Electrophysiological Markers of Social Function

理由：社交缺陷是精神分裂症的致残性、难治性症状。杏仁核是 被认为调节这种行为，并破坏NMDA受体（NMDAR）介导的谷氨酸 传播也有牵连。然而，详细了解蜂窝和区域 缺乏潜在的社会缺陷的电路机制。假设：我们认为， 基底外侧杏仁核（BLA）神经元上的NMDAR的突触能输入和功能可以破坏 获得和维持正常的社会行为。此外，增加的静息活动，即噪音， BLA导致正常信号处理中断，降低社会输入的信噪比（SNR） 大脑皮质边缘区域方法：我们将使用体内脑电图，局部场电位 (LFP)在社会行为过程中，BLA和海马中的多单位记录以及电压敏感 染料成像（VSDI）和来自NMDAR信号传导被破坏的小鼠的切片中的细胞内记录。模型 系统将包括具有NMDAR 1表达的组成性降低（NR1-/-）的小鼠，其具有以下缺陷： EEG和社会相互作用，以及使用NRIFlox小鼠的NR1杏仁核选择性减少的小鼠 注射AAV-Cre。解释：数据将为使用fMRI解释局部大脑激活提供信息 和表面脑电图（项目1）在精神分裂症和危险的主题。我们还将研究新的药理学 在休息和社会行为期间恢复BLA兴奋-抑制平衡的方法。 公益声明：精神分裂症患者社交困难，属于致残 并且对当前的治疗有抵抗力。大脑中一个叫做杏仁核的部分被认为是调节正常的 社会互动，以及NMDA受体上的神经递质谷氨酸的破坏， 与精神分裂症患者的正常社会交往有关。该项目将 确定破坏小鼠杏仁核中NMDA受体的谷氨酸活性是否会导致社会性 缺陷，以及用新的药物修复这种活动是否可以恢复正常的社会功能。

Rational: Social deficits are disabling, treatment refractory symptoms of schizophrenia. The amygdala is thought to modulate this behavior, and disruption of NMDA receptor (NMDAR) mediated glutamate transmission has been implicated as well. However, a detailed understanding of the cellular and regional circuit mechanisms underlying social deficits is lacking. Hypotheses: We propose that disrupted development and functioning of glutamatergic inputs to NMDARs on basolateral amygdala (BLA) neurons can disrupt acquisition and maintenance of normal social behavior. Furthermore, increased resting activity, i.e. noise, in BLA leads to disruption of normal signal processing and reduced signal-to-noise ratio (SNR) for social inputs from cortico-limbic brain regions. Approach: We will use in vivo electroencephalography, local field potentials (LFP) and multiunit recording in in BLA and hippocampus during social behavior as well as voltage sensitive dye imaging (VSDI) and intracellular recordings in slices from mice with disrupted NMDAR signaling. Model systems will include mice with constitutive reduction in NMDAR1 expression (NRl-/-) that have deficits in EEG and social interactions, as well as mice with amygdala-selective reduction in NRl using NRIflox mice with AAV-Cre injections. Interpretation: Data will inform interpretation of regional brain activation using fMRI and surface EEG (Project 1) in schizophrenia and at risk subjects. We will also examine novel pharmacologic approaches for restoration of excitatory-inhibitory balance in BLA at rest and during social behaviors. Public Welfare Statement: People with schizophrenia have difficulty in social interactions, which is disabling and resistant to current treatments. A part of the brain called the amygdala is thought to modulate normal social interactions, and disruption of the neurotransmitter glutamate at a receptor called the NMDA receptor, has been implicated in causing problems with normal social interactions in schizophrenia. This project will determine if disruption of glutamate activity at NMDA receptors in amygdala in mice can cause social deficits, and if fixing that activity with new medications could restore normal social function .