Dysregulation of cardiovascular activity in genetic forms of autism

自闭症谱系障碍(ASD)是一种复杂的神经发育障碍，以童年为特征，根据其不典型的社会/交流发展的核心症状以及存在重复行为和受限兴趣而诊断。除了认知和行为症状外，受影响的个人的医疗状况比率也高于预期，包括心血管措施的异常调节。自闭症症状与中枢神经系统的变化相关，包括前额叶皮质和杏仁核-大脑区域，这些区域对处理情绪和焦虑相关行为至关重要，并在调节自主神经系统(ANS)方面发挥关键作用。ANS的主要功能是维持生理内平衡，这是通过其交感和副交感神经系统之间的动态平衡实现的。这种平衡的破坏在脆性X综合征(FXS)中有很好的记录，至少在一部分自闭症患者中可以看到。在健康人中，心率(HR)和心率变异性(HRV)根据环境按可预测的模式变化，而脆性X和自闭症患者表现出静息心率升高，心率变异性降低，以及对社会和认知压力的非典型心脏反应。目前还没有有效的治疗自闭症的方法。ASD的啮齿动物模型能够研究这些疾病的原因，并支持他们的临床前研究。然而，治疗发展的一个主要限制是在这些模型中缺乏可用于预测临床疗效的强大的生理信号。我们的初步数据表明，两种不同遗传形式的ASD大鼠模型，FXS和SYNGAP1单倍体功能不全，表现出认知和探索行为的损害，需要前额叶皮质和杏仁核。基于这些发现，我们预测ANS失调将出现在我们的大鼠模型中，并将与额叶-杏仁核损伤相关的行为有关。我们还预测，在受这些条件影响的人中，这种ANS失调将是明显的。学生将确定已建立的自闭症啮齿动物模型是否表现出心血管活动的自主神经失调，并测试这些医学相关措施是否代表翻译生物标记物，通过预测他们通过以下目的建模的疾病的治疗反应来加速药物开发：1.学生将比较FXS(Fmr1基因敲除)和SYNGAP1单倍体功能不全(SynGAP杂合突变)大鼠模型中的心脏活动及其调节。由于已知心脏反应性随人体环境而异，心率及其变异性将在这些模型中在一系列实验条件下进行测量，这些条件在应激源的类型和强度上有所不同。植入式无线电遥测系统将被用来记录来自有意识的、自由移动的大鼠的多种生理信号。人体数据中心血管调节参数的验证。这名学生将确定由斯坦菲尔德实验室收集的Fragile X和SYNGAP1患者数据中的心血管测量是否表现出与啮齿动物模型类似的动态变化。

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by childhood onset and diagnosed based on its core symptoms of atypical social/communicative development and by the presence of repetitive behaviours and restricted interests. In addition to its cognitive and behavioural symptoms, affected individuals also have higher than expected rates of medical conditions including abnormal regulation of cardiovascular measures. Autism symptoms correlate with alterations in the central nervous system, including the prefrontal cortex and amygdala - brain regions central to processing emotions and anxiety related behaviours and which have key roles in modulating the autonomic nervous system (ANS). The primary function of the ANS is to maintain physiological homeostasis which is achieved through a dynamic balance between its sympathetic and parasympathetic subsystems. Disruption of this balance is well documented in fragile X syndrome (FXS) and is seen in at least a subset of autistic individuals. Whereas heart rate (HR) and HR variability (HRV) change in predictable patterns according to context in healthy people, fragile X and autistic individuals exhibit elevated resting HR, reduced HRV, and atypical cardiac reactivity in response to social and cognitive stressors.There are currently no effective treatments for autism. Rodent models of ASD enable studies of the causes underlying these disorders and support their preclinical research. However, a major limitation for treatment development is the lack of robust physiological signatures in these models that can be used to predict clinical efficacy. Our preliminary data indicate that rat models of two distinct genetic forms of ASD, FXS and SYNGAP1 haploinsufficiency, exhibit impairments in cognitive and exploratory behaviours that require the prefrontal cortex and amygdala. Based on these findings, we predict that ANS dysregulation will be present in our rat models and will relate to behaviours associated with fronto-amygdalar impairments. We also predict that this ANS dysregulation will be apparent in people affected by these conditions.The student will determine whether established rodent models of autism exhibit autonomic dysregulation of cardiovascular activity and test whether these medically relevant measures represent translational biomarkers, with the potential to accelerate drug development by predicting treatment response for the disorders they model through the following aims:1. The student will compare cardiac activity and its regulation in rat models of FXS (Fmr1 knockouts) and SYNGAP1 haploinsufficiency (Syngap heterozygous mutants). Because cardiac reactivity is known to vary according to context in humans, HR and its variability will be measured in these models across a range of experimental conditions that vary in the type and intensity of stressor. An implantable radio-telemetry system will be used to record multiple physiological signals from conscious, freely moving rats.2. Validation of cardiovascular regulation parameters in human data. The student will determine whether cardiovascular measures in fragile X and SYNGAP1 patient data, collected by the Stanfield lab, display similar dynamics as rodent models of these conditions.