Control of Fear/Defensive Behavior by Brain Derived Neurotrophic Factor

该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。我们以前发现，限制在海马CA 3区的脑源性神经营养因子（BDNF）的条件性敲除（KO）小鼠比野生型（WT）小鼠更具攻击性。由于海马体并不直接控制攻击性，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介导的，B）海马产生振荡，我们研究了BDNF缺失如何改变海马中的振荡活动。我们发现卡巴胆碱诱导的γ振荡在BDNF敲除小鼠的切片中减弱。同时发现5-HT_3受体在这些动物中的表达和活性升高。5-HT 3受体对参与产生γ振荡的GABA能神经元具有选择性，我们假设5-HT 3受体活性的增加可能是γ振荡减弱的原因。当我们再次抑制5-HT 3受体时，γ振荡的功率增加，提示BDNF基因敲除小鼠γ振荡功率的降低是由于5-HT 3受体活性增加所致。8232; BDNF基因敲除小鼠的行为特征表明，它们在一项新的试验中表现出减弱的同情样行为，在该试验中，动物暴露于处于痛苦状态的笼友动物。我们继续研究，以确定是否5-HT 3受体，这是参与攻击性行为，也有助于赤字的同情样行为

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