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: 10383734
• 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/10383734
• 关键词: ASD patient; Acute; Address; Adult; Affect; Agonist; Animal Model; Behavior; Behavioral; Behavioral Mechanisms; Brain; Brain region; Brain-Derived Neurotrophic Factor; Centers for Disease Control and Prevention (U.S.); 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; Goals; Hippocampus (Brain); 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; OXT gene; Odors; Oxytocin; Oxytocin Receptor; Peptides; Phenotype; Physiological; Process; Property; Proteins; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regimen; Regulation; Rodent Model; Role; Route; Signal Transduction; Social Behavior; Social Interaction; 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）是一种普遍存在的异质性神经发育障碍， 智力残疾的发病率。这包括难以形成情节，个人叙述，记忆， 对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 与自闭症相关的认知困难的主要贡献者。许多大脑变化潜在的异常 在ASD中出现在儿童期，提示针对脑的有效治疗策略的可能性 成熟一种候选治疗剂是下丘脑肽催产素（OXT）。产后OXT治疗 在ASD动物模型中改善了社会行为，最近的研究表明， 改善自闭症患者的社会互动。OXT急性促进突触可塑性的形式，但有 关于出生后OXT治疗对学习可能产生的持久影响， 也没有分析对情景记忆的影响。我们使用鼻内OXT（iOXT）检查了这种可能性 在脆性X综合征的Fmr 1 KO小鼠模型中的治疗，以及用于分析“什么， “何时何地”编码。我们的初步结果表明，在Fmr 1科斯iOXT治疗期间， 出生后第2周（P7-13）完全恢复海马CA 1区长时程增强，目标定位 记忆、物体身份（什么）学习和成年后评估的社会识别（即，> 40天后， 最后一次治疗）。这些发现提出了一种令人兴奋的可能性，即有限的早期OXT治疗可以 影响ASD认知功能关键要素的终身拯救。他们还提出了一些问题， iOXT对行为和相关机制的影响范围;这些问题将在 建议的研究。目标1研究将测试雄性和雌性Fmr 1 KO小鼠的出生后iOXT治疗是否 拯救了情景记忆、社会认知和刻板印象三个主要组成部分的编码 行为在成年期评估，如果影响取决于天然OXT流出。我们还将确定是否有 是持续iOXT对行为影响的关键时期。目标2将使用电生理记录， 诱发反应和网络活动，突触蛋白和信号传导的分析，以及神经元 测试出生后iOXT治疗是否使不同海马中的神经生物学过程正常化的指标 与情景记忆编码相关的细分。最后，目标3将检验早期生命iOXT 导致海马中突触营养因子受体（EGFR，TrkB）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 扩大我们目前对OXT在年轻大脑中作用的了解，包括在以下方面的潜在关键作用： 调节海马发育和突触功能。此外，研究结果将为以下方面奠定基础： 设计新的早期生命方案，以优化海马的成熟和功能，并挽救海马的生命。 ASD和相关发育障碍中情景记忆的编码。