Postnatal Oxytocin Treatment and Cognitive Function in Fragile X

脆性 X 肌瘤的产后催产素治疗和认知功能

• 批准号: 10611408
• 负责人: Christine M Gall
• 金额: $ 47.6万
• 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/10611408
• 关键词: ASD patient; Acute; Address; Adult; Affect; Agonist; Animal Model; Behavior; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; Child; Childhood; Cognitive; DTR gene; Development; Disease; Electrophysiology (science); Elements; Epidermal Growth Factor Receptor; Episodic memory; Excitatory Synapse; Exhibits; FMR1; Female; Fragile X Syndrome; Future; Genetic Techniques; Goals; Hippocampus; Hypothalamic structure; Impaired cognition; Inherited; Inhibitory Synapse; Intellectual functioning disability; Knockout Mice; Knowledge; Learning; Life; Location; Long-Term Potentiation; Measures; Mediating; Memory; Memory impairment; Modeling; Morphology; Neurobiology; Neurodevelopmental Disorder; Neurons; Neuropeptides; Neurotrophic Tyrosine Kinase Receptor Type 2; Odors; Oxytocin; Oxytocin Receptor; Peptides; Phenotype; Physiological; Process; Property; Proteins; Receptor Protein-Tyrosine Kinases; Regimen; Regulation; Rodent Model; Role; Route; Signal Transduction; Social Behavior; Social Interaction; Stereotyped Behavior; Structure; Synapses; Synaptic Receptors; Synaptic plasticity; System; Techniques; Testing; Therapeutic; Thinking; Trophic Factor Receptor; Vertebral column; Wild Type Mouse; Work; autism spectrum disorder; cellular targeting; cognitive function; comorbidity; critical developmental period; critical period; design; developmental disease; early phase clinical trial; improved; individuals with autism spectrum disorder; interest; male; memory encoding; mouse model; mutant; novel; personal narratives; postnatal; postnatal period; response; restoration; sex; social; synaptic function; therapeutic candidate; therapeutically effective

Autism Spectrum Disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder with high co- morbidity for intellectual disability. This includes difficulties forming episodic, personal narrative, 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 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 treatment in childhood improves social interactions in autistic individuals. OXT acutely facilitates forms of synaptic plasticity, 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, and novel paradigms for analyses of `What, When and Where' encoding. Our preliminary results show that in Fmr1 KOs iOXT treatments during the second postnatal week (P7-13) fully rescue hippocampal field CA1 long-term potentiation, object location memory, object identity (What) learning, and social recognition as assessed in adulthood (i.e., >40d after the last treatment). 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 effects iOXT has on behavior and the mechanisms involved; these questions will be addressed in the proposed studies. Aim 1 studies will test if postnatal iOXT treatment of male and female Fmr1 KO mice rescues encoding for the three major components of episodic memory, social recognition and stereotypic behavior as assessed in adulthood, and if effects depend on native OXT efflux. We will also determine if there is a critical period for enduring iOXT effects on behavior. Aim 2 will use electrophysiological recordings of evoked responses and network activity, analyses of synaptic proteins and signaling, and measures of neuronal arbors to test if postnatal iOXT treatment normalizes neurobiological processes in the distinct hippocampal subdivisions related to episodic memory encoding. Finally, Aim 3 will test the hypothesis that early life iOXT leads to activation of synaptic trophic factor receptors (EGFR, TrkB) in hippocampus, thereby suggesting a direct route for OXT effects on maturational changes in the structure. Overall, the proposed studies will greatly expand our current knowledge of OXT actions in the young brain, including potentially critical roles in regulating hippocampal development and synaptic function. Moreover, the results will lay the groundwork for designing novel, early life regimens to optimize hippocampal maturation and function, and to rescue the encoding of episodic memories in ASD and related developmental disorders.

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。这包括形成情节，个人叙事和记忆的困难 对于有序思考和组织未来行为至关重要。因此，情节记忆缺陷被认为是 自闭症相关的认知困难的主要贡献者。许多大脑变化的基础异常 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。一种候选治疗方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年的治疗 改善自闭症患者的社交互动。 Oxt急性促进突触可塑性的形式，但 对产后治疗对学习的可能持久影响几乎没有实验性考虑 并且没有对情节记忆的影响的分析。我们使用鼻内oxt（ioxt）检查了这种可能性 在FMR1 KO小鼠脆弱X综合征模型中的处理，以及用于分析什么的新型范式 何时何地编码。我们的初步结果表明，在FMR1 KOS IOXT治疗中 下产后周（P7-13）完全救援海马场CA1长期增强，物体位置 记忆，对象身份（什么）学习以及成年后评估的社会认可（即，> 40d之后 最后治疗）。这些发现引发了令人兴奋的可能性，即早期生活有限的治疗可以 影响ASD认知功能的关键要素的终身营救。他们还提出了有关 IOXT对行为和所涉及的机制的影响广度；这些问题将在 提出的研究。 AIM 1研究将测试雄性和雌性FMR1 KO小鼠的产后治疗 营救编码情节记忆，社会认可和刻板印象的三个主要组成部分 在成年期评估的行为，以及效果是否取决于天然OXT外排。我们还将确定是否在那里 是持续对行为影响的关键时期。 AIM 2将使用电生理记录 诱发反应和网络活动，突触蛋白和信号的分析以及神经元的测量 测试产后IOXT治疗是否在不同海马中的神经生物学过程归一化的乔木 与情节记忆编码有关的细分。最后，AIM 3将检验以下假设： 导致突触营养因子受体（EGFR，TRKB）在海马中的激活，从而表明 oxt对结构成熟变化的影响的直接途径。总体而言，拟议的研究将大大 扩大我们当前对年轻大脑中牛的行动的了解，包括在 调节海马发育和突触功能。此外，结果将为 设计小说，早期生活方案，以优化海马的成熟和功能，并营救 ASD和相关发育障碍中的情节记忆的编码。