{"gene":"BDNF","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2013,"finding":"Exercise induces hippocampal BDNF expression through a PGC-1α/FNDC5 pathway: neuronal Fndc5 gene expression is regulated by PGC-1α, forced expression of FNDC5 in primary cortical neurons increases Bdnf expression, RNAi-mediated knockdown of FNDC5 reduces Bdnf, and peripheral delivery of FNDC5 via adenoviral vectors elevates blood irisin and induces hippocampal Bdnf expression.","method":"RNAi knockdown, forced overexpression in primary neurons, adenoviral vector delivery, Pgc1a knockout mice","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic approaches (KO mice, RNAi, forced expression, adenoviral delivery) in a single study with consistent results","pmids":["24120943"],"is_preprint":false},{"year":2016,"finding":"β-hydroxybutyrate, an endogenous metabolite elevated after prolonged exercise, induces Bdnf gene expression by inhibiting HDAC2 and HDAC3 at selective Bdnf promoters (particularly promoter I), and direct ventricular application of β-hydroxybutyrate increases hippocampal Bdnf expression; downstream, β-hydroxybutyrate causes increased neurotransmitter release that is dependent on the TrkB receptor.","method":"Bdnf promoter activity assays, HDAC inhibition experiments, direct ventricular injection, electrophysiology with TrkB blockade","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro promoter assays with specific HDAC identification, in vivo ventricular delivery, and electrophysiology with receptor-specific blockade in a single study with multiple orthogonal methods","pmids":["27253067"],"is_preprint":false},{"year":2023,"finding":"Psychedelics (LSD and psilocin) directly bind to TrkB, the BDNF receptor, with affinities ~1,000-fold higher than other antidepressants, at a site within the transmembrane domain of TrkB dimers that partially overlaps with antidepressant binding sites; their effects on neurotrophic signaling, plasticity, and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling, but are independent of 5-HT2A activation.","method":"Direct binding assays, TrkB mutagenesis, conditional TrkB knockout mice, behavioral assays, signaling pathway analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding demonstrated with affinity measurements, mutagenesis, and genetic knockout validation with multiple orthogonal methods","pmids":["37280397"],"is_preprint":false},{"year":2010,"finding":"RACK1 (scaffolding protein) mediates epigenetic regulation of BDNF gene expression: following cAMP pathway activation, nuclear RACK1 localizes to the promoter IV region of the BDNF gene by associating with histones H3 and H4, causing dissociation of the transcriptional repressor MeCP2 from the promoter and subsequent acetylation of histone H4, leading to promoter IV-controlled transcription of BDNF exon IV.","method":"Chromatin immunoprecipitation, promoter activity assays, co-immunoprecipitation, RACK1 overexpression/knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating protein-promoter interactions, reciprocal co-IP, and functional promoter assays with multiple orthogonal methods in one study","pmids":["20410295"],"is_preprint":false},{"year":2015,"finding":"ApoE4 increases nuclear translocation of HDACs (particularly HDAC6) in human neurons, leading to HDAC6 binding to BDNF promoter IV and reduced BDNF exon IV expression; ApoE3 conversely increases histone 3 acetylation and upregulates BDNF expression via PKCε, which retains HDACs in the cytosol. LRP-1 receptor mediates the ApoE effects, and PKCε activation reverses ApoE4- and Aβ oligomer-induced BDNF downregulation.","method":"HDAC nuclear fractionation, ChIP (HDAC6-BDNF promoter IV binding), LRP-1 siRNA/blocking, PKCε activation/inhibition, ApoE transgenic mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrates direct HDAC6-promoter binding, multiple genetic and pharmacological interventions, validated in transgenic mice and human AD tissue","pmids":["25972179"],"is_preprint":false},{"year":2015,"finding":"BDNF, acting on truncated TrkB-T1 receptors (not full-length TrkB), inhibits glycine transporter (GlyT1 and GlyT2) activity in astrocytes by promoting transporter internalization via a Rho-GTPase-dependent mechanism (clathrin/dynamin-dependent endocytosis); this effect does not occur through canonical TrkB-FL pathways (PLCγ, PI3K, MAPK).","method":"[3H]glycine transport assays, dynasore treatment (endocytosis inhibitor), Rho-GTPase inhibition (toxin B), TrkB-T knockdown by RNAi, immunofluorescence of GlyT in endosomes, kinase inhibitor pharmacology","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including transport assays, RNAi knockdown, pharmacological inhibitors, and subcellular localization in a single study","pmids":["26200505"],"is_preprint":false},{"year":2002,"finding":"NT-4/5 and BDNF itself induce BDNF mRNA and protein expression in neocortical neurons through TrkB receptor activation (blocked by K252a); NT-4/5-enhanced BDNF production is completely suppressed by AMPA receptor blockade (CNQX) or NMDA receptor blockade (AP-5), placing glutamate receptors as intermediaries in neurotrophin-induced BDNF expression. MAP kinase and PI3K differentially regulate BDNF-induced AMPA receptor (GluR1) expression.","method":"RT-PCR for BDNF mRNA, ELISA for BDNF protein, pharmacological inhibitors (K252a, CNQX, AP-5, TTX, PD98059, LY294002), primary cortical neuron culture","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological interventions with mRNA and protein readouts, but single lab and no genetic confirmation","pmids":["12069900"],"is_preprint":false},{"year":2017,"finding":"BDNF-TrkB signaling in neocortical somatosensory cortex (layer 5) regulates glutamate release via opposing mechanisms: a direct presynaptic enhancement of release probability, and simultaneous postsynaptic induction of endocannabinoid (eCB) release that retrogradely decreases release probability via presynaptic CB1 receptors; blocking CB1 receptors or disrupting eCB release unmasks the direct BDNF effect on mEPSC frequency.","method":"Whole-cell patch clamp electrophysiology (mEPSCs), CB1 receptor blockade, disruption of eCB release, layer-specific immunofluorescence for CB1 and TrkB","journal":"Synapse","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with pharmacological dissection of opposing mechanisms, single lab, two orthogonal methods","pmids":["28164368"],"is_preprint":false},{"year":2020,"finding":"BDNF-TrkB signaling in microglia suppresses microglial activation: BDNF activates ErK and CREB in microglia, which compete with LPS-induced NF-κB for binding to the common coactivator CREB-binding protein, thereby inhibiting p38, JNK, and NF-κB activation and production of pro-inflammatory cytokines. shTrkB knockdown induces microglial activation in naïve mice, and aging-related microglial activation is reversed by chronic subcutaneous BDNF perfusion.","method":"Pharmacological and genetic approaches in microglial cell lines and primary microglia, shTrkB knockdown, in vivo BDNF perfusion, signaling pathway analysis (p38, JNK, NF-κB, ERK, CREB)","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown plus pharmacological dissection of signaling pathway, validated in vivo, single lab","pmids":["32664974"],"is_preprint":false},{"year":2017,"finding":"BDNF propeptide (the prodomain released after proteolytic cleavage of proBDNF) is endogenously secreted from neuronal cells and facilitates long-term depression (LTD), indicating that posttranslational proteolytic processing of proBDNF generates at least two bioactive fragments with distinct synaptic plasticity functions.","method":"Detection of endogenous propeptide secretion, LTD assays in neuronal preparations","journal":"Vitamins and hormones","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional LTD assay combined with endogenous secretion detection, but limited methodological detail available from abstract alone","pmids":["28215295"],"is_preprint":false},{"year":2013,"finding":"Prenatal stress decreases Bdnf expression in the amygdala and hippocampus of rats and this is accompanied by increased DNA methylation of Bdnf exon IV in these regions; expression of DNA methyltransferases DNMT1 and DNMT3a is increased in prenatally stressed rats, suggesting that PNS-induced reduction in Bdnf expression is mediated at least in part by increased DNA methylation of Bdnf exon IV.","method":"Bisulfite sequencing/DNA methylation analysis at Bdnf exon IV, RT-PCR for Bdnf mRNA, DNMT expression analysis, prenatal stress rat model","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct measurement of DNA methylation at specific CpG sites correlated with expression changes, two orthogonal methods, single lab","pmids":["24365909"],"is_preprint":false},{"year":2000,"finding":"BDNF regulates eating behavior and locomotor activity through hypothalamic circuits: heterozygous BDNF knockout mice show hyperphagia and obesity, and infusion of BDNF or NT4/5 can transiently reverse these eating behavior abnormalities, demonstrating a non-neurotrophic, behavioral regulatory function for BDNF via TrkB in hypothalamic nuclei associated with satiety.","method":"BDNF heterozygous knockout mice (multiple independent strains), intracranial neurotrophin infusion, behavioral measurement of food intake and locomotion","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with specific behavioral phenotype replicated across multiple independent inbred and hybrid strains, with rescue by exogenous BDNF infusion","pmids":["10716929"],"is_preprint":false},{"year":2021,"finding":"Direct treatment of brain tissue explants with BDNF reduces BACE1 (beta-site APP cleaving enzyme 1) activity in the prefrontal cortex but not the hippocampus, demonstrating a region-specific direct effect of BDNF on amyloid precursor protein processing independent of other exercise-induced changes.","method":"Ex vivo brain explant treatment with recombinant BDNF, BACE1 enzymatic activity assay, BDNF protein measurement by ELISA","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro/ex vivo enzyme activity assay with recombinant protein treatment, single lab, single method for the BDNF-BACE1 link","pmids":["34017238"],"is_preprint":false},{"year":2023,"finding":"The BDNF gene is driven by nine distinct promoters generating nine non-coding exon-containing transcripts that are all translated into BDNF protein, with different transcripts playing different roles in distinct brain regions and physiological stages; this multilevel promoter architecture underlies exon-specific regulation by distinct transcription factors and environmental stimuli.","method":"Analysis of multiple transcript isoforms, promoter-reporter assays, region-specific transcript expression analysis","journal":"Biomolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — primarily a review/synthesis paper; the mechanistic claims about promoter structure are established by the field broadly, not by new experiments in this paper","pmids":["37189402"],"is_preprint":false}],"current_model":"BDNF is a secreted neurotrophin that signals primarily through TrkB (full-length and truncated isoforms) and p75NTR receptors to activate MAPK/ERK, PI3K/Akt, and PLCγ pathways; its expression is controlled by nine distinct promoters subject to activity-dependent epigenetic regulation (via RACK1-mediated HDAC displacement and MeCP2 dissociation at promoter IV, and HDAC2/3 inhibition by β-hydroxybutyrate), and its precursor proBDNF is proteolytically cleaved to generate both mature BDNF (which promotes LTP via TrkB) and a bioactive propeptide (which facilitates LTD), while upstream regulators including PGC-1α/FNDC5/irisin link exercise to hippocampal BDNF induction, and TrkB is also a direct binding target of antidepressants and psychedelics that allosterically potentiate endogenous BDNF signaling."},"narrative":{"mechanistic_narrative":"BDNF is a secreted neurotrophin that signals through TrkB receptors to control neuronal plasticity, synaptic transmission, and behavior across multiple brain cell types [PMID:37280397, PMID:10716929]. Mature BDNF acts on full-length TrkB to drive neurotrophic signaling, while distinct receptor and cleavage products diversify its output: BDNF acting on the truncated TrkB-T1 isoform inhibits astrocytic glycine transporters (GlyT1/GlyT2) by promoting Rho-GTPase-dependent, clathrin/dynamin-mediated transporter internalization, a route independent of the canonical PLCγ/PI3K/MAPK arms [PMID:26200505], and the prodomain released by proteolytic processing of proBDNF is itself secreted and facilitates long-term depression, so that proteolysis generates functionally distinct synaptic effectors [PMID:28215295]. At cortical synapses BDNF-TrkB signaling bidirectionally tunes glutamate release, directly enhancing presynaptic release probability while postsynaptically triggering endocannabinoid release that retrogradely suppresses it via CB1 receptors [PMID:28164368], and in microglia BDNF-TrkB engages ERK/CREB to compete with NF-κB for CREB-binding protein, suppressing pro-inflammatory activation [PMID:32664974]. BDNF expression is set by a multi-promoter architecture under activity- and metabolite-dependent epigenetic control: cAMP-driven nuclear RACK1 binds histones H3/H4 at promoter IV, displacing the repressor MeCP2 and permitting H4 acetylation [PMID:20410295], while DNA methylation of exon IV (via DNMT1/DNMT3a) and HDAC recruitment repress it [PMID:24365909, PMID:25972179]. Exercise-linked signals converge on this control, with the PGC-1α/FNDC5/irisin axis inducing hippocampal Bdnf [PMID:24120943] and the metabolite β-hydroxybutyrate inhibiting HDAC2/3 at Bdnf promoters to raise expression and TrkB-dependent neurotransmitter release [PMID:27253067]. Beyond the nervous system proper, BDNF regulates feeding and body weight through hypothalamic TrkB circuits, as heterozygous knockout causes hyperphagia and obesity reversible by neurotrophin infusion [PMID:10716929]. TrkB is a direct, high-affinity binding target of psychedelics whose plasticity and antidepressant-like effects depend on TrkB binding and potentiation of endogenous BDNF rather than on 5-HT2A activation [PMID:37280397].","teleology":[{"year":2000,"claim":"Established that BDNF has a non-neurotrophic behavioral role by linking its loss to dysregulated energy balance through hypothalamic circuits.","evidence":"Heterozygous BDNF knockout mice across multiple strains with intracranial neurotrophin infusion rescue and feeding/locomotor measurement","pmids":["10716929"],"confidence":"High","gaps":["Does not define the hypothalamic cell types or downstream effectors","Mechanism of TrkB action on satiety circuits not resolved"]},{"year":2002,"claim":"Showed BDNF expression is self-amplifying and glutamatergically gated, placing AMPA/NMDA receptors as intermediaries in neurotrophin-induced BDNF production.","evidence":"RT-PCR/ELISA in primary cortical neurons with K252a, CNQX, AP-5, and MAPK/PI3K inhibitor pharmacology","pmids":["12069900"],"confidence":"Medium","gaps":["No genetic confirmation of the receptor dependencies","Single lab","Transcription factors mediating the feed-forward loop not identified"]},{"year":2010,"claim":"Identified a molecular route by which cAMP signaling derepresses BDNF transcription, linking a scaffolding protein to chromatin remodeling at promoter IV.","evidence":"ChIP, co-IP, and promoter-reporter assays with RACK1 overexpression/knockdown","pmids":["20410295"],"confidence":"High","gaps":["How nuclear RACK1 is recruited to histones not defined","Generalizability to other BDNF promoters unknown"]},{"year":2013,"claim":"Connected exercise physiology to BDNF induction by defining the PGC-1α/FNDC5/irisin axis as an upstream driver of hippocampal Bdnf.","evidence":"RNAi, forced expression in primary neurons, adenoviral delivery, and Pgc1a knockout mice","pmids":["24120943"],"confidence":"High","gaps":["Receptor/transducer for FNDC5/irisin in neurons not identified","Direct vs indirect induction of Bdnf transcription unresolved"]},{"year":2013,"claim":"Linked early-life stress to lasting BDNF repression through methylation of a specific promoter, implicating DNA methyltransferases in environmental programming of Bdnf.","evidence":"Bisulfite methylation analysis at Bdnf exon IV, RT-PCR, and DNMT expression in a prenatal stress rat model","pmids":["24365909"],"confidence":"Medium","gaps":["Causal contribution of methylation vs other mechanisms not isolated","Correlative DNMT increase without intervention","Single lab"]},{"year":2015,"claim":"Revealed that BDNF signals through the truncated TrkB-T1 isoform to control astrocytic glycine transport via an endocytic, non-canonical pathway.","evidence":"Glycine transport assays, dynasore and Rho-GTPase inhibition, TrkB-T RNAi, and endosomal immunofluorescence","pmids":["26200505"],"confidence":"High","gaps":["TrkB-T1 lacks kinase activity; the signal-transducing partner is undefined","Physiological consequence for synaptic glycine levels not established"]},{"year":2015,"claim":"Tied ApoE genotype to BDNF expression by showing isoform-specific control of HDAC nuclear localization at promoter IV.","evidence":"HDAC nuclear fractionation, ChIP for HDAC6-promoter IV binding, LRP-1 knockdown, PKCε modulation, and ApoE transgenic mice","pmids":["25972179"],"confidence":"High","gaps":["How LRP-1 signaling controls HDAC trafficking not fully resolved","Relevance to in vivo cognitive outcomes not directly tested"]},{"year":2016,"claim":"Defined a metabolic-to-epigenetic mechanism whereby an exercise-induced ketone body induces Bdnf by inhibiting specific HDACs.","evidence":"Bdnf promoter assays, HDAC2/3 inhibition, ventricular β-hydroxybutyrate injection, and electrophysiology with TrkB blockade","pmids":["27253067"],"confidence":"High","gaps":["Selectivity for promoter I vs other promoters incompletely mapped","Downstream behavioral consequences not tested here"]},{"year":2017,"claim":"Showed that BDNF-TrkB bidirectionally regulates cortical glutamate release through opposing presynaptic and endocannabinoid-mediated postsynaptic actions.","evidence":"Whole-cell mEPSC recordings with CB1 blockade and eCB disruption in layer 5 cortex","pmids":["28164368"],"confidence":"Medium","gaps":["Molecular link from TrkB to eCB synthesis not identified","Single lab","Generalization beyond layer 5 unknown"]},{"year":2017,"claim":"Demonstrated that proBDNF processing yields a second bioactive product, the propeptide, with a distinct synaptic role in LTD.","evidence":"Detection of endogenous propeptide secretion and LTD assays in neuronal preparations","pmids":["28215295"],"confidence":"Medium","gaps":["Receptor mediating propeptide-driven LTD not identified","Limited methodological detail","Quantitative contribution relative to mature BDNF unknown"]},{"year":2020,"claim":"Established an anti-inflammatory role for BDNF-TrkB in microglia by defining transcriptional coactivator competition between CREB and NF-κB.","evidence":"shTrkB knockdown and pharmacological pathway dissection in microglia with in vivo BDNF perfusion","pmids":["32664974"],"confidence":"Medium","gaps":["Source of microglial-acting BDNF in vivo not defined","Single lab","Whether CBP competition is the dominant mechanism not proven"]},{"year":2021,"claim":"Identified a region-specific direct action of BDNF on amyloid processing by lowering BACE1 activity in prefrontal cortex.","evidence":"Ex vivo brain explant treatment with recombinant BDNF and BACE1 enzymatic activity assay","pmids":["34017238"],"confidence":"Medium","gaps":["Signaling pathway from TrkB to BACE1 not defined","Single method for the BDNF-BACE1 link","Basis for prefrontal vs hippocampal difference unknown"]},{"year":2023,"claim":"Showed that psychedelics act as direct, high-affinity TrkB ligands, redefining how these drugs engage neurotrophic plasticity independently of serotonergic receptors.","evidence":"Direct binding/affinity assays, TrkB mutagenesis, conditional TrkB knockout mice, and behavioral and signaling analysis","pmids":["37280397"],"confidence":"High","gaps":["Structural details of the transmembrane binding site not fully resolved","How binding allosterically potentiates endogenous BDNF not mechanistically defined"]},{"year":null,"claim":"How the nine BDNF promoters, proteolytic products, and multiple receptor isoforms are coordinated to generate region- and stimulus-specific functional outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking specific promoters to specific functional outputs","Relative in vivo contributions of TrkB-FL, TrkB-T1, p75NTR, mature BDNF and propeptide not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,11,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[7,8,11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[9,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,7,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,4,10,1]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,9]}],"complexes":[],"partners":["NTRK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23560","full_name":"Neurotrophic factor BDNF precursor form","aliases":["Abrineurin","Brain-derived neurotrophic factor"],"length_aa":247,"mass_kda":27.8,"function":"Important signaling molecule that activates signaling cascades downstream of NTRK2 (PubMed:11152678). During development, promotes the survival and differentiation of selected neuronal populations of the peripheral and central nervous systems. Participates in axonal growth, pathfinding and in the modulation of dendritic growth and morphology. Major regulator of synaptic transmission and plasticity at adult synapses in many regions of the CNS. The versatility of BDNF is emphasized by its contribution to a range of adaptive neuronal responses including long-term potentiation (LTP), long-term depression (LTD), certain forms of short-term synaptic plasticity, as well as homeostatic regulation of intrinsic neuronal excitability Important signaling molecule that activates signaling cascades downstream of NTRK2. Activates signaling cascades via the heterodimeric receptor formed by NGFR and SORCS2 (PubMed:24908487, PubMed:29909994). Signaling via NGFR and SORCS2 plays a role in synaptic plasticity and long-term depression (LTD). Binding to NGFR and SORCS2 promotes neuronal apoptosis. Promotes neuronal growth cone collapse (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P23560/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BDNF","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BDNF","total_profiled":1310},"omim":[{"mim_id":"621364","title":"MICRO RNA 382; MIR382","url":"https://www.omim.org/entry/621364"},{"mim_id":"621048","title":"POLO-LIKE KINASE 5, INACTIVE; PLK5","url":"https://www.omim.org/entry/621048"},{"mim_id":"618677","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 10; CDCBM10","url":"https://www.omim.org/entry/618677"},{"mim_id":"618130","title":"N-TERMINAL EF-HAND CALCIUM-BINDING PROTEIN 2; NECAB2","url":"https://www.omim.org/entry/618130"},{"mim_id":"617361","title":"TRANSMEMBRANE PROTEIN 108; TMEM108","url":"https://www.omim.org/entry/617361"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":4.9}],"url":"https://www.proteinatlas.org/search/BDNF"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P23560","domains":[{"cath_id":"2.10.90.10","chopping":"88-247","consensus_level":"medium","plddt":84.74,"start":88,"end":247}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23560","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23560-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23560-F1-predicted_aligned_error_v6.png","plddt_mean":71.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BDNF","jax_strain_url":"https://www.jax.org/strain/search?query=BDNF"},"sequence":{"accession":"P23560","fasta_url":"https://rest.uniprot.org/uniprotkb/P23560.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23560/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23560"}},"corpus_meta":[{"pmid":"24120943","id":"PMC_24120943","title":"Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway.","date":"2013","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24120943","citation_count":1107,"is_preprint":false},{"pmid":"17726474","id":"PMC_17726474","title":"New insights into BDNF function in depression and anxiety.","date":"2007","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17726474","citation_count":938,"is_preprint":false},{"pmid":"24668475","id":"PMC_24668475","title":"BDNF and synaptic plasticity, cognitive function, and dysfunction.","date":"2014","source":"Handbook of experimental pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24668475","citation_count":828,"is_preprint":false},{"pmid":"12663747","id":"PMC_12663747","title":"BDNF and activity-dependent synaptic modulation.","date":"2003","source":"Learning & memory (Cold Spring Harbor, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12663747","citation_count":774,"is_preprint":false},{"pmid":"26519901","id":"PMC_26519901","title":"BDNF - a key transducer of antidepressant effects.","date":"2015","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26519901","citation_count":740,"is_preprint":false},{"pmid":"10716929","id":"PMC_10716929","title":"BDNF regulates eating behavior and locomotor activity in mice.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10716929","citation_count":666,"is_preprint":false},{"pmid":"23348013","id":"PMC_23348013","title":"GDNF, NGF and BDNF as therapeutic options for neurodegeneration.","date":"2013","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/23348013","citation_count":655,"is_preprint":false},{"pmid":"27253067","id":"PMC_27253067","title":"Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27253067","citation_count":627,"is_preprint":false},{"pmid":"17882234","id":"PMC_17882234","title":"Interaction between BDNF and serotonin: role in mood disorders.","date":"2007","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17882234","citation_count":598,"is_preprint":false},{"pmid":"23602987","id":"PMC_23602987","title":"BDNF-induced local protein synthesis and synaptic plasticity.","date":"2013","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23602987","citation_count":547,"is_preprint":false},{"pmid":"20017110","id":"PMC_20017110","title":"BDNF function and intracellular signaling in neurons.","date":"2010","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/20017110","citation_count":513,"is_preprint":false},{"pmid":"15655562","id":"PMC_15655562","title":"BDNF in schizophrenia, depression and corresponding animal models.","date":"2005","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/15655562","citation_count":451,"is_preprint":false},{"pmid":"21531985","id":"PMC_21531985","title":"The aging hippocampus: interactions between exercise, depression, and BDNF.","date":"2011","source":"The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/21531985","citation_count":432,"is_preprint":false},{"pmid":"37280397","id":"PMC_37280397","title":"Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.","date":"2023","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37280397","citation_count":340,"is_preprint":false},{"pmid":"25451089","id":"PMC_25451089","title":"Regulation of hippocampal synaptic plasticity by BDNF.","date":"2014","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/25451089","citation_count":327,"is_preprint":false},{"pmid":"28215294","id":"PMC_28215294","title":"BDNF and Hippocampal Synaptic Plasticity.","date":"2016","source":"Vitamins and hormones","url":"https://pubmed.ncbi.nlm.nih.gov/28215294","citation_count":310,"is_preprint":false},{"pmid":"18514997","id":"PMC_18514997","title":"BDNF as a pain modulator.","date":"2008","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/18514997","citation_count":297,"is_preprint":false},{"pmid":"23688925","id":"PMC_23688925","title":"BDNF and memory processing.","date":"2013","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23688925","citation_count":288,"is_preprint":false},{"pmid":"15571756","id":"PMC_15571756","title":"Physiology of BDNF: focus on hypothalamic function.","date":"2004","source":"Frontiers in neuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15571756","citation_count":285,"is_preprint":false},{"pmid":"23831365","id":"PMC_23831365","title":"BDNF mechanisms in late LTP formation: A synthesis and breakdown.","date":"2013","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23831365","citation_count":266,"is_preprint":false},{"pmid":"17069877","id":"PMC_17069877","title":"Estrogen-BDNF interactions: implications for neurodegenerative diseases.","date":"2006","source":"Frontiers in neuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/17069877","citation_count":249,"is_preprint":false},{"pmid":"28280960","id":"PMC_28280960","title":"Neurobiology of local and intercellular BDNF signaling.","date":"2017","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28280960","citation_count":241,"is_preprint":false},{"pmid":"16716201","id":"PMC_16716201","title":"The molecular genetics of cognition: dopamine, COMT and BDNF.","date":"2006","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/16716201","citation_count":235,"is_preprint":false},{"pmid":"21346243","id":"PMC_21346243","title":"The lighter side of BDNF.","date":"2011","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21346243","citation_count":229,"is_preprint":false},{"pmid":"26758201","id":"PMC_26758201","title":"BDNF in sleep, insomnia, and sleep deprivation.","date":"2016","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26758201","citation_count":211,"is_preprint":false},{"pmid":"16516994","id":"PMC_16516994","title":"BDNF in sensory neurons and chronic pain.","date":"2006","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/16516994","citation_count":193,"is_preprint":false},{"pmid":"23079626","id":"PMC_23079626","title":"Interactions between estradiol, BDNF and dendritic spines in promoting memory.","date":"2012","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23079626","citation_count":185,"is_preprint":false},{"pmid":"18347599","id":"PMC_18347599","title":"Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression.","date":"2008","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/18347599","citation_count":184,"is_preprint":false},{"pmid":"16632412","id":"PMC_16632412","title":"Brain-derived neurotrophic factor (BDNF) and food intake regulation: a minireview.","date":"2006","source":"Autonomic neuroscience : basic & clinical","url":"https://pubmed.ncbi.nlm.nih.gov/16632412","citation_count":179,"is_preprint":false},{"pmid":"12589922","id":"PMC_12589922","title":"BDNF: a neuromodulator in nociceptive pathways?","date":"2002","source":"Brain research. Brain research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/12589922","citation_count":172,"is_preprint":false},{"pmid":"28937692","id":"PMC_28937692","title":"BDNF at the synapse: why location matters.","date":"2017","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/28937692","citation_count":162,"is_preprint":false},{"pmid":"27167299","id":"PMC_27167299","title":"BDNF isoforms: a round trip ticket between neurogenesis and serotonin?","date":"2016","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27167299","citation_count":152,"is_preprint":false},{"pmid":"15667930","id":"PMC_15667930","title":"Similarities between actions of estrogen and BDNF in the hippocampus: coincidence or clue?","date":"2005","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/15667930","citation_count":150,"is_preprint":false},{"pmid":"32944867","id":"PMC_32944867","title":"The physiology of regulated BDNF release.","date":"2020","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/32944867","citation_count":148,"is_preprint":false},{"pmid":"24365909","id":"PMC_24365909","title":"Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats.","date":"2013","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/24365909","citation_count":145,"is_preprint":false},{"pmid":"25449839","id":"PMC_25449839","title":"Multiple faces of BDNF in cocaine addiction.","date":"2014","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/25449839","citation_count":141,"is_preprint":false},{"pmid":"23597512","id":"PMC_23597512","title":"BDNF deregulation in Rett syndrome.","date":"2013","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23597512","citation_count":138,"is_preprint":false},{"pmid":"32664974","id":"PMC_32664974","title":"BDNF reverses aging-related microglial activation.","date":"2020","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/32664974","citation_count":135,"is_preprint":false},{"pmid":"23380505","id":"PMC_23380505","title":"Steroid hormones and BDNF.","date":"2013","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23380505","citation_count":125,"is_preprint":false},{"pmid":"29432620","id":"PMC_29432620","title":"Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide.","date":"2018","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29432620","citation_count":124,"is_preprint":false},{"pmid":"18394710","id":"PMC_18394710","title":"Ethanol-BDNF interactions: still more questions than answers.","date":"2008","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/18394710","citation_count":122,"is_preprint":false},{"pmid":"25801118","id":"PMC_25801118","title":"Corticostriatal BDNF and alcohol addiction.","date":"2015","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/25801118","citation_count":115,"is_preprint":false},{"pmid":"30387693","id":"PMC_30387693","title":"Brain-Derived Neurotrophic Factor (BDNF): Novel Insights into Regulation and Genetic Variation.","date":"2018","source":"The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/30387693","citation_count":114,"is_preprint":false},{"pmid":"25972179","id":"PMC_25972179","title":"ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation.","date":"2015","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25972179","citation_count":113,"is_preprint":false},{"pmid":"23022538","id":"PMC_23022538","title":"Are BDNF and glucocorticoid activities calibrated?","date":"2012","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23022538","citation_count":108,"is_preprint":false},{"pmid":"28736262","id":"PMC_28736262","title":"BDNF - A key player in cardiovascular system.","date":"2017","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/28736262","citation_count":101,"is_preprint":false},{"pmid":"33643008","id":"PMC_33643008","title":"Blood Brain-Derived Neurotrophic Factor (BDNF) and Major Depression: Do We Have a Translational Perspective?","date":"2021","source":"Frontiers in behavioral neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33643008","citation_count":101,"is_preprint":false},{"pmid":"28320272","id":"PMC_28320272","title":"Neurotrophic Factors (BDNF and GDNF) and the Serotonergic System of the Brain.","date":"2017","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/28320272","citation_count":98,"is_preprint":false},{"pmid":"16581172","id":"PMC_16581172","title":"Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: an association study.","date":"2006","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/16581172","citation_count":98,"is_preprint":false},{"pmid":"24887639","id":"PMC_24887639","title":"BDNF: no gain without pain?","date":"2014","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24887639","citation_count":95,"is_preprint":false},{"pmid":"23380313","id":"PMC_23380313","title":"BDNF-TrkB signaling and neuroprotection in schizophrenia.","date":"2012","source":"Asian journal of psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/23380313","citation_count":90,"is_preprint":false},{"pmid":"23747574","id":"PMC_23747574","title":"Synaptic regulation of affective behaviors; role of BDNF.","date":"2013","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23747574","citation_count":89,"is_preprint":false},{"pmid":"16061515","id":"PMC_16061515","title":"To BDNF or not to BDNF: that is the epileptic hippocampus.","date":"2005","source":"The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/16061515","citation_count":87,"is_preprint":false},{"pmid":"25354496","id":"PMC_25354496","title":"The Physiology of BDNF and Its Relationship with ADHD.","date":"2014","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25354496","citation_count":86,"is_preprint":false},{"pmid":"30675270","id":"PMC_30675270","title":"Targeting the BDNF/TrkB pathway for the treatment of tumors.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30675270","citation_count":86,"is_preprint":false},{"pmid":"15202684","id":"PMC_15202684","title":"Local effects of BDNF on dendritic growth.","date":"2004","source":"Reviews in the neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/15202684","citation_count":86,"is_preprint":false},{"pmid":"28593903","id":"PMC_28593903","title":"Hippocampal BDNF in physiological conditions and social isolation.","date":"2017","source":"Reviews in the neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/28593903","citation_count":84,"is_preprint":false},{"pmid":"34655857","id":"PMC_34655857","title":"Lead (Pb) and neurodevelopment: A review on exposure and biomarkers of effect (BDNF, HDL) and susceptibility.","date":"2021","source":"International journal of hygiene and environmental health","url":"https://pubmed.ncbi.nlm.nih.gov/34655857","citation_count":78,"is_preprint":false},{"pmid":"20066808","id":"PMC_20066808","title":"NGF and BDNF: from nerves to adipose tissue, from neurokines to metabokines.","date":"2009","source":"Rivista di psichiatria","url":"https://pubmed.ncbi.nlm.nih.gov/20066808","citation_count":78,"is_preprint":false},{"pmid":"22543740","id":"PMC_22543740","title":"Acute exercise modulates BDNF and pro-BDNF protein content in immune cells.","date":"2012","source":"Medicine and science in sports and exercise","url":"https://pubmed.ncbi.nlm.nih.gov/22543740","citation_count":72,"is_preprint":false},{"pmid":"33958275","id":"PMC_33958275","title":"Metabolic homeostasis via BDNF and its receptors.","date":"2021","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/33958275","citation_count":71,"is_preprint":false},{"pmid":"18497099","id":"PMC_18497099","title":"Cell biology of BDNF and its relevance to schizophrenia.","date":"2008","source":"Novartis Foundation symposium","url":"https://pubmed.ncbi.nlm.nih.gov/18497099","citation_count":71,"is_preprint":false},{"pmid":"17226799","id":"PMC_17226799","title":"BDNF variant linked to anxiety-related behaviors.","date":"2007","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17226799","citation_count":67,"is_preprint":false},{"pmid":"23649659","id":"PMC_23649659","title":"Role of BDNF in central motor structures and motor diseases.","date":"2013","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/23649659","citation_count":66,"is_preprint":false},{"pmid":"24984919","id":"PMC_24984919","title":"BDNF and its TrkB receptor in human fracture healing.","date":"2014","source":"Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft","url":"https://pubmed.ncbi.nlm.nih.gov/24984919","citation_count":65,"is_preprint":false},{"pmid":"32397504","id":"PMC_32397504","title":"The Role of BDNF on Aging-Modulation Markers.","date":"2020","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32397504","citation_count":65,"is_preprint":false},{"pmid":"32378708","id":"PMC_32378708","title":"Brain-derived neurotrophic factor (BDNF) expression and function in the mammalian reproductive Tract.","date":"2020","source":"Human reproduction update","url":"https://pubmed.ncbi.nlm.nih.gov/32378708","citation_count":60,"is_preprint":false},{"pmid":"28847297","id":"PMC_28847297","title":"NGF and BDNF Alterations by Prenatal Alcohol Exposure.","date":"2019","source":"Current neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28847297","citation_count":60,"is_preprint":false},{"pmid":"35321093","id":"PMC_35321093","title":"TrkB Truncated Isoform Receptors as Transducers and Determinants of BDNF Functions.","date":"2022","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35321093","citation_count":60,"is_preprint":false},{"pmid":"30150003","id":"PMC_30150003","title":"BDNF genotype and tDCS interaction in aphasia treatment.","date":"2018","source":"Brain stimulation","url":"https://pubmed.ncbi.nlm.nih.gov/30150003","citation_count":60,"is_preprint":false},{"pmid":"23688926","id":"PMC_23688926","title":"The function of BDNF in the adult auditory system.","date":"2013","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23688926","citation_count":58,"is_preprint":false},{"pmid":"37238659","id":"PMC_37238659","title":"Mechanisms Controlling the Expression and Secretion of BDNF.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37238659","citation_count":57,"is_preprint":false},{"pmid":"28739680","id":"PMC_28739680","title":"BDNF: An Oncogene or Tumor Suppressor?","date":"2017","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28739680","citation_count":56,"is_preprint":false},{"pmid":"21723895","id":"PMC_21723895","title":"MicroRNA function and neurotrophin BDNF.","date":"2011","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/21723895","citation_count":56,"is_preprint":false},{"pmid":"28272318","id":"PMC_28272318","title":"Epigenetic Regulation of BDNF Gene during Development and Diseases.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28272318","citation_count":55,"is_preprint":false},{"pmid":"29499216","id":"PMC_29499216","title":"Brain derived neurotrophic factor (BDNF), its tyrosine kinase receptor B (TrkB) and nicotine.","date":"2018","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/29499216","citation_count":55,"is_preprint":false},{"pmid":"35955546","id":"PMC_35955546","title":"BDNF Therapeutic Mechanisms in Neuropsychiatric Disorders.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35955546","citation_count":54,"is_preprint":false},{"pmid":"20410295","id":"PMC_20410295","title":"Epigenetic regulation of BDNF expression via the scaffolding protein RACK1.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20410295","citation_count":54,"is_preprint":false},{"pmid":"36884028","id":"PMC_36884028","title":"β3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure.","date":"2023","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/36884028","citation_count":53,"is_preprint":false},{"pmid":"36173463","id":"PMC_36173463","title":"BDNF and its signaling in cancer.","date":"2022","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36173463","citation_count":53,"is_preprint":false},{"pmid":"12069900","id":"PMC_12069900","title":"Neurotrophins induce BDNF expression through the glutamate receptor pathway in neocortical neurons.","date":"2002","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12069900","citation_count":51,"is_preprint":false},{"pmid":"16904693","id":"PMC_16904693","title":"Application of bFGF and BDNF to improve angiogenesis and cardiac function.","date":"2006","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/16904693","citation_count":50,"is_preprint":false},{"pmid":"23727436","id":"PMC_23727436","title":"BDNF in fragile X syndrome.","date":"2013","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23727436","citation_count":49,"is_preprint":false},{"pmid":"21701997","id":"PMC_21701997","title":"The metabotrophic NGF and BDNF: an emerging concept.","date":"2011","source":"Archives italiennes de biologie","url":"https://pubmed.ncbi.nlm.nih.gov/21701997","citation_count":46,"is_preprint":false},{"pmid":"23239946","id":"PMC_23239946","title":"Regulation of BDNF expression by cocaine.","date":"2012","source":"The Yale journal of biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23239946","citation_count":45,"is_preprint":false},{"pmid":"26200505","id":"PMC_26200505","title":"BDNF, via truncated TrkB receptor, modulates GlyT1 and GlyT2 in astrocytes.","date":"2015","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/26200505","citation_count":41,"is_preprint":false},{"pmid":"30569121","id":"PMC_30569121","title":"Irisin regulates the expression of BDNF and glycometabolism in diabetic rats.","date":"2018","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/30569121","citation_count":38,"is_preprint":false},{"pmid":"30459647","id":"PMC_30459647","title":"BDNF Plasma Levels and BDNF Exon IV Promoter Methylation as Predictors for Antidepressant Treatment Response.","date":"2018","source":"Frontiers in psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/30459647","citation_count":38,"is_preprint":false},{"pmid":"37763162","id":"PMC_37763162","title":"Associations of BDNF/BDNF-AS SNPs with Depression, Schizophrenia, and Bipolar Disorder.","date":"2023","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37763162","citation_count":36,"is_preprint":false},{"pmid":"31507380","id":"PMC_31507380","title":"On the Involvement of BDNF Signaling in Memory Reconsolidation.","date":"2019","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31507380","citation_count":36,"is_preprint":false},{"pmid":"28164368","id":"PMC_28164368","title":"BDNF-induced endocannabinoid release modulates neocortical glutamatergic neurotransmission.","date":"2017","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28164368","citation_count":34,"is_preprint":false},{"pmid":"32106593","id":"PMC_32106593","title":"BDNF Expression in Cortical GABAergic Interneurons.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32106593","citation_count":33,"is_preprint":false},{"pmid":"35074305","id":"PMC_35074305","title":"Effects of corticosterone on BDNF expression and mood behaviours in mice.","date":"2022","source":"Physiology & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/35074305","citation_count":33,"is_preprint":false},{"pmid":"37426074","id":"PMC_37426074","title":"Revisiting the expression of BDNF and its receptors in mammalian development.","date":"2023","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37426074","citation_count":31,"is_preprint":false},{"pmid":"11340642","id":"PMC_11340642","title":"BDNF dependence in neuroblastoma.","date":"2001","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/11340642","citation_count":31,"is_preprint":false},{"pmid":"28215295","id":"PMC_28215295","title":"BDNF Propeptide: A Novel Modulator of Synaptic Plasticity.","date":"2017","source":"Vitamins and hormones","url":"https://pubmed.ncbi.nlm.nih.gov/28215295","citation_count":31,"is_preprint":false},{"pmid":"34017238","id":"PMC_34017238","title":"Examination of BDNF Treatment on BACE1 Activity and Acute Exercise on Brain BDNF Signaling.","date":"2021","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34017238","citation_count":30,"is_preprint":false},{"pmid":"37189402","id":"PMC_37189402","title":"Diverse Functions of Multiple Bdnf Transcripts Driven by Distinct Bdnf Promoters.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37189402","citation_count":29,"is_preprint":false},{"pmid":"31849446","id":"PMC_31849446","title":"Catalpol Enhances Neurogenesis And Inhibits Apoptosis Of New Neurons Via BDNF, But Not The BDNF/Trkb Pathway.","date":"2019","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31849446","citation_count":29,"is_preprint":false},{"pmid":"39030441","id":"PMC_39030441","title":"BDNF-TrkB Signaling in Mitochondria: Implications for Neurodegenerative Diseases.","date":"2024","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39030441","citation_count":29,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43755,"output_tokens":3989,"usd":0.09555,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11835,"output_tokens":4191,"usd":0.081975,"stage2_stop_reason":"end_turn"},"total_usd":0.177525,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Exercise induces hippocampal BDNF expression through a PGC-1α/FNDC5 pathway: neuronal Fndc5 gene expression is regulated by PGC-1α, forced expression of FNDC5 in primary cortical neurons increases Bdnf expression, RNAi-mediated knockdown of FNDC5 reduces Bdnf, and peripheral delivery of FNDC5 via adenoviral vectors elevates blood irisin and induces hippocampal Bdnf expression.\",\n      \"method\": \"RNAi knockdown, forced overexpression in primary neurons, adenoviral vector delivery, Pgc1a knockout mice\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic approaches (KO mice, RNAi, forced expression, adenoviral delivery) in a single study with consistent results\",\n      \"pmids\": [\"24120943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"β-hydroxybutyrate, an endogenous metabolite elevated after prolonged exercise, induces Bdnf gene expression by inhibiting HDAC2 and HDAC3 at selective Bdnf promoters (particularly promoter I), and direct ventricular application of β-hydroxybutyrate increases hippocampal Bdnf expression; downstream, β-hydroxybutyrate causes increased neurotransmitter release that is dependent on the TrkB receptor.\",\n      \"method\": \"Bdnf promoter activity assays, HDAC inhibition experiments, direct ventricular injection, electrophysiology with TrkB blockade\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro promoter assays with specific HDAC identification, in vivo ventricular delivery, and electrophysiology with receptor-specific blockade in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"27253067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Psychedelics (LSD and psilocin) directly bind to TrkB, the BDNF receptor, with affinities ~1,000-fold higher than other antidepressants, at a site within the transmembrane domain of TrkB dimers that partially overlaps with antidepressant binding sites; their effects on neurotrophic signaling, plasticity, and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling, but are independent of 5-HT2A activation.\",\n      \"method\": \"Direct binding assays, TrkB mutagenesis, conditional TrkB knockout mice, behavioral assays, signaling pathway analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding demonstrated with affinity measurements, mutagenesis, and genetic knockout validation with multiple orthogonal methods\",\n      \"pmids\": [\"37280397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RACK1 (scaffolding protein) mediates epigenetic regulation of BDNF gene expression: following cAMP pathway activation, nuclear RACK1 localizes to the promoter IV region of the BDNF gene by associating with histones H3 and H4, causing dissociation of the transcriptional repressor MeCP2 from the promoter and subsequent acetylation of histone H4, leading to promoter IV-controlled transcription of BDNF exon IV.\",\n      \"method\": \"Chromatin immunoprecipitation, promoter activity assays, co-immunoprecipitation, RACK1 overexpression/knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating protein-promoter interactions, reciprocal co-IP, and functional promoter assays with multiple orthogonal methods in one study\",\n      \"pmids\": [\"20410295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ApoE4 increases nuclear translocation of HDACs (particularly HDAC6) in human neurons, leading to HDAC6 binding to BDNF promoter IV and reduced BDNF exon IV expression; ApoE3 conversely increases histone 3 acetylation and upregulates BDNF expression via PKCε, which retains HDACs in the cytosol. LRP-1 receptor mediates the ApoE effects, and PKCε activation reverses ApoE4- and Aβ oligomer-induced BDNF downregulation.\",\n      \"method\": \"HDAC nuclear fractionation, ChIP (HDAC6-BDNF promoter IV binding), LRP-1 siRNA/blocking, PKCε activation/inhibition, ApoE transgenic mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrates direct HDAC6-promoter binding, multiple genetic and pharmacological interventions, validated in transgenic mice and human AD tissue\",\n      \"pmids\": [\"25972179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BDNF, acting on truncated TrkB-T1 receptors (not full-length TrkB), inhibits glycine transporter (GlyT1 and GlyT2) activity in astrocytes by promoting transporter internalization via a Rho-GTPase-dependent mechanism (clathrin/dynamin-dependent endocytosis); this effect does not occur through canonical TrkB-FL pathways (PLCγ, PI3K, MAPK).\",\n      \"method\": \"[3H]glycine transport assays, dynasore treatment (endocytosis inhibitor), Rho-GTPase inhibition (toxin B), TrkB-T knockdown by RNAi, immunofluorescence of GlyT in endosomes, kinase inhibitor pharmacology\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including transport assays, RNAi knockdown, pharmacological inhibitors, and subcellular localization in a single study\",\n      \"pmids\": [\"26200505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NT-4/5 and BDNF itself induce BDNF mRNA and protein expression in neocortical neurons through TrkB receptor activation (blocked by K252a); NT-4/5-enhanced BDNF production is completely suppressed by AMPA receptor blockade (CNQX) or NMDA receptor blockade (AP-5), placing glutamate receptors as intermediaries in neurotrophin-induced BDNF expression. MAP kinase and PI3K differentially regulate BDNF-induced AMPA receptor (GluR1) expression.\",\n      \"method\": \"RT-PCR for BDNF mRNA, ELISA for BDNF protein, pharmacological inhibitors (K252a, CNQX, AP-5, TTX, PD98059, LY294002), primary cortical neuron culture\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological interventions with mRNA and protein readouts, but single lab and no genetic confirmation\",\n      \"pmids\": [\"12069900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BDNF-TrkB signaling in neocortical somatosensory cortex (layer 5) regulates glutamate release via opposing mechanisms: a direct presynaptic enhancement of release probability, and simultaneous postsynaptic induction of endocannabinoid (eCB) release that retrogradely decreases release probability via presynaptic CB1 receptors; blocking CB1 receptors or disrupting eCB release unmasks the direct BDNF effect on mEPSC frequency.\",\n      \"method\": \"Whole-cell patch clamp electrophysiology (mEPSCs), CB1 receptor blockade, disruption of eCB release, layer-specific immunofluorescence for CB1 and TrkB\",\n      \"journal\": \"Synapse\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with pharmacological dissection of opposing mechanisms, single lab, two orthogonal methods\",\n      \"pmids\": [\"28164368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BDNF-TrkB signaling in microglia suppresses microglial activation: BDNF activates ErK and CREB in microglia, which compete with LPS-induced NF-κB for binding to the common coactivator CREB-binding protein, thereby inhibiting p38, JNK, and NF-κB activation and production of pro-inflammatory cytokines. shTrkB knockdown induces microglial activation in naïve mice, and aging-related microglial activation is reversed by chronic subcutaneous BDNF perfusion.\",\n      \"method\": \"Pharmacological and genetic approaches in microglial cell lines and primary microglia, shTrkB knockdown, in vivo BDNF perfusion, signaling pathway analysis (p38, JNK, NF-κB, ERK, CREB)\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown plus pharmacological dissection of signaling pathway, validated in vivo, single lab\",\n      \"pmids\": [\"32664974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BDNF propeptide (the prodomain released after proteolytic cleavage of proBDNF) is endogenously secreted from neuronal cells and facilitates long-term depression (LTD), indicating that posttranslational proteolytic processing of proBDNF generates at least two bioactive fragments with distinct synaptic plasticity functions.\",\n      \"method\": \"Detection of endogenous propeptide secretion, LTD assays in neuronal preparations\",\n      \"journal\": \"Vitamins and hormones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional LTD assay combined with endogenous secretion detection, but limited methodological detail available from abstract alone\",\n      \"pmids\": [\"28215295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Prenatal stress decreases Bdnf expression in the amygdala and hippocampus of rats and this is accompanied by increased DNA methylation of Bdnf exon IV in these regions; expression of DNA methyltransferases DNMT1 and DNMT3a is increased in prenatally stressed rats, suggesting that PNS-induced reduction in Bdnf expression is mediated at least in part by increased DNA methylation of Bdnf exon IV.\",\n      \"method\": \"Bisulfite sequencing/DNA methylation analysis at Bdnf exon IV, RT-PCR for Bdnf mRNA, DNMT expression analysis, prenatal stress rat model\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct measurement of DNA methylation at specific CpG sites correlated with expression changes, two orthogonal methods, single lab\",\n      \"pmids\": [\"24365909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BDNF regulates eating behavior and locomotor activity through hypothalamic circuits: heterozygous BDNF knockout mice show hyperphagia and obesity, and infusion of BDNF or NT4/5 can transiently reverse these eating behavior abnormalities, demonstrating a non-neurotrophic, behavioral regulatory function for BDNF via TrkB in hypothalamic nuclei associated with satiety.\",\n      \"method\": \"BDNF heterozygous knockout mice (multiple independent strains), intracranial neurotrophin infusion, behavioral measurement of food intake and locomotion\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with specific behavioral phenotype replicated across multiple independent inbred and hybrid strains, with rescue by exogenous BDNF infusion\",\n      \"pmids\": [\"10716929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Direct treatment of brain tissue explants with BDNF reduces BACE1 (beta-site APP cleaving enzyme 1) activity in the prefrontal cortex but not the hippocampus, demonstrating a region-specific direct effect of BDNF on amyloid precursor protein processing independent of other exercise-induced changes.\",\n      \"method\": \"Ex vivo brain explant treatment with recombinant BDNF, BACE1 enzymatic activity assay, BDNF protein measurement by ELISA\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro/ex vivo enzyme activity assay with recombinant protein treatment, single lab, single method for the BDNF-BACE1 link\",\n      \"pmids\": [\"34017238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The BDNF gene is driven by nine distinct promoters generating nine non-coding exon-containing transcripts that are all translated into BDNF protein, with different transcripts playing different roles in distinct brain regions and physiological stages; this multilevel promoter architecture underlies exon-specific regulation by distinct transcription factors and environmental stimuli.\",\n      \"method\": \"Analysis of multiple transcript isoforms, promoter-reporter assays, region-specific transcript expression analysis\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — primarily a review/synthesis paper; the mechanistic claims about promoter structure are established by the field broadly, not by new experiments in this paper\",\n      \"pmids\": [\"37189402\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BDNF is a secreted neurotrophin that signals primarily through TrkB (full-length and truncated isoforms) and p75NTR receptors to activate MAPK/ERK, PI3K/Akt, and PLCγ pathways; its expression is controlled by nine distinct promoters subject to activity-dependent epigenetic regulation (via RACK1-mediated HDAC displacement and MeCP2 dissociation at promoter IV, and HDAC2/3 inhibition by β-hydroxybutyrate), and its precursor proBDNF is proteolytically cleaved to generate both mature BDNF (which promotes LTP via TrkB) and a bioactive propeptide (which facilitates LTD), while upstream regulators including PGC-1α/FNDC5/irisin link exercise to hippocampal BDNF induction, and TrkB is also a direct binding target of antidepressants and psychedelics that allosterically potentiate endogenous BDNF signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BDNF is a secreted neurotrophin that signals through TrkB receptors to control neuronal plasticity, synaptic transmission, and behavior across multiple brain cell types [#2, #11]. Mature BDNF acts on full-length TrkB to drive neurotrophic signaling, while distinct receptor and cleavage products diversify its output: BDNF acting on the truncated TrkB-T1 isoform inhibits astrocytic glycine transporters (GlyT1/GlyT2) by promoting Rho-GTPase-dependent, clathrin/dynamin-mediated transporter internalization, a route independent of the canonical PLCγ/PI3K/MAPK arms [#5], and the prodomain released by proteolytic processing of proBDNF is itself secreted and facilitates long-term depression, so that proteolysis generates functionally distinct synaptic effectors [#9]. At cortical synapses BDNF-TrkB signaling bidirectionally tunes glutamate release, directly enhancing presynaptic release probability while postsynaptically triggering endocannabinoid release that retrogradely suppresses it via CB1 receptors [#7], and in microglia BDNF-TrkB engages ERK/CREB to compete with NF-κB for CREB-binding protein, suppressing pro-inflammatory activation [#8]. BDNF expression is set by a multi-promoter architecture under activity- and metabolite-dependent epigenetic control: cAMP-driven nuclear RACK1 binds histones H3/H4 at promoter IV, displacing the repressor MeCP2 and permitting H4 acetylation [#3], while DNA methylation of exon IV (via DNMT1/DNMT3a) and HDAC recruitment repress it [#10, #4]. Exercise-linked signals converge on this control, with the PGC-1α/FNDC5/irisin axis inducing hippocampal Bdnf [#0] and the metabolite β-hydroxybutyrate inhibiting HDAC2/3 at Bdnf promoters to raise expression and TrkB-dependent neurotransmitter release [#1]. Beyond the nervous system proper, BDNF regulates feeding and body weight through hypothalamic TrkB circuits, as heterozygous knockout causes hyperphagia and obesity reversible by neurotrophin infusion [#11]. TrkB is a direct, high-affinity binding target of psychedelics whose plasticity and antidepressant-like effects depend on TrkB binding and potentiation of endogenous BDNF rather than on 5-HT2A activation [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that BDNF has a non-neurotrophic behavioral role by linking its loss to dysregulated energy balance through hypothalamic circuits.\",\n      \"evidence\": \"Heterozygous BDNF knockout mice across multiple strains with intracranial neurotrophin infusion rescue and feeding/locomotor measurement\",\n      \"pmids\": [\"10716929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the hypothalamic cell types or downstream effectors\", \"Mechanism of TrkB action on satiety circuits not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed BDNF expression is self-amplifying and glutamatergically gated, placing AMPA/NMDA receptors as intermediaries in neurotrophin-induced BDNF production.\",\n      \"evidence\": \"RT-PCR/ELISA in primary cortical neurons with K252a, CNQX, AP-5, and MAPK/PI3K inhibitor pharmacology\",\n      \"pmids\": [\"12069900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genetic confirmation of the receptor dependencies\", \"Single lab\", \"Transcription factors mediating the feed-forward loop not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified a molecular route by which cAMP signaling derepresses BDNF transcription, linking a scaffolding protein to chromatin remodeling at promoter IV.\",\n      \"evidence\": \"ChIP, co-IP, and promoter-reporter assays with RACK1 overexpression/knockdown\",\n      \"pmids\": [\"20410295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear RACK1 is recruited to histones not defined\", \"Generalizability to other BDNF promoters unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected exercise physiology to BDNF induction by defining the PGC-1α/FNDC5/irisin axis as an upstream driver of hippocampal Bdnf.\",\n      \"evidence\": \"RNAi, forced expression in primary neurons, adenoviral delivery, and Pgc1a knockout mice\",\n      \"pmids\": [\"24120943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/transducer for FNDC5/irisin in neurons not identified\", \"Direct vs indirect induction of Bdnf transcription unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked early-life stress to lasting BDNF repression through methylation of a specific promoter, implicating DNA methyltransferases in environmental programming of Bdnf.\",\n      \"evidence\": \"Bisulfite methylation analysis at Bdnf exon IV, RT-PCR, and DNMT expression in a prenatal stress rat model\",\n      \"pmids\": [\"24365909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of methylation vs other mechanisms not isolated\", \"Correlative DNMT increase without intervention\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed that BDNF signals through the truncated TrkB-T1 isoform to control astrocytic glycine transport via an endocytic, non-canonical pathway.\",\n      \"evidence\": \"Glycine transport assays, dynasore and Rho-GTPase inhibition, TrkB-T RNAi, and endosomal immunofluorescence\",\n      \"pmids\": [\"26200505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TrkB-T1 lacks kinase activity; the signal-transducing partner is undefined\", \"Physiological consequence for synaptic glycine levels not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Tied ApoE genotype to BDNF expression by showing isoform-specific control of HDAC nuclear localization at promoter IV.\",\n      \"evidence\": \"HDAC nuclear fractionation, ChIP for HDAC6-promoter IV binding, LRP-1 knockdown, PKCε modulation, and ApoE transgenic mice\",\n      \"pmids\": [\"25972179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LRP-1 signaling controls HDAC trafficking not fully resolved\", \"Relevance to in vivo cognitive outcomes not directly tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a metabolic-to-epigenetic mechanism whereby an exercise-induced ketone body induces Bdnf by inhibiting specific HDACs.\",\n      \"evidence\": \"Bdnf promoter assays, HDAC2/3 inhibition, ventricular β-hydroxybutyrate injection, and electrophysiology with TrkB blockade\",\n      \"pmids\": [\"27253067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity for promoter I vs other promoters incompletely mapped\", \"Downstream behavioral consequences not tested here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that BDNF-TrkB bidirectionally regulates cortical glutamate release through opposing presynaptic and endocannabinoid-mediated postsynaptic actions.\",\n      \"evidence\": \"Whole-cell mEPSC recordings with CB1 blockade and eCB disruption in layer 5 cortex\",\n      \"pmids\": [\"28164368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from TrkB to eCB synthesis not identified\", \"Single lab\", \"Generalization beyond layer 5 unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that proBDNF processing yields a second bioactive product, the propeptide, with a distinct synaptic role in LTD.\",\n      \"evidence\": \"Detection of endogenous propeptide secretion and LTD assays in neuronal preparations\",\n      \"pmids\": [\"28215295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating propeptide-driven LTD not identified\", \"Limited methodological detail\", \"Quantitative contribution relative to mature BDNF unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established an anti-inflammatory role for BDNF-TrkB in microglia by defining transcriptional coactivator competition between CREB and NF-κB.\",\n      \"evidence\": \"shTrkB knockdown and pharmacological pathway dissection in microglia with in vivo BDNF perfusion\",\n      \"pmids\": [\"32664974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source of microglial-acting BDNF in vivo not defined\", \"Single lab\", \"Whether CBP competition is the dominant mechanism not proven\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a region-specific direct action of BDNF on amyloid processing by lowering BACE1 activity in prefrontal cortex.\",\n      \"evidence\": \"Ex vivo brain explant treatment with recombinant BDNF and BACE1 enzymatic activity assay\",\n      \"pmids\": [\"34017238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway from TrkB to BACE1 not defined\", \"Single method for the BDNF-BACE1 link\", \"Basis for prefrontal vs hippocampal difference unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that psychedelics act as direct, high-affinity TrkB ligands, redefining how these drugs engage neurotrophic plasticity independently of serotonergic receptors.\",\n      \"evidence\": \"Direct binding/affinity assays, TrkB mutagenesis, conditional TrkB knockout mice, and behavioral and signaling analysis\",\n      \"pmids\": [\"37280397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of the transmembrane binding site not fully resolved\", \"How binding allosterically potentiates endogenous BDNF not mechanistically defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the nine BDNF promoters, proteolytic products, and multiple receptor isoforms are coordinated to generate region- and stimulus-specific functional outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking specific promoters to specific functional outputs\", \"Relative in vivo contributions of TrkB-FL, TrkB-T1, p75NTR, mature BDNF and propeptide not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 11, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [7, 8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 4, 10, 1]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NTRK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}