Pathway

Supports BDNF signaling

BDNF

The Brain Fertilizer

15 blends on this site modulate it.

Also searched as BDNF.

You want it high: rising BDNF is the neurochemistry of plasticity, resilience and cognition.

In depth

BDNF — the growth factor that builds new synapses and neurons, the substrate of learning and mood.

What drives it

Ketone fuel increases it.

Sleiman 2016 (eLife, PMC4915811) — β-hydroxybutyrate, which rises after prolonged exercise, induces BDNF promoter activity (notably the activity-dependent promoter I) by inhibiting HDAC2 and HDAC3; ventricular BHB raised hippocampal BDNF and increased TrkB-dependent neurotransmitter release. Replicated in hippocampal neurons (PMID 29966721). Mechanism is HDAC2/HDAC3 inhibition at selective BDNF promoters. Mouse; includes intraventricular administration. PMID 29966721 · PMC4915811

Training load increases it.

10.3390/biology12010126. doi 10.3390/biology12010126

Fasting response increases it.

Caloric restriction raises BDNF in striatum and cortex, and intermittent fasting normalizes BDNF levels where regular feeding leaves them low (reviewed in PMC5742683, which also reports fasting raising the hippocampal p-CREB/CREB ratio). Fasting raises expression of brain-derived neurotrophic factor in neurons (NEJM 2019). The route runs through ketones and carries a condition: beta-hydroxybutyrate promotes BDNF expression in hippocampal neurons under adequate glucose supply (Hu 2018, Neuroscience 386:315) — so this is not a starvation effect but a fuel-switching one, and it depends on the Caloric Restriction / Fasting → β-Hydroxybutyrate link above firing first, which needs 10-14 hours. The reviewers themselves state the limit: most data come from animal studies OR short-term human trials, raising questions about generalisability to long-term clinical outcomes, and the degree to which autophagy induction produces observable improvement in human metabolic health is still not fully understood. PMC5742683

Builds mitochondria increases it.

PGC-1α-dependent route: exercise induces hippocampal Fndc5, a PGC-1α/ERRα-dependent myokine, which drives BDNF expression (Wrann 2013, documented in Sleiman 2016 eLife PMC4915811); BDNF then feeds back to inhibit Fndc5 via TrkB. Mouse evidence. PMC4915811

Lowers cortisol reduces it.

Smith 1995, J Neurosci 15:1768 — stress and glucocorticoids markedly reduce hippocampal BDNF mRNA. PMID 7891134

Longevity gene increases it.

Gating the two drivers of neuroplasticity revealed they are one pathway, not two — but the note filed at the time was explicit: search it on its own evidence, do not assume it from the neuroplasticity work. It was searched separately. It clears the bar. The mechanism is measured at the promoter, not inferred from behavior: in SIRT1-deficient mice, BDNF and CREB ARE downregulated while miR-134 is up-regulated — shown as BDNF mRNA and Western blot, with chromatin immunoprecipitation using an anti-CREB antibody followed by qPCR for BDNF promoters 1, 2 and 4. The transcription factor was caught at the gene. The route is named: SIRT1 functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and BDNF. And it is confirmed pharmacologically by a different group using a different tool: resveratrol treatment increases SIRT1, p-CREB, CREB and BDNF expression and decreases miR-134 levels in hippocampus, and the authors conclude the effects of resveratrol ARE mediated by activating the SIRT1/miR-134 pathway. Genetic deletion and pharmacological activation, opposite directions, same axis. A second independent route is also reported: resveratrol via SIRT1 directly deacetylates MeCP2 and promotes BDNF transcription — MeCP2 being a known repressor at the BDNF locus. Two mechanisms, one direction. And miR-134 inhibition alone restores CREB and BDNF in an amyloid model of Alzheimer’s, which isolates the microRNA step from SIRT1 entirely. What this fixes: the SIRT1 → Synaptic Plasticity link and the BDNF → Synaptic Plasticity link were drawn as independent parallel inputs, which made SIRT1 and BDNF look like two separate levers when one is upstream of the other. They are now correctly ordered. rodent hippocampus and cell culture throughout. A ResearchGate mirror appeared and the primary sources were used. doi 10.1016/j.bbr.2018.04.052 · PMC2928875

Cold exposure response increases it.

Verbatim: 'Conversely, following acute cold stress, the expression of c-FOS, BDNF, HSP70, HSP90, SOD, and CAT genes increased significantly after 4 h, while caspase3 expression was notably elevated at the 6-h mark, with no significant impact observed on Bax, IRE1, or GRP78 gene expression levels.' (10.3390/fishes9070248). Tier: animal. fish (Opsariichthys bidens) · whole-animal water-temperature exposure · 15 C cold vs 25 C control (35 C heat arm also run) · sampling at 2/4/6/8 h · n not stated in abstract · acu. doi 10.3390/fishes9070248

Plasticity switch increases it.

Synaptic calcium entry induced CREB activity and BDNF gene expression together; when the CREB shut-off is triggered, BDNF induction is blocked. CREB is the step at which electrical activity becomes a transcribed neurotrophin. doi 10.1038/nn835 · PMID 11953750 · PMC5339681

What it drives

It increases Mood.

Depression is strongly and consistently linked to low BDNF across preclinical and clinical studies, and BDNF signaling is a principal target of antidepressant action (PMC5742683). Context that matters more than the arrow: the neuroplasticity hypothesis exists because the monoamine one fell short. The same review states that although the monoamine hypothesis dominated the 1980s and early 1990s, subsequent studies showed depletion of serotonin and norepinephrine precursors did not decrease mood in healthy subjects — though it did in patients with mdd in remission. BDNF and neuroplasticity were advanced as the alternative account. serum/plasma BDNF is a peripheral proxy for a central process, and the same literature notes BDNF measurement is methodologically sensitive and influenced by sex hormones and by treatment itself. PMC5742683

It increases Brain adaptability.

Minichiello 2002, Neuron — BDNF/TrkB drives hippocampal long-term potentiation (synaptic plasticity) via PLCγ-CaMKIV-CREB signaling. PMID 12367511

It increases New neuron growth.

Kuipers 2016, Sci Rep 6:21222 — BDNF infusion enhances adult hippocampal neurogenesis (dentate BrdU+). DOI 10.1038/srep21222 Verbatim: “The results demonstrate that BDNF administration to the dentate gyrus leads to increased neurogenesis of granule cells”. doi 10.1038/srep21222 · PMID 15755552

It increases Memory & focus.

Alonso 2002, Hippocampus 12:551 — hippocampal BDNF is required for short- and long-term memory formation. PMID 12201640. Separately, BDNF in the dentate gyrus is required for consolidation of pattern-separation memory (Bekinschtein 2013). It is a two-way relationship, not a one-way arrow: BDNF increases the density of alpha-7 nicotinic receptors on hippocampal neurons, and activation of those same receptors upregulates BDNF — acetylcholine and BDNF regulate each other. rodent lesion work; human BDNF evidence is peripheral serum, a proxy for a central process. PMID 12201640

It reduces Supports weight management.

WAGR syndrome is an accidental experiment nobody could have run deliberately: it is caused by contiguous deletions on chromosome 11p13 hitting WT1 and PAX6, and in some patients the deletion extends far enough to take out one copy of BDNF at 11p14.1 — about 4 megabases away. That splits the syndrome into two natural groups differing in essentially one gene. A study of 33 patients found BDNF HAPLOINSUFFICIENCY associated with lower serum BDNF and with childhood-onset obesity, and 100 percent of the WAGR patients rendered BDNF-HAPLOINSUFFICIENT were obese by 10 years of AGE. Two independent single-patient confirmations: an 8-year-old girl with a de novo chromosomal inversion leaving one functional BDNF copy, with monoallelic expression confirmed; and a boy with a de novo Y722C missense in TrkB, the BDNF receptor, at a key tyrosine in the kinase activation loop. Ligand and receptor, two patients, same phenotype. And the mouse work closes the loop three ways: re-expressing Bdnf-e2 in the ventromedial hypothalamus rescued the hyperphagia and obesity; deleting TrkB in VMH neurons of wild-type mice produced them; and infusing A TrkB agonistic antibody into the VMH alleviated the phenotype. An unplanned convergence: the Thyroid Hormone (T3) → Weight & Body Fat link was drawn on TR-beta knockdown in the ventromedial hypothalamus. Two independent drivers of weight, evidenced separately from separate literatures, both land in the same nucleus. Rare monogenic and syndromic obesity — WAGR prevalence about 1 in 500,000. Nothing here shows ordinary BDNF variation explains ordinary body weight. doi 10.1056/NEJMoa0801119 · PMC4898883

It increases Sexual function.

Named across six reviews of endothelial dysfunction as part of the shared mechanism set: reduced nitric oxide availability, oxidative stress, inflammatory responses, apoptosis of endothelial cells, and the emerging concept of endothelial-mesenchymal transition. doi 10.3390/jcm15041621 · PMID 33923709 · PMC11988752

It reduces Nerve protection.

It increases Strengthens veins.

It increases Stress resilience.

10.1007/s00213-022-06176-8 — The aging outcome lists the thirteen hallmarks themselves, each mapped to its pathway and labeled with its hallmark number. (from the reviews of this outcome). doi 10.1007/s00213-022-06176-8

It reduces Calm pain signaling.

The defining feature is that the pain is real and the tissue is not damaged: central sensitization manifests as hyperalgesia, allodynia, expanded receptive fields, and impaired endogenous pain inhibition, and in osteoarthritis the same phenomenon does not correlate with radiographic findings - severe pain may persist despite stable joint structure. The mechanism is a balance failure in both directions at once: in the dorsal horn there is excessive release of glutamate, ATP, and substance P, leading to activation of NMDA receptors - while at the same time descending inhibitory mechanisms, notably those mediated by GABA, ARE weakened. Too much excitation and too little inhibition. And mast cells carry a specific hypothesis: thalamic mast cells releasing histamine, IL-1-beta, IL-6, TNF, CGRP and substance P, either stimulating thalamic nociceptive neurons directly or via microglia. Stated by the authors as a hypothesis, not an established mechanism. The reviewers ARE blunt about the state of knowledge: the pathophysiology and etiopathogenesis remain largely unknown, and there is NO definitive pathogenesis except for altered central pain pathways. doi 10.3390/biomedicines12071543 · PMC6687840

It increases Fear extinction.

BDNF gene expression and activation of its TrkB receptor are necessary in the amygdala, hippocampus and prefrontal cortex for the formation of emotional memories; BDNF appears to enhance extinction of fear. doi 10.1111/j.1601-183X.2012.00801.x · PMC2787650

It reduces Trauma symptoms.

In the PTSD animal model BDNF was higher in prelimbic cortex and amygdala and lower in infralimbic cortex and every hippocampal subfield — elevated where fear is expressed, depleted where the extinction brake lives. doi 10.1111/j.1601-183X.2012.00801.x · PMC2787650

It reduces Neuronal overexcitation.

Neurotrophic signaling protects neurons against excitotoxic injury. The evidence here is weaker than the calcium and mitochondrial arms and is recorded at that strength. doi 10.1186/s40035-021-00278-7 · PMC8788129

It increases Learning & memory.

10.1038/sj.mp.4001957 — Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. Ying et al. J Neurosci 2002;22:1532-1540. doi 10.1038/sj.mp.4001957