Electrophysiological Markers of Social Function

社会功能的电生理标志物

• 批准号: 8704387
• 负责人: STEVEN J SIEGEL
• 金额: $ 25.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8704387
• 关键词: Agonist; Amygdaloid structure; Architecture; Baclofen; Bathing; Behavior; Behavioral; Biological Markers; Biological Models; Brain; Brain Part; Brain region; Data; Development; Disease; Dopamine D2 Receptor; Dyes; Electroencephalography; Electrophysiology (science); Equilibrium; Functional Magnetic Resonance Imaging; Glutamates; Hippocampus (Brain); Human; Image; Injection of therapeutic agent; Instruction; Maintenance; Measures; Mediating; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; NR1 gene; Neurons; Neurotransmitters; Noise; Pattern; Pharmaceutical Preparations; Receptor Signaling; Refractory; Resistance; Rest; Risk; Risperidone; Schizophrenia; Signal Transduction; Slice; Social Behavior; Social Functioning; Social Interaction; Social Welfare; Surface; Symptoms; Synaptic Potentials; Testing; Therapeutic; Time; base; drug candidate; in vivo; inhibitor/antagonist; neurotransmission; novel; receptor; restoration; signal processing; social; transmission process; voltage

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 .

理性：社会缺陷是残疾，精神分裂症的治疗难治症状。杏仁核是 想到调节这种行为，并破坏NMDA受体（NMDAR）介导的谷氨酸 传输也被牵涉。但是，对细胞和区域的详细理解 缺乏社会缺陷的电路机制。假设：我们提出了破坏的发展 在基底外侧杏仁核（BLA）神经元上向NMDARS的谷氨酸能输入的功能可能会破坏 获得和维持正常的社会行为。此外，增加静止活动，即噪声，在 BLA导致正常信号处理和降低的社会输入信号噪声比率（SNR） 来自Cortico-Limbic脑区域。方法：我们将使用体内脑电图，局部现场电位 （LFP）和在社会行为期间在BLA和海马中进行的多单元记录以及电压敏感 NMDAR信号传导的小鼠切片中的染料成像（VSDI）和细胞内记录。模型 系统将包括具有构成性降低NMDAR1表达（NRL - / - ）的小鼠 脑电图和社交互动，以及使用Nriflox小鼠在NRL中减少杏仁核选择性的小鼠 用AAV-CRE注射。解释：数据将使用功能磁共振成像的解释区域大脑激活 精神分裂症和风险受试者的表面脑电图（项目1）。我们还将检查新颖的药理学 在休息和社交行为期间恢复BLA兴奋性抑制平衡的方法。 公共福利声明：精神分裂症的人在社交互动中难以进行，这正在禁用 并抵抗当前治疗。人们认为大脑的一部分被称为杏仁核调节正常 社交相互作用，以及在称为NMDA受体的受体上神经递质谷氨酸的破坏， 已经涉及引起精神分裂症正常社交互动问题的问题。这个项目将 确定小鼠杏仁核NMDA受体中谷氨酸活性的破坏是否会导致社会 缺陷，如果用新药物修复该活动可以恢复正常的社会功能。