Postnatal Oxytocin Treatment and Cognitive Function in Fragile X

自闭症谱系障碍(ASD)是一种常见的异质性神经发育障碍。 智力残疾的发病率。这包括难以形成插曲的个人叙事、记忆 对于有序的思考和组织未来的行为至关重要。因此，间歇性记忆缺陷被认为是 与自闭症相关的认知困难的主要因素。许多大脑变化是潜在的异常 ASD在儿童时期出现，提示有可能针对大脑采取有效的治疗策略 成熟。一种候选的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能力。OXT极大地促进了突触的可塑性，但 对于出生后OXT治疗对学习的可能持久影响，很少有实验考虑 也没有对情节记忆的影响进行分析。我们使用鼻腔OXT(IOXT)研究了这种可能性。 脆性X综合征Fmr1KO小鼠模型的治疗，以及分析“什么”的新范式， 何时何地进行编码。我们的初步结果表明，在Fmr1 KOS iOXT处理期间 出生后第二周(P7-13)完全挽救海马区CA1区长时程增强，物体定位 成年后评估的记忆、物体身份(什么)学习和社会认可度(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，即有限的早期生命牛治疗可以 对自闭症认知功能的一个关键因素进行终生挽救。他们还提出了关于 IOXT对行为的广泛影响和涉及的机制；这些问题将在 建议进行的研究。目的1研究将测试iOXT对雄性和雌性Fmr1KO小鼠出生后的治疗 对情景记忆、社会识别和刻板印象的三个主要组成部分的编码 成年后评估的行为，以及影响是否取决于天然牛粪排出。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、突触蛋白和信号的分析以及神经元的测量 测试出生后iOXT治疗是否使不同海马区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将测试早期生命iOXT的假设 导致海马区突触营养因子受体(EGFR，TrkB)的激活，从而表明 OXT对结构成熟变化影响的直接途径。总的来说，拟议的研究将极大地 扩展我们目前对OXT在年轻大脑中的作用的知识，包括潜在的关键角色 调节海马体发育和突触功能。此外，结果将为以下工作奠定基础 设计新颖的早期生命疗法，以优化海马体的成熟和功能，并拯救 自闭症及相关发育障碍患者情节记忆的编码。

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.