Exercise and BDNF: How Training Changes Brain Chemistry

What Is BDNF and Why Does It Matter for the Brain?

BDNF (brain-derived neurotrophic factor) is a protein from the neurotrophin family. It supports neuronal survival, enables the formation and strengthening of synapses, and governs neurogenesis in the dentate gyrus of the hippocampus. At the molecular level, BDNF activates the TrkB receptor, triggering cascades responsible for long-term potentiation — the cellular basis of learning and memory.

Chronically reduced BDNF levels are associated with depression, cognitive decline, and a range of neurodegenerative conditions. Physical exercise is the most well-studied non-pharmacological stimulator of BDNF production in humans.

How Does Exercise Intensity Affect BDNF?

A randomized crossover trial (Birinci et al., Scientific Reports, 2026, n = 12 healthy young men) compared three 24-minute protocols: low-intensity continuous (50–60% MAS), moderate continuous (70–80% MAS), and high-intensity interval — HIIT (110–120% MAS, 15-second intervals). Serum BDNF results:

• Low-intensity exercise: +16%
• Moderate continuous exercise: +32%
• HIIT: +82% (statistically significantly better than both other protocols and control; p < 0.001)

Only HIIT produced a significant improvement in cognitive function: Stroop test completion time decreased by 6.3% versus −0.9% in the rest group. Peak lactate after HIIT was 14.97 ± 0.84 mmol/L versus 4.51 with moderate exercise — the authors link the more pronounced BDNF rise specifically to lactate signaling.

A systematic review of 12 studies (Mielniczek & Aune, Brain Sciences, 2024) confirmed: HIIT produces BDNF elevations more consistently than other protocols, although results are heterogeneous due to differences in intensity, duration, and study populations. A meta-analysis of 17 RCTs in older adults (Cheng et al., Frontiers in Aging Neuroscience, 2025, n = 900): overall effect of aerobic exercise on BDNF — SMD = 0.62 (95% CI: 0.06–1.18; p = 0.03).

The Role of Lactate: Brain Fuel or Signaling Molecule?

Lactate produced by muscles during intense exercise crosses into the brain via the monocarboxylate transporter MCT1. A review by Zhu et al. (Frontiers in Endocrinology, 2025) showed: during exercise the brain increases lactate oxidation by 33% while simultaneously reducing glucose uptake by 25% — lactate becomes the preferred metabolic substrate at high activity levels. Intracellularly, lactate activates the Sirt1/PGC-1α/FNDC5 axis, which triggers BDNF gene transcription. The cAMP/PKA/CREB pathway also operates in parallel, participating in the regulation of neurogenesis.

Direct confirmation in humans: intravenous sodium lactate infusion (Roja et al., Frontiers in Cellular Neuroscience, 2025, n = 18 healthy volunteers) to a level of 5.9 mmol/L — comparable to moderate exercise — raised circulating pro-BDNF by 55–68%. An important caveat: mature BDNF (mBDNF), the biologically active form, did not increase with isolated lactate infusion — its formation apparently requires additional exercise stimuli: catecholamines and mechanical muscle tension.

What Happens with Regular Training?

A systematic review of 8 RCTs in adolescents (Rico-Gonzalez et al., Sports, 2025) showed: sustained BDNF elevation is achieved with high intensity and a duration of at least six weeks. BDNF gains across different protocols ranged from +6.99% (moderate aerobic) to +19.22% (high-intensity aerobic) and +16.17% (taekwondo, 16 weeks).

In older adults (meta-analysis Cheng et al., 2025, 17 RCTs, n = 900) all three forms of aerobic exercise — walking, running, cycling — raised BDNF (overall SMD = 0.62; p = 0.03). In depression, a meta-analysis of 36 RCTs involving 2515 patients (Depression and Anxiety, 2024) showed that combining aerobic and resistance training produced the greatest BDNF elevation of all compared formats.

What Remains Unproven?

A meta-analysis of 12 RCTs in older adults (Zhang et al., Medicine, 2025, n = 774) found no statistically significant increase in hippocampal volume from exercise (SMD = 0.09; p = 0.20) — this challenges the widely repeated claim about hippocampal growth from physical exercise, which is based primarily on the single study by Erickson et al. (PNAS, 2011). The authors conclude that exercise provides functional neuroplasticity without measurable structural changes.

The mechanism of the HCAR1 (GPR81) lactate receptor is a working hypothesis that requires clarification. Knockout mice with HCAR1 removed did not lose behavioral adaptations to exercise (Klahn et al., eNeuro, 2026), indicating that lactate signaling operates through multiple channels. Most data on molecular mechanisms come from animal experiments or in vitro studies.