Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain

Abstract

To study possible effects of physical training on the expression of neurotrophic factors and their receptors in the brain, we used a rat strain (spontaneously hypertensive rat, SHR), known to spontaneously run up to 20 km/night. We show that such long-distance running affects the brain-derived neurotrophic factor (BDNF) and TrkB system in hippocampus, and in particular that abrupt deprivation of habitual running leads to long-lasting decreases of BDNF/TrkB expression in hippocampus. Quantitative in situ hybridization demonstrates that running increases the expression of mRNA coding for BDNF and its high affinity receptor TrkB in hippocampus in a running length dependent manner. In addition, we show that an abrupt interruption of prolonged spontaneous exercise decrease expression of mRNA encoding BDNF and TrkB in certain hippocampal areas and that this decrease lasts at least 10 days. This down-regulation was most prominent in medial cornu ammonis 3 (CA3M). Several other trophic factors and receptors were investigated, including NGF, NT3, GDNF, trkC and p75. For these other probes investigated, no robust changes in mRNA expression were noted. Areas examined included sensorimotor cortex and hippocampus. For RET, p75, NT3, TrkB and BDNF we also examined the spinal cord without detecting any robust changes. We conclude that spontaneous running as well as its abrupt termination, leads to area-specific and trophic factor-specific changes in hippocampus.

Introduction

In the developing brain, cortical synaptogenesis is closely coupled to sensory input. In the adult brain, morphological plasticity is retained and may help explain diverse phenomena such as memory, training, kindling and drug addiction. Transmitter signalling across the synaptic cleft is believed to lead to both retrograde and anterograde signals, mediated by neurotrophic molecules, moderating the strength of the synaptic contact in response to intensity of synaptic use. BDNF (Barde, 1994) is one trophic factor that appears to be closely regulated by activity both under physiological and pathological circumstances. Being a member of the NGF family (Barde, 1994), consisting of the ligands NGF, BDNF, NT3 and NT4, and the receptors, Trk:s and p75 (Barbacid, 1994, Barde, 1994). BDNF is expressed in several brain regions, including hippocampus and neocortex (Phillips et al., 1990, Wetmore et al., 1990). TrkB, the high affinity receptor for BDNF, is synthezised by most neurons throughout CNS (see Ringstedt et al., 1993). BDNF is required for activity-dependent survival of cortical neurons in vitro (Ghosh et al., 1994), and influences synapse development (Lu and Figurov, 1997). In adulthood BDNF and TrkB are also involved in plasticity. Thus BDNF is synthesized and secreted in an activity-dependent manner by pyramidal neurons in hippocampus and might mediate some of the actions of neuronal activity on GABAergic neurons (Marty et al., 1997). In addition, TrkB has been shown to be involved in long-term potentiation in hippocampal neurons (Kang et al., 1997). Following severe experimental perturbations, such as kainic acid injections, brain or spinal cord contusions, trophic factor mRNA levels are known to be regulated. However, many reports indicate that BDNF and TrkB mRNA expression levels are more easily altered than those of other neurotrophins. Thus, BDNF transcription has been likened to immediate-early gene responses via specific promoters (Lauterborn et al., 1996). Moreover BDNF mRNA is upregulated in the barrel cortex after sensory stimulation (Rocamora et al., 1996) and light regulates the expression of both BDNF and TrkB mRNA expression in visual cortex (Castrén et al., 1992).

It is well known that physical activity influence mood and changes the activity of different neurotransmitter systems in the brain. Thus, physical activity influences cholinergic parameters including choline uptake in hippocampus and cortex cerebri and enhances spatial memory (Fordyce and Farrar, 1991). Opioid systems are also influenced (Christie and Chesher, 1983, Blake et al., 1984, Sforzo et al., 1986, Hoffman et al., 1996, Hoffman, 1997). A few days of running has been shown to increase hippocampal expression of BDNF and NGF mRNA in rats (Neeper et al., 1995, Neeper et al., 1996). In order to further investigate trophic factor mRNA changes, we designed experiments to study the possible long-term effects of running as well as its interruption. Animals were given free access to running wheels for 5 weeks, during which a considerable degree of physical activity was carried out by all rats. We demonstrate that increasing running activity increase BDNF and TrkB message in hippocampus, correlating well with data from short-term running studied by Neeper et al., 1995, Neeper et al., 1996). Furthermore, interruption of access to running wheels after 5 weeks of continuous habitual running leads to long-term decreases of BDNF and trkB mRNA in hippocampus and cortex cerebri. Other members of the NGF family are not similarly affected.