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（Autism Spectrum Disorder， ASD）是一种普遍存在的异质性神经发育障碍