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

基本信息

批准号：
10679025
负责人：
Cynthia Schumann
金额：
$ 24万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10679025
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 Emotional Enzymes Epilepsy Exclusion Future 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 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 neuropathology sex symptomatology transmission process

项目摘要

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.

抽象的前额皮质和杏仁核始终与大多数行为定义的神经发育障碍，包括自闭症 (ASD) 和精神病谱系障碍，例如精神分裂症 (SCZ)，尽管 ASD 和 SCZ 在某些方面确实有所不同。核心症状学，它们具有共同的神经生物学、遗传和行为特征 - 主要是社会情绪障碍和焦虑。皮层（mPFC）和杏仁核（调节焦虑的关键神经回路）将表现出类似的各种疾病的神经病理学特征，特别是对神经系统的抑制控制减少通过 GABAergic 系统进行的回路通常可以控制广泛的焦虑。其他大脑区域（包括背外侧前额叶皮层（dlPFC））的证据表明 ASD 中 GABA 能中间神经元数量的减少和/或 GABA 传输的减少然而，GABA 能通过 mPFC-杏仁核通路进行调节焦虑。令人惊讶的是，这两种疾病都没有被研究过，这一关键的知识差距阻碍了这一点。我们建议开发有针对性的、神经科学驱动的生物治疗药物。确定 mPFC 的 GABA 能系统是否发生改变的基本第一步颗粒下层（具体目标 1）和杏仁核总杏仁核、侧杏仁核、基底杏仁核、辅助基底杏仁核和自闭症谱系障碍 (ASD) 和/或 SCZ 患者大脑中的中央核（具体目标 2）与年龄相关和性别匹配的对照大脑是由于：i) GABA 细胞数量减少 – 由谷氨酸脱羧酶 67—GAD67（即 GAD1）的存在来定义，该酶需要用于 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。此外，我们认为 GABA 能抑制神经元的一个亚类是小清蛋白 mPFC 颗粒下层以及 mPFC 中的阳性 (PV+) 将不成比例地减少最后，根据我们之前的工作结果，我们预计杏仁核外侧核和基底核。这些地区与年龄相关的变化，因此将本研究限制为 36 个特征明确的地区我们收集的年龄和性别匹配的成人大脑将作为基础。这些人类特有疾病的机制研究和动物模型的参考可以建立在。