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

基本信息

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
项目类别：
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

项目摘要

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，具有高共智力障碍的发病率。这包括形成情景、个人叙述、记忆的困难对于有序思考和组织未来行为至关重要。因此，情景记忆缺陷被认为是与自闭症相关的认知困难的主要原因。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治疗改善自闭症动物模型的社会行为，最近的研究表明，儿童时期的治疗改善自闭症患者的社交互动。 OXT 极大地促进了突触可塑性的形成，但是很少有实验考虑产后 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) 检查了这种可能性脆性 X 综合征 Fmr1 KO 小鼠模型的治疗，以及分析“什么、何时何地'编码。我们的初步结果表明，在 Fmr1 KOs iOXT 处理过程中产后第二周（P7-13）全面抢救海马区CA1长时程增强、物体定位成年期（即成年后 >40 天）评估的记忆、物体识别（什么）学习和社会认知最后一次治疗）。这些发现提出了一个令人兴奋的可能性，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。他们还提出了以下问题 iOXT 对行为和所涉及机制的影响的广度；这些问题将在拟议的研究。目标 1 研究将测试雄性和雌性 Fmr1 KO 小鼠的产后 iOXT 治疗是否有效拯救情景记忆、社会认知和刻板印象三个主要组成部分的编码成年期评估的行为，以及影响是否取决于天然 OXT 流出。我们还将确定是否有是 iOXT 对行为产生持久影响的关键时期。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分析以及神经元测量乔木测试产后 iOXT 治疗是否使不同海马的神经生物学过程正常化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 的假设导致海马突触营养因子受体（EGFR、TrkB）的激活，从而表明 OXT 影响结构成熟变化的直接途径。总体而言，拟议的研究将极大地扩展我们目前对年轻大脑中 OXT 作用的了解，包括在调节海马发育和突触功能。此外，结果将为设计新颖的早期生命疗法，以优化海马的成熟和功能，并拯救自闭症谱系障碍和相关发育障碍中情景记忆的编码。