A MOUSE MODEL FOR AUTISM: POSTNATAL SEROTONERGIC EFFECTS

自闭症小鼠模型：产后血清素效应

• 批准号: 6670962
• 负责人: Mary E Blue
• 金额: $ 26.31万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6670962
• 关键词: AMPA receptors; NMDA receptors; attention; autism; autoradiography; brain morphology; cerebral cortex; cognition; cooperative study; developmental neurobiology; disease /disorder model; fluoxetine; high performance liquid chromatography; hippocampus; hydroxyindoleacetate; immunocytochemistry; laboratory mouse; mental disorder chemotherapy; neural transmission; newborn animals; nonhuman therapy evaluation; psychomotor function; receptor expression; sensory feedback; serotonin; serotonin receptor

The serotonergic (5-HT) neurotransmitter system plays a major role in modulating postnatal development of the brain, including neuronal differentiation, synaptogenesis and developmental plasticity. Perturbations in 5-HT neurotransmission affect neuronal development and plasticity. Studies in rodents and humans indicate that markers for serotonin neurotransmission are enhanced in the immature brain compared to adults. However PET studies show that the early rise in serotonin metabolism is blunted in some children with autism. Clinical trials with drugs targeting serotonin neurotransmission demonstrate ameliorative potential for several debilitating autistic deficits, e.g., self-injury; stereotypy; mood disorders; cognitive parameters. Proposed experiments will determine in an animal model that involves neonatal 5-HT depletions whether selected structural and pharmacological changes in neocortex resemble those observed in autistic patients. Consistent with recent findings of increases in cortical volume in autistic brains, we have recently shown that cortical width expands when 5-HT afferents to rodent cortex are depleted at birth with the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). As in autism, specific changes vary by sex, cortical region and hemisphere. These neonatal 5-HT depletions also precipitate behavioral changes, indicative of altered attentional processes. This has lead us to the hypotheses that the cerebral cortical alterations observed in autism, are 1) the result of altered development of the 5-HT innervation cortex and 2) that cognitive changes and disturbances in sensory processing are the consequence of altered cortical development. Our specific aims are 1) to determine the time course of altered 5-HT innervation and function after neonatal 5,7 DHT injections into the medial forebrain bundle and 2) to characterize the effect of neonatal 5-HT depletion on development of thalamocortical connectivity and receptor ontogeny, 3) to characterize changes in social, affective and cognitive behaviors in mice with neonatal serotonergic depletions and to compare these to behavioral changes in mice with early prenatal serotonergic hypoinnervation and 4) to determine whether cortical volume is altered after neonatal 5-HT depletion and whether any alterations are due to changes in white or gray matter.

5-羟色胺(5-羟色胺)能神经递质系统在调节大脑出生后发育，包括神经元分化、突触发生和发育可塑性等方面发挥着重要作用。5-羟色胺神经传递的紊乱会影响神经元的发育和可塑性。对啮齿动物和人类的研究表明，与成年人相比，未成熟大脑中5-羟色胺神经传递的标志物有所增强。然而，PET研究表明，在一些自闭症儿童中，5-羟色胺代谢的早期上升是迟钝的。针对5-羟色胺神经传递的药物的临床试验表明，几种使自闭症衰弱的缺陷有改善的潜力，例如，自我伤害；刻板印象；情绪障碍；认知参数。拟议的实验将在涉及新生儿5-羟色胺耗竭的动物模型中确定新皮质中选定的结构和药理学变化是否与自闭症患者观察到的相似。与最近自闭症患者大脑皮质体积增加的发现一致，我们最近发现，当5-羟色胺(5-HT)神经毒素5，7-二羟色胺(5，7-DHT)在出生时耗尽啮齿动物皮质的5-羟色胺传入时，皮质宽度会扩大。就像自闭症一样，具体的变化因性别、皮质区域和大脑半球而异。这些新生儿5-羟色胺的缺乏也会加速行为的改变，这表明注意力过程发生了变化。这导致了我们的假设，即自闭症患者大脑皮质的改变是1)5-羟色胺神经皮质发育改变的结果，2)认知改变和 感觉处理的障碍是皮质发育改变的结果。我们的具体目标是：1)确定新生儿5，7-二羟色胺注入前脑内侧束后5-羟色胺神经支配和功能改变的时间进程；2)表征新生儿5-羟色胺缺乏对丘脑皮质连接和受体个体发育的影响；3)表征5-羟色胺能缺乏小鼠的社会、情感和认知行为的变化，并将这些变化与早期产前小鼠的行为变化进行比较。 5)5-羟色胺能神经减退；4)确定新生儿5-羟色胺耗竭后皮质体积是否改变，以及是否有任何改变是由于白质或灰质的改变。