Control of Fear/Defensive Behavior by Brain Derived Neurotrophic Factor

这个项目的主要目标是了解海马体的变化如何导致病理性攻击和反社会行为。我们之前已经发现，脑源性神经营养因子(BDNF)的条件敲除(KO)限于海马区CA3区的小鼠比它们的野生型(WT)小鼠更具攻击性。由于海马体不直接控制攻击性，我们假设它作用于增强或抑制攻击性的远程目标。鉴于a)大脑中的远程通信是由振荡调节的，以及b)海马体产生振荡，我们正在研究BDNF缺失如何改变海马体的振荡活动。我们发现，在脑源性神经营养因子基因敲除小鼠的切片中，卡巴胆碱诱导的伽马振荡被减弱。同时，我们发现在这些动物中5-HT3受体的表达和活性增加。由于5-HT3受体对参与产生伽马振荡的GABA能神经元具有选择性，我们推测5-HT3受体活性的增加可能是导致伽马振荡减弱的原因。当我们从药物上抑制5-HT3受体时，伽马振荡的功率增加，这表明BDNF基因敲除小鼠伽马功率的降低是由于5-HT3受体活性增加所致。 我们继续对BDNF KO小鼠进行行为特征描述，发现除了增加攻击性外，它们还表现出减弱的同理心样行为，以及一种新颖的测试，即动物暴露在处于困境中的笼友动物中。我们继续研究，以确定参与攻击性行为的5-HT3受体是否也与共情样行为缺陷有关。

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.