Reverse Translation of Psychosis - associated Hippocampal Hyperactivity in the mouse

精神病相关的小鼠海马过度活跃的反向翻译

• 批准号: 10473803
• 负责人: Carol A Tamminga
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473803
• 关键词: Adolescence; Adolescent; Adult; Affect; Age; Amygdaloid structure; Anatomy; Animal Behavior; Animal Testing; Animals; Area; Attenuated; Autopsy; Back; Behavior; Behavioral; Brain; Brain Diseases; Brain Pathology; Brain imaging; Brain-Derived Neurotrophic Factor; Cell Culture Techniques; Characteristics; Cognitive; DLG4 gene; Development; Disease; Electrophysiology (science); Functional disorder; Gene Expression; Generations; Glutamate Receptor; Goals; Golgi Apparatus; Hippocampus (Brain); Human; Hyperactivity; Image Analysis; Knock-in; Knock-out; Knockout Mice; Medial; Mediating; Memory; Modeling; Molecular; Molecular Genetics; Mus; NMDA receptor A1; Neurobiology; Neurons; Nucleus Accumbens; Outcome; Pathology; Pathway interactions; Pattern; Phase; Phenotype; Prefrontal Cortex; Preparation; Proteins; Psychoses; Pyramidal Cells; Reporting; Sampling; Schizophrenia; Signal Transduction; Site; Structure; Synapses; Techniques; Testing; Time; Tissues; Translations; Work; base; behavioral outcome; brain tissue; critical period; dentate gyrus; designer receptors exclusively activated by designer drugs; experimental study; human tissue; knockout animal; molecular marker; molecular pathology; mossy fiber; transcriptome; transmission process

ABSTRACT The hippocampus has been implicated in numerous functions related to normal memory and its dysfunction in several diseases. Our lab has investigated the hippocampus in relation to schizophrenia (SZ) pathophysiology using cognitive and behavioral outcomes(1-3) and brain image analyses(4-6). These consistently show that hippocampal (Hipp) activity is elevated in schizophrenic psychosis (SZ), especially in early illness. To test the molecular basis of this hyperactivity, we examined human postmortem hippocampal tissue by subfield, contrasting healthy and schizophrenia cases, using excitatory and inhibitory synaptic markers and Golgi. We found a reduction in GluN1 limited to dentate gyrus (DG) and an increase in markers of synaptic strength in CA3 in the SZ tissue; these changes are consistent with the observations that Lee et al(7) reported in hippocampal cell cultures (see A.1). Lee showed that CA3 pyramidal cell sensitivity is inversely and powerfully controlled by afferent input from DG, with decreased afferent input associated with increased pyramidal cell activity. We have been able to recapitulate this human-specific SZ pathology in a mouse using a DG-selective GluN1 knock out (KO)(8). This back-translation mouse KO demonstrated Hipp hyperactivity and alterations in Hipp-mediated behaviors (8). We are piloting an inhibitory DREADD technique in DG to mimic the DG-selective GluN1 KO mouse and saw evidence of a sensitive period during ‘adolescence’, when reduced DG activity could stimulate hyperactivity in CA3/CA1. This time phase cannot be resolved in the KO animal, so we had not seen it before and can only study it using DREADDs. The goal of these experiments are to causally define the mechanisms underlying the neurobiological outcomes of temporary DG hypofunction in mouse using DREADD constructs, and to show the extent, development, and critical periods of vulnerability of brain-wide changes. Having found a discrete circuit of Hipp projection regions hyperactive in the KO mouse, we will test human SZ vs HC tissue in these regions for evidence of hyperactivity and coherence with Hipp. The goal is to build a model of how hippocampal hyperactivity affects behavior and brain pathology, and specifically how this tissue pathology could support aberrant memories with psychotic content.

抽象的 海马体与正常记忆及其功能障碍相关的许多功能有关。 我们的实验室研究了海马体与精神分裂症 (SZ) 病理生理学的关系。 使用认知和行为结果 (1-3) 以及大脑图像分析 (4-6) 这些一致表明。 精神分裂症精神病 (SZ) 中的海马 (Hipp) 活性升高，尤其是在疾病早期。 这种过度活跃的分子基础，我们按子领域检查了人类死后海马组织， 使用兴奋性和抑制性突触标记物以及高尔基体来对比健康和精神分裂症病例。 发现仅限于齿状回 (DG) 的 GluN1 减少，而 CA3 中的突触强度标记物增加 在 SZ 组织中；这些变化与 Lee 等人 (7) 在海马中报告的观察结果一致 细胞培养物（见 A.1）表明，CA3 锥体细胞敏感性受以下因素的反向且强有力的控制。 来自 DG 的传入输入，传入输入减少与锥体细胞活动增加相关。 能够使用 DG 选择性 GluN1 敲除在小鼠中重现这种人类特异性 SZ 病理学 (KO)(8) 这种反向翻译小鼠 KO 表现出 Hipp 过度活跃和 Hipp 介导的改变。 我们正在 DG 中试验一种抑制性 DREADD 技术来模拟 DG 选择性 GluN1 KO。 小鼠，发现了“青春期”敏感期的证据，此时 DG 活性降低可能会刺激 CA3/CA1 的过度活跃在 KO 动物中无法解决，因此我们以前没有见过它。 并且只能使用 DREADD 来研究它。这些实验的目标是因果地定义机制。 使用 DREADD 构建小鼠暂时性 DG 功能减退的神经生物学结果的基础， 并显示全脑变化的程度、发展和脆弱性的关键时期。 KO 小鼠中 Hipp 投影区域过度活跃的离散电路，我们将测试人类 SZ 与 HC 组织 这些区域的过度活跃和与希普的一致性的证据我们的目标是建立一个模型。 海马过度活跃会影响行为和大脑病理学，特别是这种组织病理学如何影响 用精神病内容支持异常记忆。