Dysregulation of cardiovascular activity in genetic forms of autism

点击翻译按钮获取中文摘要

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.