Thalamic Mechanisms for generating abnormal low frequency oscillations relevant to Schizophrenia

丘脑产生与精神分裂症相关的异常低频振荡的机制

• 批准号: 9154728
• 负责人: JOHN E LISMAN
• 金额: $ 40.54万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9154728
• 关键词: 22q11.2; Acute; Affect; Animal Model; Animals; Axon; Basal Ganglia; Behavior; Behavioral; Biological Assay; Cell Nucleus; Cells; Chromosome Deletion; Chromosome abnormality; Communication; Data; Disease; Drug usage; Electroencephalography; Evaluation; Failure; Frequencies; Generations; Goals; Health; Hippocampus (Brain); Human; Injection of therapeutic agent; Ketamine; Knowledge; Lighting; Literature; Measures; Medial; Membrane; Memory impairment; Mental Processes; Methods; Modeling; Molecular; Motivation; Mus; N-Methylaspartate; Output; Pathway interactions; Patients; Penetrance; Performance; Pharmaceutical Preparations; Play; Preparation; Process; Protein Isoforms; Rattus; Research; Reuniens Thalamic Nucleus; Risk Factors; Role; Schizophrenia; Short-Term Memory; Slice; Structure; Symptoms; System; Testing; Thalamic structure; Therapeutic; Work; awake; base; behavior test; cognitive function; cognitive process; design; drug testing; genome-wide analysis; in vivo; inhibitory neuron; memory recall; mouse model; novel; novel therapeutic intervention; nucleus reticularis; optogenetics; reduce symptoms; research study; risk variant

Project Description In schizophrenia (SZ), the power of low-frequency EEG oscillations (delta/theta; 1-7 Hz) is elevated in the awake state in subregions of the thalamocortical system. NMDAR antagonist induces similar low-frequency oscillations and also produces many of the symptoms of SZ, thus raising the possibility that the abnormal delta oscillations in SZ are causal in producing symptoms of the disease. Our previous work using the NMDA hypofunction model shows that T-type Ca channels and NR2C are critical for generation of abnormal delta oscillations. We further showed that optogenetically inducing delta oscillation in the nucleus reuniens of the thalamus is sufficient to interfere with working memory, a cognitive process that shows deficits in SZ. This supports the hypothesis that abnormal delta in SZ could be causal in generating disease symptoms. Independent support for this framework for understanding SZ has come from two genome-wide studies; these identified the same isoform of the T-type channel as a risk gene for SZ. Thus, there is strong rationale for further understanding of how abnormal delta can produce symptoms of SZ. Furthermore, elucidation of the cellular and molecular mechanisms may suggest new strategies for disease treatment. In Aim 1, we will further analyze how optogenetic stimulation of the reuniens at delta frequency interferes with working memory. The experiments are designed to determine whether the oscillations interfere with encoding or recall processes. The goal of Aim 2 is to test, in vivo, our understanding of delta generation and to determine whether drugs that reduce delta ameliorate symptoms in an animal model. Our specific hypothesis is that drugs that inhibit T- channel function directly, or reduce their function by depolarizing cells (thus producing inactivation of T channels), will reduce delta oscillations and ameliorate behavioral deficits. We have developed an in vivo assay in which we can evoke delta oscillations by injection of ketamine into the thalamus; we will use this model to evaluate drugs for their ability to reduce the power of these oscillations. We will further test drugs using the Df(16)A+/- mice that have been generated to model the human chromosomal deletion 22q11.2 that is the largest known risk factor for SZ. Consistent with the importance of delta oscillations, these mice have elevated delta power in the awake state. With this model, we can test for drugs that reduce delta power and determine whether these drugs ameliorate the working memory deficits in these animals. In Aim 3, we test a novel hypothesis about the negative symptoms of SZ, symptoms that have been particularly difficult to understand and treat. This explanation is built on a proposal by Graybiel/Surmeier according to which activity in the parafasicular/centro-medial (PF/CM) nucleus of the thalamus preferentially activates the indirect (NoGo) pathway of the basal ganglia. Activity in the indirect (NoGo) pathway is thought to inhibit behavior and could thus produce avolition. We will use optogenetic methods to test whether imposing delta oscillations in PF/CM produces avolition.

项目描述 在精神分裂症（SZ）中，低频EEG振荡（δ/θ; 1 - 7 Hz）的功率在 清醒状态下的丘脑皮质系统的分区。NMDAR拮抗剂诱导类似的低频 振荡，也产生了许多SZ的症状，从而提高了异常三角洲的可能性， SZ的振荡是产生疾病症状的原因。我们以前的工作使用NMDA 功能减退模型显示T型Ca通道和NR2C对于异常δ的产生是关键的 振荡我们进一步表明，光遗传学诱导的δ振荡在核团聚的， 丘脑足以干扰工作记忆，这是一种显示SZ缺陷的认知过程。这 支持SZ中异常δ可能是产生疾病症状的原因的假设。 两项全基因组研究独立支持了这一理解SZ的框架， 鉴定了与SZ风险基因相同的T型通道亚型。因此， 进一步了解异常delta如何产生SZ症状。此外，阐明了 细胞和分子机制可能为疾病治疗提供新的策略。在目标1中，我们将进一步 分析在δ频率下的光遗传学刺激是如何干扰工作记忆的。的 设计实验以确定振荡是否干扰编码或回忆过程。 目标2的目标是在体内测试我们对δ生成的理解，并确定 在动物模型中减少Δ改善症状。我们的假设是抑制T- 通道功能，或通过使细胞去极化而降低其功能（从而使T细胞失活）。 通道），将减少三角洲振荡和改善行为缺陷。我们已经开发了一种体内 在这项试验中，我们可以通过向丘脑注射氯胺酮来诱发δ振荡;我们将使用这种 模型来评估药物降低这些振荡的能力。我们将进一步测试药物 使用已经产生的Df（16）A +/-小鼠来模拟人类染色体缺失22q11.2， SZ的最大已知风险因素。与δ振荡的重要性一致，这些小鼠具有 在清醒状态下提高的Δ功率。有了这个模型，我们可以测试降低δ功率的药物， 确定这些药物是否改善了这些动物的工作记忆缺陷。在目标3中，我们测试了 关于SZ阴性症状的新假设，症状特别难以解释， 理解和治疗。这个解释是建立在Graybiel/Surmeier的建议上的，根据该活动 丘脑束旁核/中央内侧核（PF/CM）优先激活间接（NoGo） 基底神经节通路。间接（NoGo）途径的活性被认为会抑制行为， 从而产生一种欲望。我们将使用光遗传学方法来测试是否在PF/CM中施加δ振荡 产生了厌恶感。