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.

摘要 前额叶皮质和杏仁核在大多数情况下都是强烈和持续的 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，如精神分裂症(SCZ)。尽管ASD和SCZ在某些方面有所不同 从核心症状来看，它们具有共同的神经生物学、遗传和行为特征- 主要是社交情绪障碍和焦虑。我们假设内侧前额叶 大脑皮质(MPFC)和杏仁核--调节焦虑的关键神经回路--也会表现出类似的情况 这些障碍的神经病理特征，特别是减少了对 通过GABA能系统的回路，正常情况下可以控制焦虑。广为传播 其他大脑区域，包括背外侧前额叶皮质(DlPFC)的证据表明 ASD中GABA能中间神经元数量的减少和/或GABA的传递 和SCZ。然而，GABA能通过调节焦虑的mPFC-杏仁核途径进行控制 令人惊讶的是，这两种疾病都没有进行检查。这一关键的知识差距阻碍了 开发有针对性的、神经科学驱动的生物疗法。我们建议采取 确定mPFC的GABA能系统是否发生改变的基本第一步 颗粒下层(特定目标1)和杏仁核全层、外侧层、基底层、副基底层和 ASD和/或SCZ患者大脑中的中央核团(特异性目标2)与年龄相关。 而性别匹配的对照大脑是由于：i)GABA能细胞数量的减少- 由谷氨酸脱羧酶-67-GAD67(即GAD1)定义，该酶需要 对于GABA合成，和/或II)中间神经元产生的GABA减少到 锥体/主要兴奋性神经元-用GAD67 mRNA转录水平测量。在……里面 此外，我们假设GABA能抑制神经元的一个亚类是小白蛋白 正离子(PV+)在mPFC颗粒下层以及 杏仁核外侧核和基底核。最后，根据我们之前工作的发现，我们预计 这些地区与年龄相关的变化，因此将把这项研究限制在36个具有良好特征的 来自我们收集的年龄和性别匹配的成人大脑。我们的发现将作为一项基本的 这些独特的人类疾病的机制研究和动物模型的参考 可以建立在此基础上。