Brain-derived Neurotrophic Factor Signaling Research Articles

The Compelling Role of Brain-Derived Neurotrophic Factor Signaling in Multiple Sclerosis: Role of BDNF Activators.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin, acting as a neurotrophic signal and neuromodulator in the central nervous system (CNS). BDNF is synthesized from its precursor proBDNF within the CNS and peripheral tissues. Through activation of NTRK2/TRKB (neurotrophic receptor tyrosine kinase 2), BDNF promotes neuronal survival, synaptic plasticity, and neuronal growth, whereas it inhibits microglial activation and the release of pro-inflammatory cytokines. BDNF is dysregulated in different neurodegenerative diseases and depressions. However, there is a major controversy concerning BDNF levels in the different stages of multiple sclerosis (MS). Therefore, this review discusses the potential role of BDNF signaling in stages of MS, and how BDNF modulators affect the pathogenesis and outcomes of this disease.

Abstract B043: BDNF-TrkB.T1 signaling increases neutrophil recruitment and epithelial-to- mesenchymal transition in gliomas

Abstract Gliomas are the most common type of brain tumor in both children and adults. Communication between glioma cells and the brain tumor microenvironment (TME) is a fundamental aspect of brain cancer pathophysiology. Glioma cells secrete factors that act as chemoattractants, influencing the TME. In addition, neuronal activity within the TME drives the proliferation and growth of gliomas through paracrine signaling, with brain-derived neurotrophic factor (BDNF) being a key mediator. BDNF binds with high affinity to the tropomyosin receptor kinase B (TrkB). Recent work from our group has demonstrated that the TrkB.T1 splice variant is upregulated in human gliomas. Furthermore, TrkB.T1 overexpression enhances tumor aggressiveness in vivo and is associated with the downregulation of genes involved in tumor cell recognition and elimination. However, the role of the TrkB.T1 splice variant in the bidirectional communication between glioma cells and the surrounding microenvironment remains unexplored. Our aim was to investigate whether the increased levels of TrkB.T1 observed in gliomas contribute to modulating immune responses. We investigated the immune cell heterogeneity associated with elevated TrkB.T1 levels in vivo using a glioma mouse model engineered with RCAS/tv-a technology. Tumors overexpressing TrkB.T1 exhibited increased neutrophil recruitment, a phenomenon linked to tumor growth, metastasis and therapeutic resistance. To further dissect the signaling mechanisms underlying the BDNF-TrkB.T1 axis, we conducted in vitro studies using glioma stem cells (GSCs) that express high levels of TrkB.T1. GSCs were treated with BDNF, after which the conditioned media was analyzed using a cytokine multiplex assay, and cell lysates were subjected to proteomic analysis. Our findings revealed that TrkB.T1 significantly upregulates key chemokines previously implicated in neutrophil recruitment. Moreover, BDNF signaling increased the expression of N-cadherin, β- catenin, and Snail, markers indicative of the epithelial-to-mesenchymal transition (EMT) phenotype. To further explore the role of TrkB.T1, we used CRISPR/Cas9-based genome editing to knock down TrkB.T1 in GSCs. In conclusion, our findings suggest that the highly expressed TrkB.T1 receptor in gliomas contributes to creating an immunosuppressive microenvironment by recruiting neutrophils and promoting EMT. These insights highlight TrkB.T1 as a potential therapeutic target for modulating glioma-immune cell interactions, which could be crucial in curbing disease progression. Citation Format: Leyre Merino-Galan, Sergio Ortiz-Espinosa, Hawa L. Jagana, John M. Hemenway, Ashmitha Rajendran, Taylor S. Jackson, Daniel A. Kuppers, Sonali Arora, Patrick J. Paddison, Siobhan S. Pattwell. BDNF-TrkB.T1 signaling increases neutrophil recruitment and epithelial-to- mesenchymal transition in gliomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B043.

Neurocognitive impairments in rat offspring after maternal exposure to vortioxetine: Involvement of BDNF, apoptosis and cholinergic mediated signaling pathways

Depression in pregnant women raises concerns about the safety of antidepressants use, particularly its impact on offspring’s neurocognition. This study investigates the effects of maternal exposure to vortioxetine (VOX) on the neurocognitive development of rat offspring. Pregnant Wistar rats were administered clinically pertinent doses of VOX, 1 mg/kg/day or 2 mg/kg/day from gestational day 6–21. The dams delivered their offspring naturally and reared until postnatal day (PND) 70. Offspring of both sexes were assessed for postnatal growth by measuring body weight from PND 1–70 weekly and cognitive function using Morris water maze (MWM) test and passive avoidance learning test from PND 49–70. After behavioral assessments, adult rat offspring were sacrificed, and their brains were dissected out for assessment of brain morphology as well as biochemical analysis. The results demonstrated that VOX exposure potentially impaired cognitive performance, evidenced by increased latency in MWM and passive avoidance learning tests. Additionally, it led to decreased body weight, altered brain morphology, and disrupted neurobiochemical profiles. Specifically, VOX 2 mg/kg exposure significantly reduced brain-derived neurotrophic factor (BDNF) expression, increased pro-apoptotic BAX expression, decreased anti-apoptotic Bcl-2 expression, and elevated acetylcholinesterase (AChE) activity in the hippocampus. Lower dose of VOX (1 mg/kg) did not show significant adverse effects on neurocognition, suggesting a dose-dependent impact. No sex specific neurocognitive deficits were observed in current study. These findings indicate that while VOX may offer a safer profile compared to SSRIs, high doses during pregnancy can still result in neurocognitive impairments in offspring.

Peptidomimetic inhibitors targeting TrkB/PSD-95 signaling improves cognition and seizure outcomes in an Angelman Syndrome mouse model.

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived neurotrophic factor (BDNF), and its receptor tropomyosin receptor kinase B (TrkB), have a well-established role as regulators of synaptic plasticity, dendritic outgrowth and spine formation. Previously, we reported that the association of postsynaptic density protein 95 (PSD-95) with TrkB is critical for intact BDNF signaling in the AS mouse model, as illustrated by attenuated PLCγ and PI3K signaling and intact MAPK pathway signaling. These data suggest that drugs tailored to enhance the TrkB-PSD-95 interaction may provide a novel approach for the treatment of AS and a variety of neurodevelopmental disorders (NDDs). To evaluate this critical interaction, we synthesized a class of high-affinity PSD-95 ligands that bind specifically to the PDZ3 domain of PSD-95, denoted as Syn3 peptidomimetic ligands. We evaluated Syn3 and its analog D-Syn3 (engineered using dextrorotary (D)-amino acids) in vivo using the Ube3a exon 2 deletion mouse model of AS. Following systemic administration of Syn3 and D-Syn3, we demonstrate improvement in the seizure domain of AS. Learning and memory using the novel object recognition assay also illustrated improved cognition following Syn3 and D-Syn3, along with restored long-term potentiation. A pharmacokinetic analysis of D-Syn3 demonstrates that it crosses the blood-brain barrier (BBB), and the brain influx rate is in the range of CNS therapeutics. Finally, D-Syn3 treated mice showed a partial rescue in motor learning. Neither Syn3 nor D-Syn3 improved gross exploratory locomotion deficits, nor gait impairments that have been well documented in the AS rodent models. These findings highlight the need for further investigation of this compound class as a potential therapeutic for AS and other genetic NDDs.

A sexually dimorphic signature of activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the prefrontal cortex.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. We and others hypothesize that diminished activity-dependent neural signaling is a common molecular pathway dysregulated in ASD caused by diverse genetic mutations. Brain-derived neurotrophic factor (BDNF) is a key growth factor mediating activity-dependent neural signaling in the brain. A common single nucleotide polymorphism (SNP) in the pro-domain of the human BDNF gene that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) significantly decreases activity-dependent BDNF release without affecting basal BDNF secretion. By using mice with genetic knock-in of this human BDNF methionine (Met) allele, our previous studies have shown differential severity of autism-like social deficits in male and female BDNF+/Met mice. Pyramidal neurons are the principal neurons in the prefrontal cortex (PFC), a key brain region for social behaviors. Here, we investigated the impact of diminished activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the PFC. Surprisingly, diminished activity-dependent BDNF signaling significantly increased the intrinsic excitability of pyramidal neurons in male mice, but not in female mice. Notably, significantly decreased thresholds of action potentials were observed in male BDNF+/Met mice, but not in female BDNF+/Met mice. Voltage-clamp recordings revealed that the sodium current densities were significantly increased in the pyramidal neurons of male BDNF+/Met mice, which were mediated by increased transcriptional level of Scn2a encoding sodium channel NaV 1.2. Medium after hyperpolarization (mAHP), another important parameter to determine intrinsic neuronal excitability, is strongly associated with neuronal firing frequency. Further, the amplitudes of mAHP were significantly decreased in male BDNF+/Met mice only, which were mediated by the downregulation of Kcnn2 encoding small conductance calcium-activated potassium channel 2 (SK2). This study reveals a sexually dimorphic signature of diminished activity-dependent BDNF signaling on the intrinsic neuronal excitability of pyramidal neurons in the PFC, which provides possible cellular and molecular mechanisms underpinning the sex differences in idiopathic ASD patients and human autism victims who carry BDNF Val66Met SNP.

Transcriptomic Profile of the Male Rat Hypothalamus and Nucleus Accumbens After Paroxetine Treatment and Withdrawal: Possible Causes of Sexual Dysfunction.

Paroxetine, a selective serotonin reuptake inhibitor (SSRI), may induce sexual dysfunction during treatment and upon discontinuation. The mechanisms involved have been poorly explored so far. We have analyzed, by RNA sequencing, the whole transcriptomic profile in the hypothalamus and nucleus accumbens (NAc) (two brain regions involved in sexual behavior) of male rats daily treated for 2weeks with paroxetine (T0) and at 1month of withdrawal (T1). Data here reported show seven differentially expressed genes (DEGs) at T0 and 1 at T1 in the hypothalamus and 245 at T0 and 6 at T1 in the NAc. In addition, Gene-Set Enrichment, Gene Ontology, and Reactome analyses confirm that inflammatory signature and immune system activation were present at T0 in both brain areas. Considering that inflammation is generally associated with depression and that no paradigms inducing the pathology were here applied, these SSRI pro-depressive effects should be considered in patients without a clear indication of depression. Moreover, DEGs related to neurotransmitters with a role in sexual behavior and the reward system, such as dopamine (e.g., sialyltransferase 8B-ST8SIA3), glutamate (e.g., glutamate receptor ionotropic delta-2-GRID2) and GABA (e.g., glutamate decarboxylase type 2-GAD2) or associated with neurexin and neuroligin pathways and brain-derived neurotrophic factor (BDNF) signaling, were reported to be dysregulated in the NAc, further confirming dysfunction in this brain area. Interestingly, the analysis of DEGs altered at T1 in the NAc confirms the persistence of some of these side effects providing further information for post-SSRI sexual dysfunction (PSSD) etiopathogenesis.

BDNF and Cerebellar Ataxia.

Brain-derived neurotrophic factor (BDNF) has been proposed as a treatment for neurodegeneration, including diseases of the cerebellum, where BDNF levels or those of its main receptor, TrkB, are often diminished relative to controls, thereby serving as replacement therapy. Experimental evidence indicates that BDNF signaling countered cerebellar degeneration, sensorimotor deficits, or both, in transgenic ATXN1 mice mutated for ataxin-1, Cacna1a knock-in mice mutated for ataxin-6, mice injected with lentivectors encoding RNA sequences against human FXN into the cerebellar cortex, Kcnj6Wv (Weaver) mutant mice with granule cell degeneration, and rats with olivocerebellar transaction, similar to a BDNF-overexpressing transgenic line interbred with Cacng2stg mutant mice. In this regard, this study discusses whether BDNF is effective in cerebellar pathologies where BDNF levels are normal and whether it is effective in cases with combined cerebellar and basal ganglia damage.

Brain-derived neurotrophic factor modulation in response to oxidative stress and corticosterone: role of scopolamine and mirtazapine

Major Depressive Disorder (MDD) is a very complex disease, challenging to study and manage. The complexities of MDD require extensive research of its mechanisms to develop more effective therapeutic approaches. Crucial in the context of this disease is the role of brain-derived neurotrophic factor (BDNF) signaling pathway. AimThis manuscript aims to explore the complex relationship between MDD and BDNF signaling pathway, focusing on how BDNF is modulated in response to oxidative stress and corticosterone, known to be altered in MDD and contributing to the pathology of the disorder, when treated with scopolamine and mirtazapine. MethodsTo assess BDNF levels after the different treatment conditions, rat hippocampal slices and mice primary hippocampus and cortical cell culture were analyzed by immunofluorescence and Western blot. Key findingsBoth mirtazapine and scopolamine under stress conditions induced by hydrogen peroxide (H2O2) and corticosterone, had a significant impact on BDNF levels, and this was distinct in different neuronal models. Mirtazapine, especially when combined with H2O2, altered BDNF expression. Scopolamine when combined with both stressors also altered BDNF levels. However, its effects varied depending on the specific neuronal model and stress condition. In accordance with BDNF results, phosphorylated tropomyosin receptor kinase B (pTrkB) presented increased activation when neuronal cells subjected to stress were treated with mirtazapine or scopolamine. SignificanceCollectively, this study highlights the complex connection between these compounds, stress conditions, and BDNF/TrkB modulation, supporting the potential therapeutic effects of scopolamine and mirtazapine in modulating BDNF levels, even in stressful conditions.

SPROUTY2, a Negative Feedback Regulator of Receptor Tyrosine Kinase Signaling, Associated with Neurodevelopmental Disorders: Current Knowledge and Future Perspectives

Growth-factor-induced cell signaling plays a crucial role in development; however, negative regulation of this signaling pathway is important for sustaining homeostasis and preventing diseases. SPROUTY2 (SPRY2) is a potent negative regulator of receptor tyrosine kinase (RTK) signaling that binds to GRB2 during RTK activation and inhibits the GRB2-SOS complex, which inhibits RAS activation and attenuates the downstream RAS/ERK signaling cascade. SPRY was formerly discovered in Drosophila but was later discovered in higher eukaryotes and was found to be connected to many developmental abnormalities. In several experimental scenarios, increased SPRY2 protein levels have been observed to be involved in both peripheral and central nervous system neuronal regeneration and degeneration. SPRY2 is a desirable pharmaceutical target for improving intracellular signaling activity, particularly in the RAS/ERK pathway, in targeted cells because of its increased expression under pathological conditions. However, the role of SPRY2 in brain-derived neurotrophic factor (BDNF) signaling, a major signaling pathway involved in nervous system development, has not been well studied yet. Recent research using a variety of small-animal models suggests that SPRY2 has substantial therapeutic promise for treating a range of neurological conditions. This is explained by its function as an intracellular ERK signaling pathway inhibitor, which is connected to a variety of neuronal activities. By modifying this route, SPRY2 may open the door to novel therapeutic approaches for these difficult-to-treat illnesses. This review integrates an in-depth analysis of the structure of SPRY2, the role of its major interactive partners in RTK signaling cascades, and their possible mechanisms of action. Furthermore, this review highlights the possible role of SPRY2 in neurodevelopmental disorders, as well as its future therapeutic implications.

Вміст гамма-аміномасляної кислоти та мозкоспецифічного нейротрофічного фактора в структурах головного мозку щурів із алкогольною залежністю та після фізичних навантажень

The state of alcohol dependence is usually accompanied by emotional disorders, such as anxiety, depression, and aggressiveness. They arise against the background of disturbances in central neurotransmission and neurotrophic processes. Exercise is effective in restoring some damaged brain functions. The aim of our work was to identify disturbances in the g-aminobutyric acid (GABA) and brain-derived neurotrophic factor (BDNF) regulatory systems and the possibilities of their correction by exercise in rats with alcohol dependence. Alcohol dependence was modeled by ingesting food with alcohol at a dose of 1.25 g per kg body weight for 30 days, followed by alcohol withdrawal for 10 days. In rats under alcohol withdrawal, we found an imbalance of GABAergic activity between the frontal neocortex, hippocampus, and amygdala, a decrease in BDNF concentrations in the frontal neocortex, hippocampus, and serum, accompanied by increased anxiety levels. Wheel running during alcohol withdrawal (30 min daily for 10 days) restored the balance of GABA content in the brain structures and the reduced levels of BDNF (excluding reduced GABA and BDNF content in the frontal neocortex), and also reduced anxiety. Exercise increased hippocampal weight, which was decreased in alcohol-dependent animals. The negative correlation was found between indices of hippocampal weight and GABA concentration in hippocampus in intact and alcohol-dependent animals, which persisted even after exercise. The findings suggest that exercise is effective in restoring GABAergic and BDNF signaling impaired by alcohol intake. Restoration of synchronizing GABAergic regulation and BDNF levels contributes to anxiety reduction in alcohol-dependent rats

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

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

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

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

The modulatory effect of oat on brain-derived neurotrophic factor, orexigenic neuropeptides, and dopaminergic signaling in obesity-induced rat model: a comparative study to orlistat.

Obesity is a non-communicable complex disease that is the fifth leading cause of death worldwide. According to a novel viewpoint, the brain plays a significant role in the central regulation of satiety and energy homeostasis. Because of its rich nutritional profile and versatile uses, oat (Avena sativa) is one of the most popular functional foods recommended by many nutritionists. The anti-obesity effect of oat was hypothesized, focusing on the brain as the target organ. In the current study, the interplay between brain biomarkers, obesity, and its related complications was evaluated in diet-induced obese rats for 25 weeks, in which 60 adult male white albino Wistar rats were divided into three control and seven treatment groups given oat extracts in a dose-dependent manner. Oat significantly improved obesity-related metabolic complications. In terms of brain function, oat significantly increased dopaminergic signaling, brain-derived neurotrophic factor levels, vaspin, irisin, and uncoupling protein-1 brain levels, while decreasing the expression of agouti-related peptide and neuropeptide Y (P-value < 0.05). The current study proposes oat supplementation as a new conceptual framework with numerous implications for hedonic and homeostatic mechanisms that control satiety. © 2024 Society of Chemical Industry.

Upregulation of Phosphodiesterase 7A Contributes to Concurrent Pain and Depression via Inhibition of cAMP-PKA-CREB-BDNF Signaling and Neuroinflammation in the Hippocampus of Mice.

Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression. C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior. This induction of chronic pain and depression in the 2 animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB, and p65. cAMP agonist forskolin reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice. Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling. Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression.

A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer's disease

In Alzheimer’s disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs Brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, as well as synaptic transmission and plasticity. Using cerebrospinal fluid and post-mortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential of a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.

MiR-184-3p in the paraventricular nucleus participates in the neurobiology of depression via regulation of the hypothalamus-pituitary-adrenal axis

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for the pathogenesis of depression, and increased activity of cAMP response element binding protein (CREB)-regulated transcription co-activator 1 (CRTC1) in the paraventricular nucleus (PVN) plays a critical role. As a well-investigated microRNA (miRNA), miR-184 has two forms, miR-184-3p and miR-184-5p. Recently, miRNAs target genes predictive analysis and dual-luciferase reporter assays identified an inhibitory role of miR-184-3p on CRTC1 expression. Therefore, we speculated that miR-184-3p regulation was responsible for the effects of chronic stress on CRTC1 in the PVN. Various methods, including the chronic social defeat stress (CSDS) model of depression, behavioral tests, Western blotting, co-immunoprecipitation (Co-IP), quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence, and adeno-associated virus (AAV)-mediated gene transfer, were used. CSDS evidently downregulated the level of miR-184-3p, but not miR-184-5p, in the PVN. Genetic knockdown and pharmacological inhibition of miR-184-3p in the PVN induced various depressive-like symptoms (e.g., abnormal behaviors, HPA hyperactivity, enhanced CRTC1 function in PVN neurons, downregulation of hippocampal neurogenesis, and decreased brain-derived neurotrophic factor (BDNF) signaling) in naïve male C57BL/6J mice. In contrast, genetic overexpression and pharmacological activation of miR-184-3p in the PVN produced significant beneficial effects against CSDS. MiR-184-3p in the PVN was necessary for the antidepressant actions of two well-known SSRIs, fluoxetine and paroxetine. Collectively. miR-184-3p was also implicated in the neurobiology of depression and may be a viable target for novel antidepressants.

The Role of Central and Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker of Anorexia Nervosa Reconceptualized as a Metabo-Psychiatric Disorder.

Neurotrophic factors play pivotal roles in shaping brain development and function, with brain-derived neurotrophic factor (BDNF) emerging as a key regulator in various physiological processes. This review explores the intricate relationship between BDNF and anorexia nervosa (AN), a complex psychiatric disorder characterized by disordered eating behaviors and severe medical consequences. Beginning with an overview of BDNF's fundamental functions in neurodevelopment and synaptic plasticity, the review delves into recent clinical and preclinical evidence implicating BDNF in the pathophysiology of AN. Specifically, it examines the impact of BDNF polymorphisms, such as the Val66Met variant, on AN susceptibility, prognosis, and treatment response. Furthermore, the review discusses the interplay between BDNF and stress-related mood disorders, shedding light on the mechanisms underlying AN vulnerability to stress events. Additionally, it explores the involvement of BDNF in metabolic regulation, highlighting its potential implications for understanding the metabolic disturbances observed in AN. Through a comprehensive analysis of clinical data and animal studies, the review elucidates the nuanced role of BDNF in AN etiology and prognosis, emphasizing its potential as a diagnostic and prognostic biomarker. Finally, the review discusses limitations and future directions in BDNF research, underscoring the need for further investigations to elucidate the complex interplay between BDNF signaling and AN pathology.

Examination of Akt and GSK3β in BDNF-mediated reductions in BACE1 activity in neuronal cells.

Brain-derived neurotrophic factor (BDNF) content and signaling has been identified as one potential regulator of amyloid precursor protein (APP) processing. Recently published work has demonstrated that BDNF reduces BACE1 activity while also elevating the inhibition of GSK3β in the prefrontal cortex of male C57BL/6J mice. These results provide evidence that BDNF alters APP processing by reducing BACE1 activity, which may act through GSK3β inhibition. The purpose of this study was to further explore the role of GSK3β in BDNF-induced regulation on BACE1 activity. We utilized a cell culture and an invitro activity assay model to pharmacologically target BDNF and GSK3β signaling to confirm its involvement in the BDNF response. Treatment of differentiated SH-SY5Y neuronal cells with 75 ng/mL BDNF resulted in elevated pTrkB content, pAkt content, pGSK3β content, and reduced BACE1 activity. An invitro BACE1 activity assay utilizing mouse prefrontal cortex (n = 6/group) supplemented with BDNF, BDNF + ANA12 (Trkb antagonist), or BDNF + wortmannin (Akt inhibitor) demonstrated that BDNF reduced BACE1 activity; however, in the presence of TrkB or Akt inhibition, this effect was abolished. An invitro ADAM10 activity assay utilizing mouse prefrontal cortex (n = 6/group) supplemented with BDNF, BDNF + ANA12 (Trkb antagonist), or BDNF + wortmannin (Akt inhibitor) demonstrated that BDNF did not alter ADAM10 activity. However, inhibiting BDNF signaling reduced ADAM10 activity. Collectively these studies suggest that GSK3β inhibition may be necessary for BDNF-induced reductions in BACE1 activity. These findings will allow for the optimization of future therapeutic strategies by selectively targeting TrkB activation and GSK3β inhibition.

The multifaceted effects of fluoxetine treatment on cognitive functions.

Fluoxetine, the prototypical selective serotonin reuptake inhibitor (SSRI), is widely used to treat major depressive disorder (MDD) and a variety of other central nervous system conditions, primarily due to its established clinical safety profile. Although its efficacy in treating depression is well-recognized, the impact of fluoxetine on cognitive functions remains inconsistent and elusive. In this review, we first examine the well-substantiated biological mechanisms underlying fluoxetine's antidepressant effects, which include serotonin reuptake inhibition and activation of TrkB receptors-key to brain-derived neurotrophic factor (BDNF) signaling. Subsequently, we delve into the cognitive side effects observed in both preclinical and clinical studies, affecting domains such as memory, attention, and executive functions. While certain studies indicate cognitive improvements in patients with underlying disorders, there is also evidence of negative effects, influenced by variables like gender, duration of treatment, age, disease pathology, and the specifics of cognitive testing. Significantly, the negative cognitive outcomes reported in preclinical research often involve healthy, non-diseased animals. This review underscores the necessity for heightened caution in fluoxetine prescription and further investigation into its potentially detrimental cognitive effects, even when used prophylactically.

Genetic Variations in TrkB.T1 Isoform and Their Association With Somatic and Psychological Symptoms in Individuals With IBS

Irritable bowel syndrome (IBS), a disorder of gut-brain interaction, is often comorbid with somatic pain and psychological disorders. Dysregulated signaling of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), has been implicated in somatic-psychological symptoms in individuals with IBS. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the regulatory 3′ untranslated region of neurotrophic receptor tyrosine kinase-2 (NTRK2) kinase domain-deficient truncated isoform (TrkB.T1) and BDNF Val66Met SNP with somatic and psychological symptoms and quality-of-life (QoL) in a cohort from the United States (IBS, n = 464; healthy controls, n = 156). We found that the homozygous recessive genotype (G/G) of rs2013566 in individuals with IBS is associated with worsened somatic symptoms, including headache, back pain, joint pain, muscle pain, and somatization as well as diminished sleep quality, energy level, and overall QoL. Validation using United Kingdom BioBank data confirmed the association of rs2013566 with an increased likelihood of headache. Several SNPs (rs1627784, rs1624327, and rs1147198) showed significant associations with muscle pain in our U.S. cohort. These 4 SNPs are predominantly located in H3K4Me1-enriched regions, suggesting their enhancer and/or transcription regulation potential. Our findings suggest that genetic variation within the 3′ untranslated region region of the TrkB.T1 isoform may contribute to comorbid conditions in individuals with IBS, resulting in a spectrum of somatic and psychological symptoms impacting their QoL. These findings advance our understanding of the genetic interaction between BDNF/TrkB pathways and somatic-psychological symptoms in IBS, highlighting the importance of further exploring this interaction for potential clinical applications. PerspectiveThis study aims to understand the genetic effects on IBS-related symptoms across somatic, psychological, and quality-of-life (QoL) domains, validated by United Kingdom BioBank data. The rs2013566 homozygous recessive genotype correlates with worsened somatic symptoms and reduced QoL, emphasizing its clinical significance.