Postnatal Oxytocin Treatment and Cognitive Function in FragileX

摘要/母公司奖R 01 HD 101642摘要 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，情节记忆缺陷被认为是主要的 导致自闭症认知困难的因素。许多潜在的大脑异常变化 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 改善ASD动物模型的社会行为，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， 学习，但很少有实验考虑可能的持久影响，出生后OXT 治疗对学习的影响，没有分析对情景记忆的影响。我们研究了这种可能性， 鼻内OXT（iOXT）治疗在脆性X综合征（FXS）的Fmr 1 KO小鼠模型中的应用，以及新的 分析“什么、何时、何地”编码的范式。我们的研究结果表明，在Fmr 1科斯iOXT 在出生后第二周（P7-13）期间的治疗完全挽救海马区CA 1 LTP、对象定位 记忆，以及成年期评估的物体身份学习（即，2-7岁）。iOXT还改善了 社会认可。这些发现提出了一个令人兴奋的可能性，即有限的早期生活OXT治疗 可以实现对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对行为影响的广度和相关机制。目标1研究将测试出生后iOXT是否 治疗男性和女性Fmr 1科斯挽救了三个主要的神经元依赖性编码， 在成年期评估的情景记忆的组成部分，如果影响取决于本地OXT流出。我们将 进一步测试iOXT效应的广度，特别是这些治疗是否会减弱主要行为 FXS和其他ASD的异常（过度运动，重复行为）。目标2将使用 电生理学记录、突触蛋白和信号传导的分析以及神经元乔木的测量 以测试iOXT治疗是否使与海马体中的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，从而提出了一个直接的路线OXT的成熟的结构变化的影响。 这些研究将大大扩展我们目前对催产素在年轻大脑中作用的认识，包括 在调节海马发育和突触功能中的潜在作用。此外，结果将奠定 为设计新型、有效和耐受性良好的OXT治疗方案以优化海马 成熟和功能，从而挽救ASD和相关发育障碍中的情景记忆。

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.