Control of Fear/Defensive Behavior by Brain Derived Neurotrophic Factor

该项目的主要目的是了解海马体的变化如何导致病理性攻击和反社会行为。我们之前发现，局限于海马区CA3的脑源性神经营养因子（BDNF）条件敲除（KO）小鼠比野生型（WT）小鼠更具攻击性。由于海马体不直接控制攻击，我们假设它对远程目标起作用，从而增强或抑制攻击。考虑到a)大脑中的远程通信是由振荡介导的，b)海马产生振荡，我们正在研究BDNF缺失如何改变海马的振荡活动。我们发现，在BDNF敲除小鼠的切片中，碳水化合物诱导的伽马振荡减弱。同时我们发现5-HT3受体在这些动物中表达和活性升高。由于5-HT3受体对gaba能神经元具有选择性，而gaba能神经元参与产生伽马振荡，我们假设5-HT3受体活性的增加可能是伽马振荡减弱的原因。当我们从药理学上抑制5-HT3受体时，伽马振荡的功率增加，这表明BDNF敲除小鼠的伽马功率下降是由于5-HT3受体活性增加所致。

The main goal of this project is to understand how changes in the hippocampus may cause pathological aggression and antisocial behaviors. We have 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. Since hippocampus does not control aggression directly, we hypothesized that it acts on remote targets which either enhance or suppress aggression. Given that a) remote communications in the brain are mediated by oscillations and b) hippocampus generates oscillations, we were investigating 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. Since that 5-HT3 receptor is selective for GABAergic neurons, which participate in generating gamma oscillations, 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. We continued behavioral characterization of BDNF KO mice and found that in addition to elevated aggression they exhibit attenuated empathy-like behavior and 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 aggressinve behaviors, also contribute to deficit in empathy-like behaviors.