain areas of subjects with major depressive disorder (MDD). Rodent genetic studies suggest that they are linked and that both contribute to the illness. However, the mechanism by which they contribute to the pathophysiology of the illness has remained elusive. MethodsWith quantitative polymerase chain reaction, we determined the expression level of BDNF transcript variants and synaptic markers in the prefrontal cortex of patients with MDD and matched control subjects (n = 19/group) and of C57BL/6J mice exposed to chronic stress or control conditions (n = 12/group). We next suppressed Bdnf transcripts with long 3′ untranslated region (L-3′-UTR) using short hairpin RNA and investigated changes in cell morphology, gene expression, and behavior. ResultsL-3′-UTRs containing BDNF messenger RNAs, which migrate to distal dendrites of pyramidal neurons, are selectively reduced, and their expression was highly correlated with SST expression in the prefrontal cortex of subjects with MDD. A similar downregulation occurs in mice submitted to chronic stress. We next show that Bdnf L-3′-UTR knockdown is sufficient to induce 1) dendritic shrinkage in cortical neurons, 2) cell-specific MDD-like gene changes (including Sst downregulation), and 3) depressive- and anxiety-like behaviors. The translational validity of the Bdnf L-3′-UTR short hairpin RNA–treated mice was confirmed by significant cross-species correlation of changes in MDD-associated gene expression. ConclusionsThese findings provide evidence for a novel MDD-related pathological mechanism linking local neurotrophic support, pyramidal cell structure, dendritic inhibition, and mood regulation.

BDNF-TrkB signaling in oxytocin neurons contributes to maternal behavior.

Brain-derived neurotrophic factor (Bdnf) transcription is controlled by several promoters, which drive expression of multiple transcripts encoding an identical protein. We previously reported that BDNF derived from promoters I and II is highly expressed in hypothalamus and is critical for regulating aggression in male mice. Here we report that BDNF loss from these promoters causes reduced sexual receptivity and impaired maternal care in female mice, which is concomitant with decreased oxytocin (Oxt) expression during development. We identify a novel link between BDNF signaling, oxytocin, and maternal behavior by demonstrating that ablation of TrkB selectively in OXT neurons partially recapitulates maternal care impairments observed in BDNF-deficient females. Using translating ribosome affinity purification and RNA-sequencing we define a molecular profile for OXT neurons and delineate how BDNF signaling impacts gene pathways critical for structural and functional plasticity. Our findings highlight BDNF as a modulator of sexually-dimorphic hypothalamic circuits that govern female-typical behaviors.

Visualizing BDNF Transcript Usage During Sound-Induced Memory Linked Plasticity.

Activity-dependent BDNF (brain-derived neurotrophic factor) expression is hypothesized to be a cue for the context-specificity of memory formation. So far, activity-dependent BDNF cannot be explicitly monitored independently of basal BDNF levels. We used the BLEV (BDNF-live-exon-visualization) reporter mouse to specifically detect activity-dependent usage of Bdnf exon-IV and -VI promoters through bi-cistronic co-expression of CFP and YFP, respectively. Enriching acoustic stimuli led to improved peripheral and central auditory brainstem responses, increased Schaffer collateral LTP, and enhanced performance in the Morris water maze. Within the brainstem, neuronal activity was increased and accompanied by a trend for higher expression levels of Bdnf exon-IV-CFP and exon-VI-YFP transcripts. In the hippocampus BDNF transcripts were clearly increased parallel to changes in parvalbumin expression and were localized to specific neurons and capillaries. Severe acoustic trauma, in contrast, elevated neither Bdnf transcript levels, nor auditory responses, parvalbumin or LTP. Together, this suggests that critical sensory input is essential for recruitment of activity-dependent auditory-specific BDNF expression that may shape network adaptation.

Beta-hydroxybutyrate Promotes the Expression of BDNF in Hippocampal Neurons under Adequate Glucose Supply

Neurobiological evidence suggests that the ketone metabolite β-hydroxybutyrate (BHBA) exerts many neuroprotective functions for the brain. The previous study revealed that BHBA could promote the expression of brain-derived neurotrophic factor (BDNF) at glucose inadequate condition. Here we demonstrated that BHBA administration induced the expression of BDNF in the hippocampus of mice fed with normal diet. In vitro experiment results also showed that 0.02–2 mM BHBA significantly increased BDNF expression in both the primary hippocampal neurons and the hippocampus neuron cell line HT22 under adequate glucose supply. Bdnf transcription induced by BHBA stimulus was mediated through the cAMP/PKA-triggered phosphorylation of CREB (S133) and the subsequent up-regulation of histone H3 Lysine 27 acetylation (H3K27ac) binding at Bdnf promoters I, II, IV, and VI. Moreover, BHBA stimulus induced a decrease in tri-methylation of H3K27 (H3K27me3) binding at the Bdnf promoters II and VI and the elevation of H3K27me3-specific demethylase JMJD3, which also contributed to the activation of Bdnf transcription. These results demonstrated that BHBA within the physiological range could promote BDNF expression in neurons via a novel signaling function. Moreover, BHBA might possess more broad epigenetic regulatory activities, which affected both the acetylation and demethylation of H3K27. Our findings reinforce the beneficial effect of BHBA on the central nervous system (CNS) and suggest that BHBA administration with no need for energy restriction might also be a promising intervention to improve the neuronal activity and ameliorate the degeneration of CNS.

Cortical Axonal Secretion of BDNF in the Striatum Is Disrupted in the Mutant-huntingtin Knock-in Mouse Model of Huntington's Disease

Deficient BDNF signaling is known to be involved in neurodegenerative diseases such as Huntington's disease (HD). Mutant huntingtin (mhtt)-mediated disruption of either BDNF transcription or transport is thought to be a factor contributing to striatal atrophy in the HD brain. Whether and how activity-dependent BDNF secretion is affected by the mhtt remains unclear. In the present study, I provide evidence for differential effects of the mhtt on cortical BDNF secretion in the striatum during HD progression. By two-photon imaging of fluorescent BDNF sensor (BDNF-pHluorin and -EGFP) in acute striatal slices of HD knock-in model mice, I found deficient cortical BDNF secretion regardless of the HD onset, but antisense oligonucleotide (ASO)-mediated reduction of htts only rescues BDNF secretion in the early HD brain before the disease onset. Although secretion modes of individual BDNF-containing vesicle were not altered in the pre-symptomatic brain, the full-fusion and partial-fusion modes of BDNF-containing vesicles were significantly altered after the onset of HD symptoms. Thus, besides abnormal BDNF transcription and transport, our results suggest that mhtt-mediated alteration in activity-dependent BDNF secretion at corticostriatal synapses also contributes to the development of HD.

Electroconvulsive seizures influence dendritic spine morphology and BDNF expression in a neuroendocrine model of depression

BackgroundElectroconvulsive therapy (ECT) is a rapid and effective treatment for major depressive disorder. Chronic stress-induced depression causes dendrite atrophy and deficiencies in brain-derived neurotrophic factor (BDNF), which are reversed by anti-depressant drugs. Electroconvulsive seizures (ECS), an animal model of ECT, robustly increase BDNF expression and stimulate dendritic outgrowth. ObjectiveThe present study aims to understand cellular and molecular plasticity mechanisms contributing to the efficacy of ECS following chronic stress-induced depression. MethodsWe quantify Bdnf transcript levels and dendritic spine density and morphology on cortical pyramidal neurons in mice exposed to vehicle or corticosterone and receiving either Sham or ECS treatment. ResultsECS rescues corticosterone-induced defects in spine morphology and elevates Bdnf exon 1 and exon 4-containing transcripts in cortex. ConclusionsDendritic spine remodeling and induction of activity-induced BDNF in the cortex represent important cellular and molecular plasticity mechanisms underlying the efficacy of ECS for treatment of chronic stress-induced depression.

Sexually Dimorphic Epigenetic Regulation of Brain-Derived Neurotrophic Factor in Fetal Brain in the Valproic Acid Model of Autism Spectrum Disorder

Prenatal exposure to the antiepileptic, mood-stabilizing drug, valproic acid (VPA), increases the incidence of autism spectrum disorders (ASDs); in utero administration of VPA to pregnant rodents induces ASD-like behaviors such as repetitive, stereotyped activity, and decreased socialization. In both cases, males are more affected than females. We previously reported that VPA, administered to pregnant mice at gestational day 12.5, rapidly induces a transient, 6-fold increase in BDNF (brain-derived neurotrophic factor) protein and mRNA in the fetal brain. Here, we investigate sex differences in the induction of Bdnf expression by VPA as well as the underlying epigenetic mechanisms. We found no sex differences in the VPA stimulation of total brain Bdnf mRNA as indicated by probing for the BDNF protein coding sequence (exon 9); however, stimulation of individual transcripts containing two of the nine 5′-untranslated exons (5′UTEs) in Bdnf (exons 1 and 4) by VPA was greater in female fetal brains. These Bdnf transcripts have been associated with different cell types or subcellular compartments within neurons. Since VPA is a histone deacetylase inhibitor, covalent histone modifications at Bdnf 5′UTEs in the fetal brain were analyzed by chromatin immunoprecipitation. VPA increased the acetylation of multiple H3 and H4 lysine residues in the vicinity of exons 1, 2, 4, and 6; minimal differences between the sexes were observed. H3 lysine 4 trimethylation (H3K4me3) at those exons was also stimulated by VPA. Moreover, the VPA-induced increase in H3K4me3 at exons 1, 4, and 6 was significantly greater in females than in males, i.e., sexually dimorphic stimulation of H3K4me3 by VPA correlated with Bdnf transcripts containing exons 1 and 4, but not 6. Neither H3K27me3 nor cytosine methylation at any of the 117 CpGs in the vicinity of the transcription start sites of exons 1, 4, and 6 was affected by VPA. Thus, of the 6 epigenetic marks analyzed, only H3K4me3 can account for the sexually dimorphic expression of Bdnf transcripts induced by VPA in the fetal brain. Preferential expression of exon 1- and exon 4-Bdnf transcripts in females may contribute to sex differences in ASDs by protecting females from the adverse effects of genetic variants or environmental factors such as VPA on the developing brain.

The neurotrophic effects of different human dental mesenchymal stem cells

The current gold standard treatment for peripheral nerve injury is nerve grafting but this has disadvantages such as donor site morbidity. New techniques focus on replacing these grafts with nerve conduits enhanced with growth factors and/or various cell types such as mesenchymal stem cells (MSCs). Dental-MSCs (D-MSCs) including stem cells obtained from apical papilla (SCAP), dental pulp stem cells (DPSC), and periodontal ligament stem cells (PDLSC) are potential sources of MSCs for nerve repair. Here we present the characterization of various D-MSCs from the same human donors for peripheral nerve regeneration. SCAP, DPSC and PDLSC expressed BDNF, GDNF, NGF, NTF3, ANGPT1 and VEGFA growth factor transcripts. Conditioned media from D-MSCs enhanced neurite outgrowth in an in vitro assay. Application of neutralizing antibodies showed that brain derived neurotrophic factor plays an important mechanistic role by which the D-MSCs stimulate neurite outgrowth. SCAP, DPSC and PDLSC were used to treat a 10 mm nerve gap defect in a rat sciatic nerve injury model. All the stem cell types significantly enhanced axon regeneration after two weeks and showed neuroprotective effects on the dorsal root ganglia neurons. Overall the results suggested SCAP to be the optimal dental stem cell type for peripheral nerve repair.

A single bout of exercise increases hippocampal Bdnf: influence of chronic exercise and noradrenaline.

Research in human subjects suggests that acute exercise can improve memory performance, but the qualities of the exercise necessary to promote improved memory, and the signaling pathways that mediate these effects are unknown. Brain-derived neurotrophic factor (Bdnf), noradrenergic signaling, and post-translational modifications to AMPA receptors have all been implicated in the enhancement of memory following emotional or physical arousal; however, it is not known if a single bout of exercise is sufficient to engage these pathways. Here we use a rodent model to investigate the effects of acute and chronic exercise on hippocampal transcript-specific Bdnf expression and phosphorylation of the GluR1 subunit of the AMPA-type glutamate receptor. A single bout of treadmill exercise was insufficient to mimic the increased expression of GluR1 protein and phosphorylation at Ser845 observed following 1 month of voluntary wheel running. However, acute exercise was sufficient to increase Bdnf transcript IV messenger RNA (mRNA) expression in sedentary subjects, but not subjects housed for 1 month with a running wheel. High-intensity acute exercise increased total Bdnf mRNA in sedentary mice, but not above levels observed following chronic access to the running wheel. Although depletion of central noradrenergic signaling with DSP-4 reduced Bdnf IV mRNA, the effect of acute exercise on Bdnf mRNA persisted. Our characterization of the effects of acute exercise on Bdnf expression and persistence in the absence of noradrenergic modulation may inform strategies to employ physical activity to combat cognitive aging and mental health disorders.

A Novel Ataxic Mutant Mouse Line Having Sensory Neuropathy Shows Heavy Iron Deposition in Kidney

Background/Aims: A novel ataxic mouse line was established from the offspring of a male mouse administered cyclophosphamide in a juvenile period. Methods: We have attempted to examine the phenotype and histopathological changes of affected mice. Furthermore, linkage analysis and sequencing of the mutant was performed to reveal the causative gene locus. Results and Conclusion: The affected mouse was characterized by heavy hind limb ataxia with gait disorder, which was first recognized at about 4 weeks of age and slowly progressed with advancing age. The phenotype was inherited in an autosomal recessive pattern. The genetic locus associated with the phenotype was named hak and mapped to 107,305,356-108,637,615 on chromosome 2qE3, non-coding sequences in the vicinity of Bdnf gene. Many spheroids were noticed in the cerebellar medulla and the brain stem. In the peripheral nerves, some sensory ganglionic cells showed deposition of NF-200 in the perikaryon and NF-200-positive spheroids in nerve fibers. No inflammatory cell infiltration was observed. In addition, the adult affected mouse had distinct iron deposition in the kidney and the liver, but not in the heart, the skeletal muscle and the central nervous system. These results suggest that the hak mouse has a tissue-specific impairment in the expression of a type of Bdnf transcripts.

The Effects of Voluntary Physical Exercise-Activated Neurotrophic Signaling in Rat Hippocampus on mRNA Levels of Downstream Signaling Molecules.

Physical exercise results in the increased expression of neurotrophic factors and the subsequent induction of signal transduction cascades with a positive impact on neuronal functions. In this study, we used a voluntary physical exercise rat model to determine correlations in hippocampus mRNA expression of the neurotropic factors Bdnf, VegfA, and Igf1; their receptors TrkB, Igf1R, VegfR1, and VegfrR2; and downstream signal transducers Creb, Syn1, and Vgf. In hippocampi of physically exercised rats, the mRNA expression levels of Bdnf transcript 4 (Bdnf-t4), VegfA, and Igf1, as well as VegfR1, TrkB, Creb, Vgf, and Syn1, were increased. Bdnf-t4 mRNA expression positively correlated with mRNA expression of Creb, Vgf, and Syn1 in hippocampi of exercised rats. A correlation between Bdnf-t4 and Syn1 mRNA expression was also observed in hippocampi of sedentary rats. Igf1 and VegfA mRNA expression was positively correlated in hippocampi of both exercised and sedentary rats. But, neither Igf1 nor VegfA mRNA expression was correlated with the expression of Bdnf-t4 or the expression of the signal transducers Creb, Syn1, and Vgf. In hippocampi of exercised rats, Creb mRNA expression was positively correlated with TrkB, Syn1, and Vgf mRNA expression and with the correlation between Creb and Vgf mRNA expression also observed in hippocampi of sedentary rats. To examine for causality of the in vivo observed correlated mRNA expression levels between Bdnf-t4 and the other examined transcripts, we used nuclease-deactivated CRISPR-Cas9 fused with VP64 to induce mRNA expression of endogenous Bdnf-t4 in rat PC12 cells. Following Bdnf-t4 mRNA induction, we observed increased Creb mRNA expression. This in vitro result is in accordance with the in vivo results and supports that under specified conditions, an increase in Creb mRNA expression can be a downstream signal transduction event due to induction of endogenous Bdnf mRNA expression.

Carnosine activates the CREB pathway in Caco-2 cells.

Imidazole dipeptide, carnosine, is a versatile compound composed of β-Ala and L-His. A recent study showed that carnosine might benefit the treatment of Alzheimer's disease and the maintenance of cognitive function. Based on the observation that carnosine is immediately degraded by serum carnosinase, we hypothesized that carnosine improves brain function by promoting brain-gut interaction. This study sought to present possible mechanisms regulating carnosine-induced activation of brain-gut interaction. We had previously found that carnosine augmented the expression of BDNF in human colorectal cancer cells, thus we became interested in cAMP-responsive element binding protein (CREB), which is a dominant regulator of BDNF transcription. We found that carnosine activates CREB and CREB-related pathways by activating Ca2+-related pathways. Our findings suggest that carnosine augments the expression of CREB-regulated genes in the intestine; this augmentation contributes to the carnosine-induced activation of brain-gut interaction.

Depressive-Like Behaviors Are Regulated by NOX1/NADPH Oxidase by Redox Modification of NMDA Receptor 1.

Involvement of reactive oxygen species (ROS) has been suggested in the development of psychiatric disorders. NOX1 is a nonphagocytic form of NADPH oxidase whose expression in the nervous system is negligible compared with other NOX isoforms. However, NOX1-derived ROS increase inflammatory pain and tolerance to opioid analgesia. To clarify the role of NOX1 in the brain, we examined depressive-like behaviors in mice deficient in Nox1 (Nox1-/Y). Depressive-like behaviors induced by chronic social defeat stress or administration of corticosterone (CORT) were significantly ameliorated in Nox1-/Y Generation of ROS was significantly elevated in the prefrontal cortex (PFC) of mice administrated with CORT, while NOX1 mRNA was upregulated only in the ventral tegmental area (VTA) among brain areas responsible for emotional behaviors. Delivery of miRNA against NOX1 to VTA restored CORT-induced depressive-like behaviors in wild-type (WT) littermates. Administration of CORT to WT, but not to Nox1-/Y, significantly reduced transcript levels of brain-derived neurotrophic factor (bdnf), with a concomitant increase in DNA methylation of the promoter regions in bdnf Delivery of miRNA against NOX1 to VTA restored the level of BDNF mRNA in WT PFC. Redox proteome analyses demonstrated that NMDA receptor 1 (NR1) was among the molecules redox regulated by NOX1. In cultured cortical neurons, hydrogen peroxide significantly suppressed NMDA-induced upregulation of BDNF transcripts in NR1-expressing cells but not in cells harboring mutant NR1 (C744A). Together, these findings suggest a key role of NOX1 in depressive-like behaviors through NR1-mediated epigenetic modification of bdnf in the mesoprefrontal projection.SIGNIFICANCE STATEMENT NADPH oxidase is a source of reactive oxygen species (ROS) that have been implicated in the pathogenesis of various neurological disorders. We presently showed the involvement of a nonphagocytic type of NADPH oxidase, NOX1, in major depressive disorders, including behavioral, biochemical, and anatomical changes in mice. The oxidation of NR1 by NOX1-derived ROS was demonstrated in prefrontal cortex (PFC), which may be causally linked to the downregulation of BDNF, promoting depressive-like behaviors. Given that NOX1 is upregulated only in VTA but not in PFC, mesocortical projections appear to play a crucial role in NOX1-dependent depressive-like behaviors. Our study is the first to present the potential molecular mechanism underlying the development of major depression through the NOX1-induced oxidation of NR1 and epigenetic modification of bdnf.