Modeling 5-HT-absorbing neurons in neuropathology of autism

自闭症神经病理学中 5-HT 吸收神经元的建模

• 批准号: 8366781
• 负责人: JI Y SZE
• 金额: $ 25.05万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-20 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366781
• 关键词: Ablation; Affect; Alleles; Amygdaloid structure; Anatomy; Anxiety; Area; Auditory area; Autistic Disorder; Autopsy; Axon; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Caenorhabditis elegans; Cells; Cognitive deficits; Communication; Defect; Development; Diagnosis; Disease; Embryo; Exhibits; Family; Functional disorder; Genes; Goals; Hippocampus (Brain); Human; Knockout Mice; Lead; Lesion; Light; Link; Maps; Modeling; Morphology; Mus; Neonatal; Neurodevelopmental Disorder; Neurons; Nonverbal Communication; Obsessive compulsive behavior; Patients; Pattern; Peripheral; Prefrontal Cortex; Primary Lesion; Property; Prosencephalon; Pyramidal Cells; Rodent; Role; Selective Serotonin Reuptake Inhibitor; Sensory; Serotonin; Sex Bias; Signal Transduction; Site; Social Behavior; Social Interaction; Somatosensory Cortex; Staging; Stress; Synapses; System; Testing; Time; Transgenic Organisms; Vertebral column; Visual Cortex; base; behavior influence; density; design; frontal lobe; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; improved; inhibitor/antagonist; insight; neuronal circuitry; neuronal patterning; neuropathology; neurotransmission; novel; postnatal; postsynaptic; research study; reuptake; somatosensory; synaptogenesis; trait

DESCRIPTION (provided by applicant): Autism is a postnatal neurodevelopmental disorder diagnosed based on a core of deficits in communication, social interaction, and stereotypic patterns of behavior. Postmortem studies revealed alterations in anatomical organizations and axonal and dendritic arborization in the prefrontal cortex, amygdala and hippocampus, leading to the notion that autism is a disease of synaptic connectivity and that disruption of critical neuronal circuitry underscores the behavioral and cognitive deficits. Family based association studies indicated a link between reduced expression/function of serotonin reuptake transporter (SERT) gene SLC6A4 and autism. Consistent with the idea that reduced SERT function perturbs neuronal circuitry underlying autism, SERT knockout mice exhibit deficits in somatosensory maps, alterations in pyramidal cell dendritic morphology in the infralimbic area and amygdala and enhanced anxiety traits. However, Selective Serotonin Reuptake Transporter Inhibitors (SSRIs) are found to be useful for improving repetitive and compulsive behavior of autistic patients, posting a paradox. Overcoming this paradox will help our understanding the mechanisms underlying the neuropathophysiology of autism and designing rational treatments. To understand the role of SERT deficiency in neuropathophysiology of autism, it is critical to elucidate at which developmental stage do the primary brain lesions occur and what are the mechanisms. The goal of this proposal is to investigate how a transient expression of SERT in a particular set of neurons -- 5-HT-absorbing neurons, during the neonatal stage regulates neuronal synaptic patterning in particular brain regions and whether ablating this SERT function would lead to behavioral deficits seen in autism, by making use of our unique conditional SERT knockout mouse. This proposal is inspired by our recent discovery that 5-HT-absorbing neurons, which absorb extra-synaptic 5-HT via SERT but do not synthesize 5-HT, control stress behavior in C. elegans. We demonstrated that transgenic expression of SERT in the 5-HT-absorbing neurons is necessary and sufficient to correct exaggerated behavior of SERT-null worms. Remarkably, 5-HT-absorbing neurons are present transiently in the neonatal rodent and human brains. In mouse, 5-HT-absorbing neurons are present in primary sensory areas including somatosensory, visual and auditory cortices, the hippocampus, and forebrain sites including the infralimbic area. The proposed experiments will determine the effects of 5-HT-absorbing neuron- specific inactivation of SERT on somatosensory map patterning, axonal and dendritic arborization in the frontal cortex and amygdala, and stress and social behavior. We will assess whether ablating this transient SERT function would lead to lasting alterations in brain anatomy and behavior, and if those effects are sex biased. The results will provide new insights into fundamental mechanisms of 5-HT neurotransmission and illuminate how SERT acts in right cells at right time to regulate brain anatomy and behavioral circuits implicated in autism. PUBLIC HEALTH RELEVANCE: Family based association studies indicated a link between reduced expression/function of serotonin reuptake transporter (SERT) gene SLC6A4 and autism. Consistent with the idea that reduced SERT function perturbs neuronal circuitry underlying autism, SERT knockout mice exhibit deficits in somatosensory maps, alterations in pyramidal cell dendritic morphology in the infralimbic area and amygdala, and enhanced anxiety traits. However, Selective Serotonin Reuptake Transporter Inhibitors (SSRIs) are found to be useful for improving repetitive and compulsive behavior of autistic patients, posting a paradox. To goal of this proposal is to elucidate how SERT acts in right cells at right time to regulate bran anatomy and behavior. By making use of our unique conditional SERT knockout mouse, the proposed experiments will determine the function of a transient SERT expression in specific cells in particular brain regions during the postnatal development. The results will shed light on the mechanisms underlying the neuropathophysiology of autism and provide novel experimental paradigms for designing rational treatments.

描述（由申请人提供）：自闭症是一种基于沟通，社交互动和刻板印象模式的核心诊断的产后神经发育障碍。验尸研究表明，前额叶皮层，杏仁核和海马的解剖组织以及轴突和树突状树皮的改变，导致自闭症是自闭症是突触连通性的疾病，并且是关键神经电路的破坏，使行为和认知能力抑制了行为和认知性防御。基于家庭的关联研究表明，血清素再摄取转运蛋白（SERT）基因SLC6A4的表达/功能与自闭症的表达/功能降低。与降低SERT功能的想法相一致，即自闭症的神经元电路，SERT敲除小鼠在体感图中表现出缺陷，iNimbic区域中金字塔细胞树突状形态的改变，杏仁核和杏仁核的变化以及增强的焦虑特征。但是，发现选择性5-羟色胺再摄取转运蛋白抑制剂（SSRI）可用于改善自闭症患者的重复性和强迫性行为，并发布悖论。克服这一悖论将有助于我们理解自闭症神经病理生理学和设计理性治疗的机制。要了解SERT缺乏在自闭症的神经病理生理学中的作用，阐明发育阶段的主要脑损伤发生以及机制是什么，这一点至关重要。该提案的目的是研究在新生儿阶段，在特定的一组神经元中SERT的短暂性表达如何调节特定大脑区域的神经元突触模式，并如何通过使用我们独特的状态锯齿状的锯齿状静态局部的静态局限性来调节这种SERT功能的神经元突触模式。该提议的灵感来自我们最近发现的5-HT吸收神经元，该神经元通过SERT吸收外突触的5-HT，但不能合成5-HT，控制秀丽隐杆线虫的控制应力行为。我们证明了SERT在5-HT吸收神经元中的转基因表达是必要的，足以纠正Sert-Null蠕虫的夸张行为。值得注意的是，在新生儿啮齿动物和人的大脑中，瞬时存在5-HT吸收神经元。在小鼠中，5-HT吸收神经元存在于主要感觉区域，包括体感，视觉和听觉皮层，海马和前脑位点，包括iNpralimbic区域。提出的实验将确定SERT的5-HT吸收神经元特异性灭活对体感应图案图案，轴突和树突状含量在额叶皮层和杏仁核以及压力和社会行为中的影响。我们将评估消融这种短暂的SERT功能是否会导致脑解剖学和行为的持久改变，以及这些影响是否有偏见。结果将为5-HT神经传递的基本机制提供新的见解，并阐明SERT在正确的细胞中如何在正确的细胞中起作用，以调节与自闭症有关的脑部解剖结构和行为回路。 公共卫生相关性：基于家庭的关联研究表明，血清素再摄取转运蛋白转运蛋白（SERT）基因SLC6A4与自闭症的表达/功能之间存在联系。与降低SERT功能的想法相一致，即自闭症的神经元电路，Sert敲除小鼠在体感图中表现出缺陷，inimbbic区域中的金字塔细胞树突状形态的改变和杏仁核的变化以及增强的焦虑特征。但是，发现选择性5-羟色胺再摄取转运蛋白抑制剂（SSRI）可用于改善自闭症患者的重复性和强迫性行为，并发布悖论。该提议的目标是阐明SERT在正确的时间在正确的细胞中如何作用以调节脑解剖学和行为。通过使用我们独特的条件SERT基因敲除小鼠，提出的实验将确定产后发育过程中特定大脑区域的特定细胞中瞬时SERT表达的功能。结果将阐明自闭症神经病理生理学的基础机制，并为设计有理治疗提供新的实验范例。