Hyper-emotional neurophysiology in a rat model of autism

Autism is a pervasive neurodevelopmental disorder of unknown etiology, characterized by a spectrum of symptoms of social impairment, abnormal communication, and unusual restricted, inflexible behaviors. Patients also frequently present various levels of sensory, learning, memory and attention abnormalities, anxiety and phobias, in addition to disturbances in gastrointestinal, sleep, metabolic and immune functions, also with higher rates of physical malformations and seizures. There is currently no empirically based consensus on the causes of symptoms and their remarkable heterogeneity. It is also unknown if associated symptoms are directly linked to autism etiology or if they represent parallel comorbidities. In consequence of our incomplete understanding of the disease process, treatment options are vast and not equally efficacious across all diagnosed individuals. Thus, autism today leads to a lifelong disability that requires significant assistance from health care providers, educational systems and family members. Ultimately, improved diagnostic indicators and personalized therapies should allow the autistic individual to live with reduced costs and more independently. Prenatal exposure to compounds such as valproic acid (VPA) has been associated with higher risk for development of autistic features. The teratogenic and neurodevelopmental effects of VPA in humans are replicated in rodents exposed early in embryonic development, at the time neural tube closure. Thus, the VPA-rat has emerged as a well validated model of autism for controlled investigations of the neurobiological basis of autistic-like symptoms and individual response to environmental interventions. Our laboratory previously demonstrated in the model that the primary sensory cortical, frontal cortical, and amygdala microcircuits are hyper-functional in the pup, in parallel to excessive conditioned fear responses, over-generalization of fear to non-conditioned stimuli, and resistance to fear extinction, in the adult. Together with the full range of autistic symptoms and increasing evidence for local hyper-functional connections and cortical minicolumnpathy in patients, data from the VPA model inspired the hypothesis of autism as an Intense World Syndrome. The theory proposes that the polygenetic background of each individual sets the threshold for susceptibility to their prenatal and post natal environments. At the event of a biological insult, be it exogenous such as VPA-exposure, or genetic, such as a rare set of polymorphisms, a cascade of molecular events would lead to hyper-plastic and hyper-reactive neural microcircuits creating a hyper-functional endophenotype. Depending on the developmental trajectory of each individual, this would lead to abnormalities in four dimensions: hyper-attention, hyper-memory and hyper-perception, and hyper-emotionality. Different patterns of hyper-functional outcomes in each individual would then create a fragmented, intense and even aversive experience of the world, and explain the wide heterogeneity in symptom severity and most, if not all, characteristics of autistic people. Thus, inherent to the theory is the description of autistic individuals as highly biologically sensitive and thus that a predictable, positive, safe and calm environment is an essential feature of early postnatal life for positive outcomes in the child. For my doctoral dissertation, I addressed if embryonic exposure to VPA in the rat leads to hyper-functional emotion system, and if this leads to differential response of individuals to postnatal environment. In Chapter 1, I introduce the clinical characteristics of autism and the brain systems involved in emotion and cognition through modulation of fear, anxiety learning and memory. Then I introduce the research rationale for this project. In Chapter 2, I present our published manuscript describing physical malformations, and other teratogenic and developmental health effects in the VPA-rat. This study further validates the VPA-rat as a model of effects in humans, and summarizes important outstanding questions in the VPA-model, in view of the variability in protocols for model generation. We emphasize that such general health parameters could serve as indicators of the precise time and location of toxic event, and thus as potential predictors of differential symptom dimensions and severities. In Chapter 3, I present our study of predictability in the environment of VPA animals as an essential feature for beneficial effects of enrichment, on autism-like hyper-emotionality. This study provides an elegant and computationally accessible method for multivariate analysis of group effects and individual-based effects. In support of the Intense World Theory, our results suggest that VPA-exposed animals are particularly sensitive to their environment, and point to the hippocampus and amygdala as candidate targets of environmental enrichment predictability effects in reducing fear and anxiety in certain VPA exposed individuals. Finally, in Chapter 4, I present some concluding remarks on the implications of this project and future perspectives.