The role of brain-derived neurotrophic factor (BDNF) in fear conditioning.

摘要

The experiments presented in this thesis help to clarify the role of brain-derived neurotrophic factor (BDNF) and its signal transduction pathway in fear conditioning. Understanding biochemical and molecular mechanisms underlying fear conditioning will help to explain some controversial issues like consolidation and storage of fear memory, in addition, to screen out promising drug candidate(s) to treat learning/memory deficits or anxiety disorders.; In Chapter 2, BDNF heterozygous knockout mice, impaired in contextual fear learning but not tone learning, were used for behavioral studies to investigate the role of the BDNF gene. A subsequent infusion study showed that BDNF recombinant protein was able to partially restore this deficit. The results reveal that BDNF is critically important for contextual fear learning.; In Chapter 3, old BDNF knockouts and wild types were trained, followed by analysis of BDNF expression levels in the brain to investigate the possible correlations between BDNF expression level, aging and behavior. Results showed that expression of BDNF is related to age and correlated with the ability to memorize context. Tone learning is less dependent on BDNF level. However, when a low BDNF level is combined with hearing reduction, aged animals became impaired in tone learning.; In Chapter 4, activation time course and location of Trk receptors were detected in the brains of conditioned mice. Intense immunoreactivity was shown in the hippocampal CA1 area 24 hours after fear conditioning. These data further supports the observation reported by Hall et al., (2000) that BDNF mRNA is up-regulated in the CA1 region after contextual fear learning. The BDNF-induced TrkB signal transduction pathway thus may participate in CA1 synaptic plasticity underlying fear conditioning.; Overall the results of these experiments reveal that the BDNF and Trk signaling are critically important for fear conditioning. BDNF may participate in modulation of synaptic plasticity underlying fear conditioning. Future studies need to focus on post-training changes of downstream effectors like Src, MAP kinase, CREB etc., in order to further delineate the route for transmission of conditioned fear.