Control of Fear/Defensive Behavior by Brain Derived Neurotrophic Factor

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The main goal of this project is to understand how changes in the hippocampus may cause pathological aggression and antisocial behaviors. We previously found that mice with the conditional knockout (KO) of Brain Derived Neurotrophic Factor (BDNF) restricted to the hippocampal area CA3 are more aggressive than their wild type (WT) counterparts. Because hippocampus does not directly control aggression, we hypothesized that it acts on remote targets that either enhance or suppress aggression. Given that a) remote communications in the brain are mediated by oscillations and b) hippocampus generates oscillations, we investigated how BDNF deletion altered oscillatory activity in the hippocampus. We found that carbachol-induced gamma oscillations are attenuated in slices from BDNF knockout mice. At the same time we found elevated expression and activity of 5-HT3 receptor in these animals. The 5-HT3 receptor is selective for GABAergic neurons, which participate in generating gamma oscillations, and we hypothesized that the increase in 5-HT3 receptor activity might be responsible for attenuated gamma oscillations. When we pharmacologically suppressed 5-HT3 receptor, the power of gamma oscillations increased, which suggests that decrease of gamma power in BDNF knockout mice results from the increased activity of 5-HT3 receptor.
Behavioral characterization of BDNF KO mice showed that they exhibit attenuated empathy-like behavior in a novel test in which animal is exposed to a cage-mate animal under distress. We continue investigation to determine whether the 5-HT3 receptor, which is involved in aggressive behaviors, also contribute to deficit in empathy-like behaviors