Various types of rhythmic oscillations in the brain are associated with specific stages of sleep and wakefulness and also correlate with degrees of arousal. It is hypothesized that some of these rhythms may be required for the acquisition and consolidation of memories and affect mental state; however, direct evidence for this hypothesis is lacking. One way to test the role of these oscillations is to interfere with the function of neurons producing those oscillations. There are multiple neuronal populations involved in generation and maintenance of rhythmic firing. Multiple studies suggest that interaction between higher brain structures such as 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 these hypotheses, we designed experiments to identify molecular mechanisms regulating fear/defensive response and 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 knock out mice. 2) Finding areas in the brain responsible for these change. 3) Determining molecular and neuronal mechanisms underlying such changes. During the last fiscal year, we tested BDNF knockout mice using tasks for fear/defensive behaviors and identified three changes indicating increased defensiveness in the absence of BDNF. These changes include elevated startle, high aggressiveness and reduced fear of novelty. To determine brain areas, which mediate BDNF-dependent behavioral changes, we are using the following approaches: 1) generation of mice with a more restricted pattern of BDNF deletion, 2) combining BDNF knockout with chemical lesions of selected brain areas, 3) using lentivirus and sindbis virus mediated rescue of abnormal behaviors. Using these approaches, we discovered that BDNF in the CA3 area of the hippocampus is required to control aggressive behavior, whereas the amygdala is responsible for a reduced fear of novelty in BDNF knockout mice. We have started lentivirus and sindbis virus-mediated rescue experiments to determine whether behavioral changes caused by the absence of BDNF in the forebrain could be reversed by reintroducing BDNF.
