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: 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
• 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

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 前额叶皮层和杏仁核在大多数情况下都有强烈而一致的牵连。 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）。虽然ASD和SCZ在某些方面确实不同， 他们有着共同的神经生物学、遗传学和行为学特征 主要是社会情感障碍和焦虑。我们假设内侧前额叶 大脑皮层（mPFC）和杏仁核，调节焦虑的关键神经回路，将显示类似的 这些疾病的神经病理学特征，特别是对神经元的抑制控制减少 通过γ-氨基丁酸能系统，通常会控制焦虑。广泛 其他大脑区域的证据，包括背外侧前额叶皮层（dlPFC），指向 ASD中GABA能中间神经元的数量减少和/或GABA的传递 和SCZ。然而，通过调节焦虑的mPFC-杏仁核通路的GABA能控制 令人惊讶的是，在这两种疾病中都没有被研究过。这一关键的知识差距阻碍了 发展有针对性的、神经科学驱动的生物疗法。我们建议采取 基本的第一步，以确定是否在mPFC的GABA能系统的改变， 颗粒下层（特定目标1）和杏仁核总、外侧、基底、副基底，以及 ASD和/或SCZ个体大脑中的中央核（特异性目标2）相对于年龄- 和性别匹配的对照大脑是由于：i）GABA能细胞数量减少- 由谷氨酸脱羧酶-67-GAD 67（即GAD 1）的存在来定义，所述谷氨酸脱羧酶-67-GAD 67（即GAD 1）是所需的酶， ii）减少GABA从中间神经元的产生， 锥体/主要兴奋性神经元-通过GAD 67 mRNA转录水平测量。在 此外，我们假设一个GABA能抑制性神经元的亚类是小清蛋白， 阳性（PV+）将在mPFC颗粒下层中不成比例地减少， 杏仁核外侧核和基底核。最后，根据我们以前工作的发现，我们预计 这些区域的年龄相关变化，因此将本研究限制在36个特征良好的 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 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。