Multiple studies suggest that interaction between higher brain structures like cortex and hippocampus and a so-called defensive circuitry (which includes amygdala, hypothalamus and periaqueductal grey) determines fear/defensive behavior. Moreover, changes in such interactions may lead to mental illness. We hypothesized that 1) fear/defensive behavior can be altered by modulating synapses, which mediate this interaction, and 2) this modulation involves Brain Derived Neurotrophic Factor (BDNF) which is known to be required for synaptic plasticity. To test this hypothesis and to identify molecular mechanisms regulating fear/defensive response, we are studying behavioral and related neuronal changes in mice with forebrain restricted knockout of BDNF. The goals of this study include: 1) Identification of possible changes in fear/defensive behaviors in BDNF KO mice 2) Finding areas in the brain responsible for these change 3) Determining molecular and neuronal mechanisms underlying such changes. During the past fiscal year, we established techniques necessary for identification of neuronal circuits where BDNF regulates defensive behaviors. To map these circuits, we created lentiviral vector expressing BDNF protein. The important part of this work was developing technology for effective purification and concentration of the virus, because only well purified virus can easily diffuse in the brain tissue and infect large number of neurons. Currently, our viruses can infect more than 70 % of neurons in the injection site. In the previous year, we have found that mice lacking BDNF in the CA3 area of the hippocampus have increased aggressive behavior. We carried out the first rescue experiment by injecting BDNF expressing virus into the CA3 area of adult BDNF knockout mice. Interestingly, in spite of high levels of BDNF expression in these animals, the level of aggression did not change following the reintroduction of BDNF. This result suggests that absence of BDNF during development may result in irreversible changes, which can not be reversed by reintroducing BDNF in adulthood.
