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，以儿童期发病为特征，其诊断基于非典型社交/交流发展的核心症状以及重复行为和限制兴趣的存在。除了认知和行为症状外，受影响的个体也有高于预期的医疗状况，包括心血管指标的异常调节。自闭症症状与中枢神经系统的改变有关，包括前额叶皮层和杏仁核——大脑处理情绪和焦虑相关行为的中心区域，在调节自主神经系统（ANS）中起着关键作用。ANS的主要功能是维持生理稳态，这是通过其交感神经和副交感神经子系统之间的动态平衡实现的。这种平衡的破坏在脆性X染色体综合征（FXS）中有很好的记录，至少在自闭症个体的一部分中可以看到。在健康人群中，心率（HR）和心率变异性（HRV）会根据环境以可预测的模式变化，而脆性X和自闭症个体在面对社会和认知压力时表现出静止HR升高、HRV降低和非典型心脏反应性。目前还没有有效的治疗自闭症的方法。ASD的啮齿动物模型使研究这些疾病的潜在原因和支持他们的临床前研究成为可能。然而，治疗发展的一个主要限制是这些模型中缺乏可用于预测临床疗效的强大生理特征。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单倍不全，表现出认知和探索行为障碍，这需要前额叶皮层和杏仁核。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，并将与额杏仁核损伤相关的行为有关。我们还预测，这种ANS失调在受这些疾病影响的人群中会很明显。该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，并测试这些医学上相关的措施是否代表翻译生物标志物，通过预测他们所模拟的疾病的治疗反应，有可能加速药物开发。该学生将比较FXS （Fmr1敲除）和SYNGAP1单倍不全（Syngap杂合突变）大鼠模型中的心脏活动及其调节。由于已知人类心脏反应性会根据环境而变化，因此这些模型将在一系列不同应激源类型和强度的实验条件下测量HR及其变异性。一种可植入的无线电遥测系统将用于记录有意识的、自由活动的大鼠发出的多种生理信号。心血管调节参数在人体数据中的验证。该学生将确定由斯坦菲尔德实验室收集的脆性X和SYNGAP1患者数据中的心血管测量是否显示出与这些条件下的啮齿动物模型相似的动态。

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.