GABAergic expression in MPFC-amygdala pathway of adults with autism or psychosis

自闭症或精神病成人 MPFC-杏仁核通路中 GABA 表达

• 批准号: 10527728
• 负责人: Cynthia Schumann
• 金额: $ 19.94万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527728
• 关键词: Adult; Age; Age-Years; Amygdaloid structure; Animal Model; Anxiety; Autopsy; Basal Ganglia; Behavioral; Biological Response Modifier Therapy; Brain; Brain region; Cell Density; Cell Nucleus; Cells; Characteristics; Collection; Development; Disease; Enzymes; Future; GAD67 enzyme; Genetic; Genetic Transcription; Glutamate Decarboxylase; Human; Impairment; In Situ Hybridization; Interneurons; Knowledge; Lateral; Measures; Medial; Mediating; Messenger RNA; Neurobiology; Neurodevelopmental Disorder; Neurons; Neurosciences; Overdose; Parvalbumins; Pathway interactions; Persons; Pharmaceutical Preparations; Prefrontal Cortex; Production; Proxy; Psychoses; Regulation; Schizophrenia; Stratum Granulosum; Structure; Study models; System; Transcript; Work; adult with autism spectrum disorder; age related; autism spectrum disorder; brain tissue; density; design; excitatory neuron; gamma-Aminobutyric Acid; individuals with autism spectrum disorder; inhibitory neuron; mind control; neural circuit; sex; symptomatology; transmission process

ABSTRACT The prefrontal cortex and amygdala are strongly and consistently implicated in most behaviorally-defined neurodevelopmental disorders, including the autism (ASD) and psychosis spectrum disorders, such as schizophrenia (SCZ). Although ASD and SCZ do differ in some core symptomatology, they share common neurobiological, genetic, and behavioral features – chiefly socioemotional impairments and anxiety. We hypothesize that the medial prefrontal cortex (mPFC) and amygdala, key neural circuitry that regulates anxiety, will show similar neuropathological features across the disorders, specifically reduced inhibitory control over the circuit via the GABAergic system that would normally keep anxiety in check. Widespread evidence in other brain regions, including the dorsolateral prefrontal cortex (dlPFC), point to either reductions in the number of GABAergic interneurons and/or transmission of GABA in ASD and SCZ. However, GABAergic control via the mPFC-amygdala pathway that modulates anxiety has surprisingly not been examined in either disorder. This key gap in knowledge hinders development of targeted, neuroscience-driven biotherapeutics. We propose to take the fundamental first step to determine if alterations in the GABAergic system of mPFC supra- and infra- granular layers (Specific Aim 1) and amygdala total, lateral, basal, accessory basal, and central nuclei (Specific Aim 2) in the brains of individuals with ASD and/or SCZ relative to age- and sex-matched control brains are due to a: i) decrease in the number of GABAergic cells – defined by presence of glutamate decarboxylase-67—GAD67 (i.e. GAD1), the enzyme required for GABA synthesis, and/or ii) decrease in GABA production from interneurons to pyramidal/principal excitatory neurons – measured by GAD67 mRNA transcription levels. In addition, we hypothesize that a subclass of GABAergic inhibitory neurons that are parvalbumin positive (PV+) will disproportionately be reduced in mPFC infragranular layers as well as amygdala lateral and basal nuclei. Lastly, given findings from our previous work, we anticipate age-related changes in these regions and therefore will limit this study to 36 well-characterized age- and sex-matched adult brains from our collection. Our findings will serve as a fundamental reference for which mechanistic studies and animal models of these uniquely human disorders can be built upon.

抽象的 前额叶皮层和杏仁核在大多数 行为定义的神经发育障碍，包括自闭症（ASD）和精神病 虽然ASD和SCZ在某些方面有所不同 核心症状学，它们具有共同的神经生物学，遗传和行为特征 - 主要是社会情感障碍和动画。我们假设媒体前额叶 皮质（MPFC）和杏仁核（调节焦虑的关键神经元电路）将显示相似 各种疾病的神经病理特征，特别降低了对抑制性的控制 通过通常会检查动画的GABA能系统电路。广泛 其他大脑区域的证据，包括背外侧前额叶皮层（DLPFC），指向 减少GABA能中间神经元的数量和/或ASD中GABA的传播 和SCZ。但是，通过MPFC-Amygdala途径调节焦虑的GABA能控制 令人惊讶的是，在任何一种疾病中都没有检查。知识阻碍的关键差距 开发靶向神经科学驱动的生物治疗剂。我们建议接受 基本的第一步，确定MPFC上和上线的GABA能体系的变化是否 颗粒层（特定目标1）和杏仁核总，侧面，基底，辅助基底和 与年龄相比，具有ASD和/或SCZ个体的个体的中央核里（特定目标2） 性别匹配的对照大脑是由于A：i）gabagagric细胞数量减少 - 由谷氨酸脱羧酶-67-GAD67（即GAD1）定义，需要酶 对于GABA合成和/或II）从中间神经元到GABA的产生减少 锥体/主兴奋性神经元 - 通过GAD67 mRNA转录水平测量。在 另外，我们假设是白蛋白的GABA能抑制神经元的子类 在MPFC的层和 杏仁核外侧和碱性核。最后，鉴于我们以前的工作中的发现，我们期望 这些地区与年龄相关的变化，因此将将这项研究限制为36个良好的特征 我们收藏的年龄和性别匹配的成人大脑。我们的发现将成为基本 参考这些独特人类疾病的机械研究和动物模型 可以建立。