Postnatal Oxytocin Treatment and Cognitive Function in FragileX

FragileX 的产后催产素治疗和认知功能

• 批准号: 10842114
• 负责人: Christine M Gall
• 金额: $ 5.24万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10842114
• 关键词: Acute; Adult; Age; Animal Model; Attenuated; Award; Behavior; Behavioral; Brain; Childhood; Clinical; Cognitive; Development; Electrophysiology (science); Elements; Epidermal Growth Factor Receptor; Episodic memory; FMR1; Female; Fragile X Syndrome; Future; Goals; Hippocampus; Hypothalamic structure; Impaired cognition; Inherited; Inhibitory Synapse; Intellectual functioning disability; Jasminum; Knockout Mice; Knowledge; Learning; Life; Location; Locomotion; Measures; Memory; Memory impairment; Modeling; Neurobiology; Neurodevelopmental Disorder; Neurons; Oxytocin; Parents; Peptides; Phenotype; Predisposition; Process; Protein Subunits; Proteins; Research; Role; Route; Seizures; Signal Transduction; Social Behavior; Social Interaction; Stereotyped Behavior; Structure; Synapses; Synaptic plasticity; Testing; Thinking; Training; Treatment Protocols; Trophic Factor Receptor; Work; audiogenic seizure; autism spectrum disorder; cognitive function; comorbidity; design; developmental disease; graduate student; improved; individuals with autism spectrum disorder; male; memory encoding; mouse model; mutant; novel; parent grant; postnatal; postnatal period; receptor; repetitive behavior; sex; social; synaptic function; therapeutic candidate; therapeutic target; therapeutically effective

Abstract/Summary of parent award R01HD101642 Autism Spectrum Disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder with high co- morbidity for intellectual disability. This includes difficulties forming episodic memories that are critical for orderly thinking and organizing future behaviors. Episodic memory deficits are thus thought to be major contributors to cognitive difficulties associated with autism. Many of the brain changes underlying abnormalities in ASD appear in childhood suggesting the possibility for effective therapeutic strategies targeting brain maturation. One candidate therapeutic is the hypothalamic peptide Oxytocin (OXT). Postnatal OXT treatment improves social behavior in animal models of ASDs and recent work indicates that OXT treatment in childhood improves social interactions in autistic individuals. OXT acutely facilitates forms of synaptic plasticity underlying learning, but there has been little experimental consideration of possible enduring effects of postnatal OXT treatment on learning and no analyses of effects on episodic memory. We examined this possibility using intranasal OXT (iOXT) treatment in the Fmr1 KO mouse model of Fragile X Syndrome (FXS), and novel paradigms for analyses of ‘What, When and Where’ encoding. Our results show that in Fmr1 KOs iOXT treatments during the second postnatal week (P7-13) fully rescue hippocampal field CA1 LTP, object location memory, and object identity learning as assessed in adulthood (i.e., from 2-7 mo of age). iOXT also improved social recognition. These findings raise the exciting possibility that a limited period of early life OXT treatment can effect a life-long rescue of a critical element of cognitive function in ASD. They also raise questions as to the breadth of iOXT effects on behavior and the mechanisms involved. Aim 1 studies will test if postnatal iOXT treatment of male and female Fmr1 KOs rescues hippocampus-dependent encoding for the three major components of episodic memory as assessed in adulthood, if effects depend on native OXT efflux. We will further test the breadth of iOXT effects and, specifically if these treatments attenuate the cardinal behavioral abnormalities in FXS and other ASDs (hyperlocomotion, repetitive behavior). Aim 2 will use electrophysiological recordings, analyses of synaptic proteins and signaling, and measures of neuronal arbors to test if iOXT treatment normalizes neurobiological processes related to encoding in hippocampus. Aim 3 will then test the hypothesis that early life iOXT activates synaptic trophic factor receptors (EGFR, TrkB) in hippocampus, thereby suggesting a direct route for OXT effects on maturational changes in the structure. These studies will greatly expand our current knowledge of oxytocin actions in the young brain, including potential roles in regulating hippocampal development and synaptic function. Moreover, the results will lay the groundwork for designing novel, effective, and well tolerated OXT treatment regimens to optimize hippocampal maturation and function, and thereby rescue episodic memory in ASD and related developmental disorders.

摘要/父母奖R01HD101642的摘要/摘要 自闭症谱系障碍（ASD）是一种普遍且异质性神经发育障碍 智力残疾的发病率。这包括构成对情节记忆的困难 有序思考和组织未来的行为。因此，情节记忆被认为是主要的 与自闭症相关的认知困难的贡献者。许多大脑的变化是基本的异常 在ASD中出现在童年时期，暗示了针对大脑的有效治疗策略的可能性 成熟。一种候选疗法是下丘脑肽催产素（OXT）。产后治疗 改善ASD的动物模型和最近工作的社会行为表明，童运的治疗 改善加速个人的社交互动。 Oxt敏锐的偶像构成合成可塑性的形式 学习，但几乎没有实验考虑到产后OXT的可能持久影响 在学习上进行治疗，没有对情节记忆的影响分析。我们使用 FMR1 KO小鼠易碎X综合征（FXS）和新颖的鼻内OXT（IOXT）治疗 分析“什么，何时何地编码”的范例。我们的结果表明，在FMR1 KOS IOXT中 第二次产后周（P7-13）的治疗完全救援海马场CA1 LTP，对象位置 记忆和对象身份学习，如成年时（即从2-7个年龄段）所评估。 ioxt也有所改善 社会认可。这些发现引发了令人兴奋的可能性，即早期生命的有限时期OXT治疗 可以影响ASD中认知功能的关键要素的终身营救。他们还提出了有关 IOXT对行为和所涉及机制的广度。 AIM 1研究将测试产后ioxt 男性和雌性FMR1 KO的处理对三个主要的海马依赖性编码做出了反应 如果效果取决于天然OXT外排，则成年中的情节记忆组成部分。我们将 进一步测试IOXT效果的广度，特别是这些治疗方法是否减轻了基本行为 FXS和其他ASD的异常（超倒置，重复行为）。 AIM 2将使用 电生理记录，突触蛋白的分析和信号传导以及神经元乔木的测量 测试IOXT治疗是否使与海马中编码有关的神经生物学过程归一化。目标3意志 然后测试早期生命IOXT激活突触营养因子受体（EGFR，TRKB）的假设 海马，从而提出了对结构成熟变化的影响的直接途径。 这些研究将大大扩展我们当前对年轻大脑中氧加毒素作用的了解，包括 在确定海马发育和突触功能方面的潜在作用。此外，结果将放置 设计新颖，有效且耐受性良好的OXT治疗方案以优化海马 成熟和功能，从而在ASD和相关发育障碍中挽救情节记忆。