1062 Exp Physiol 94.10 pp 1062–1069 Experimental Physiology – Research Paper Evidence for a release of brain-derived neurotrophic factor from the brain during exercise Peter Rasmussen 1,2 ∗ , Patrice Brassard 1,2 ∗ , Helle Adser 1,3,4 , Martin V. Pedersen 5 , Lotte Leick 1,3,4 , Emma Hart 6 , Niels H. Secher 1,2 , Bente K. Pedersen 1,3 and Henriette Pilegaard 1,3,4 1 Copenhagen Muscle Research Centre, 2 Department of Anaesthesia, 3 Centre of Inflammation and Metabolism and 3 Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark 4 Department of Biology and 5 Institute of Neuroscience & Pharmacology, Protein Laboratory, University of Copenhagen, Denmark 6 Centre for Sports Medicine and Human Performance, Brunel University, Uxbridge, UK Brain-derived neurotrophic factor (BDNF) has an important role in regulating maintenance, growth and survival of neurons. However, the main source of circulating BDNF in response to exercise is unknown. To identify whether the brain is a source of BDNF during exercise, eight volunteers rowed for 4 h while simultaneous blood samples were obtained from the radial artery and the internal jugular vein. To further identify putative cerebral region(s) responsible for BDNF release, mouse brains were dissected and analysed for BDNF mRNA expression following treadmill exercise. In humans, a BDNF release from the brain was observed at rest (P < 0.05), and increased two- to threefold during exercise (P < 0.05). Both at rest and during exercise, the brain contributed 70–80% of circulating BDNF, while that contribution decreased following 1 h of recovery. In mice, exercise induced a three- to fivefold increase in BDNF mRNA expression in the hippocampus and cortex, peaking 2 h after the termination of exercise. These results suggest that the brain is a major but not the sole contributor to circulating BDNF. Moreover, the importance of the cortex and hippocampus as a source for plasma BDNF becomes even more prominent in response to exercise. (Received 28 April 2009; accepted after revision 3 August 2009; first published online 7 August 2009) Corresponding author P. Rasmussen: AN2041, Blegdamsvej 9, Copenhagen 2100, Denmark. Email: peter@prec.dk Brain-derived neurotrophic factor (BDNF) is a key protein in regulating maintenance, growth and even survival of neurons (Mattson et al. 2004). Brain-derived neurotrophic factor also influences learning and memory (Tyler et al. 2002), and brain tissue from patients with Alzheimer’s disease and clinical depression exhibit low expression of BDNF (Connor et al. 1997; Karege et al. 2002). Brain- derived neurotrophic factor has also been identified as a key component of the hypothalamic pathway that controls body weight and energy homeostasis (Wisse & Schwartz, 2003). Obese phenotypes are found in BDNF- heterozygous mice and are associated with hyperphagia, hyperleptinaemia, hyperinsulinaemia and hyperglycaemia (Lyons et al. 1999). In addition, BDNF reduces food intake and lowers blood glucose in diabetic mice (Nakagawa et al. 2000). In humans, similar symptoms are associated with ∗ P. Rasmussen and P. Brassard contributed equally to the manuscript. the functional loss of one copy of the BDNF gene and with a mutation in the BDNF receptor Ntrk2 gene (Yeo et al. 2004; Gray et al. 2006). Physically and socially more complex housing leads to increased neurogenesis, improved learning and less weight gain in rats (Young et al. 1999; Cao et al. 2004) associated with consistent up-regulation of BDNF expression, and a direct role for BDNF has recently been reported (Cao et al. 2009). A better understanding of therapeutic actions aimed at increasing BDNF levels, such as exercise (Neeper et al. 1995), is of clinical relevance. It is well known that BDNF synthesis is centrally mediated and activity dependent (Johnson & Mitchell, 2003) and that exercise enhances BDNF transcription in the brain (Oliff et al. 1998). In addition, exercise induces brain uptake of insulin-like growth factor 1, which is a prerequisite for the elevation in BDNF mRNA expression (Carro et al. 2000). However, the regions within the brain responsible for the production of BDNF are not known. Physical exercise DOI: 10.1113/expphysiol.2009.048512 C  2009 The Authors. Journal compilation C  2009 The Physiological Society