Thalamic Mechanisms for generating abnormal low frequency oscillations relevant to Schizophrenia

项目说明 在精神分裂症(SZ)患者中，低频脑电振荡(Delta/theta；1-7赫兹)的功率在 丘脑皮质系统各亚区处于清醒状态。NMDAR拮抗剂诱导类似的低频 并产生SZ的许多症状，从而增加了异常三角洲 SZ的振荡是产生疾病症状的原因。我们之前使用NMDA进行的工作 功能减退模型显示，T型钙通道和NR2C是异常三角洲发生的关键 震荡。我们进一步证明了光遗传学诱导的星云核单位的Delta振荡。 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的异常增量可能是疾病症状产生的原因的假设。 对理解SZ的这个框架的独立支持来自两项全基因组研究；这两项研究 发现相同的T型通道亚型是SZ的危险基因。因此，有很强的理由认为 进一步了解三角异常是如何产生SZ症状的。此外，还澄清了 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 分析在德尔塔频率的光遗传刺激如何干扰工作记忆。这个 实验的目的是确定振荡是否会干扰编码或回忆过程。 目标2的目标是在体内测试我们对增量生成的理解，并确定药物是否 降低增量改善动物模型中的症状。我们的具体假设是抑制T-T的药物- 通道直接起作用，或通过使细胞去极化而降低其功能(从而产生T细胞失活 通道)，将减少增量振荡和改善行为缺陷。我们已经开发出一种体内的 我们可以通过将氯胺酮注射到丘脑来唤起增量振荡的实验；我们将使用这个 评估药物降低这些振荡能量的能力的模型。我们将进一步测试药物 用已经产生的DF(16)A+/-小鼠模拟人类染色体缺失22q11.2，即 SZ已知的最大危险因素。与增量振荡的重要性一致，这些小鼠有 唤醒状态下的增量功率升高。有了这种模型，我们可以测试降低德尔塔功率和 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，我们测试了一个 关于SZ阴性症状的新假说，这些症状特别难 理解和对待。这一解释是建立在Graybiel/Surmeier根据哪项活动提出的建议之上的 在丘脑叶旁/中央内侧核(Pf/CM)优先激活间接核(NoGo)。 基底神经节的通路。间接(NoGo)途径的活动被认为是抑制行为的，并可能 从而产生剥离。我们将使用光发生方法来测试是否在PF/CM中施加增量振荡 会产生撕裂。

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.