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.

家长奖摘要/摘要 R01HD101642 自闭症谱系障碍 (ASD) 是一种普遍存在的异质性神经发育障碍，具有高共 智力障碍的发病率。这包括形成情景记忆的困难，这对于 有序的思考和组织未来的行为。因此，情景记忆缺陷被认为是主要的原因。 导致与自闭症相关的认知困难的因素。许多大脑变化都存在潜在的异常 自闭症谱系障碍（ASD）在儿童时期出现，表明针对大脑的有效治疗策略的可能性 成熟。一种候选治疗方法是下丘脑肽催产素（OXT）。产后OXT治疗 改善 ASD 动物模型的社会行为，最近的研究表明，儿童时期的 OXT 治疗 改善自闭症患者的社交互动。 OXT 极大地促进了潜在的突触可塑性形式 学习，但很少有实验考虑产后 OXT 可能产生的持久影响 对学习进行治疗，但没有分析对情景记忆的影响。我们使用以下方法检查了这种可能性 脆性 X 综合征 (FXS) 的 Fmr1 KO 小鼠模型中的鼻内 OXT (iOXT) 治疗，以及新颖 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 产后第二周（P7-13）的治疗完全挽救海马区CA1 LTP，物体定位 成年期（即 2-7 个月大）评估的记忆和物体识别学习。 iOXT 也有所改进 社会认可。这些发现提出了一种令人兴奋的可能性，即生命早期有限时期的 OXT 治疗 可以对自闭症谱系障碍（ASD）认知功能的关键要素进行终生挽救。他们还提出以下问题 iOXT 对行为和所涉及机制的影响的广度。目标 1 研究将测试产后 iOXT 是否有效 男性和女性 Fmr1 KO 的治疗可挽救海马依赖的三种主要编码 如果效果取决于天然 OXT 流出，则可以在成年后评估情景记忆的组成部分。我们将 进一步测试 iOXT 效果的广度，特别是这些治疗是否会减弱主要行为 FXS 和其他 ASD 异常（运动过度、重复行为）。目标2将使用 电生理记录、突触蛋白和信号传导分析以及神经元乔木测量 测试 iOXT 治疗是否使与海马编码相关的神经生物学过程正常化。目标3将 然后检验生命早期 iOXT 激活突触营养因子受体（EGFR、TrkB）的假设 海马体，从而表明 OXT 影响结构成熟变化的直接途径。 这些研究将极大地扩展我们目前对年轻大脑中催产素作用的了解，包括 调节海马发育和突触功能的潜在作用。此外，结果将奠定 为设计新颖、有效且耐受性良好的 OXT 治疗方案以优化海马奠定基础 成熟和功能，从而挽救自闭症谱系障碍和相关发育障碍的情景记忆。