|dc.description.abstract||Autism spectrum disorder (ASD), which affects circa 1% of the global population, is characterized by impairments in social communication, interaction, language disability, sensory anomalies, repetitive behaviours, and intellectual disability. Aberrant feeding behaviour is a common comorbidity of ASD. ASD individuals often demonstrate extreme food selectivity, refusal, dependence on few very particular food items, neophobia etc. which can lead to nutritional deficiencies affecting development. However, the underlying neurophysiological mechanisms of aberrant food intake in ASD are not well known.
Prenatal exposure to the antiepileptic drug, valproic acid (VPA), leads to autism. The prenatally VPA-exposed rats are model organisms to study ASD and they show ASD-like symptoms of, among others, elevated anxiety and decreased social interaction. Importantly, very little is known about appetite control in these animals. The overall goal of the studies included in this thesis was to identify potential feeding behavioural anomalies and associated neuromolecular changes in the VPA rat model of ASD. We thus hypothesize that ASD is associated with abnormal appetite and reward-driven feeding.
The key factors shaping consumption involve hunger (determines search for calories), satiation (underpins termination of feeding) and reward (consumption for the 'pleasantness' of food, regardless of the energy requirements). Thus, in the first Specific Aim of this thesis, the hunger processing in the VPA animals was investigated. The ad libitum intake of ‘bland’ standard laboratory chow was assessed in VPA versus non-VPA controls maintained continuously on this diet. The adult VPA rats ate less ‘bland’ chow than healthy controls did, and it was coupled with a moderately lower body weight than that of the controls. VPA rats also ate less of the standard chow after acute food deprivation. There was an aberrant change in c-Fos immunoreactivity in key brain sites that govern food intake, including the hypothalamic and brain stem areas, in the VPA animals in contrast to the healthy controls upon food deprivation, which indicates differences in neural processing of hunger in autism. This finding is further supported by a lack of change in expression patterns of feeding-related genes
(including oxytocin (OT), Agouti-related protein (AgRP) and mu opioid receptor (MOR)) upon hunger in the hypothalamus in the VPAs as opposed to the controls. Cumulatively, these findings suggest that hunger processing is altered in the VPA rats.
In the second Specific Aim of this project, intake of rewarding diets in the VPA rats was examined to address whether ASD affects pleasure-driven consumption. In episodic meal consumption paradigms, i.e., in scenarios in which energy non-deprived animals were given a brief and non-habitual access to diets that differ in palatability, the VPA rats were found to consume elevated amounts of tasty liquid and solid diets. These data suggest that VPA rats display not only altered energy homeostatis processing (as shown in Specific Aim 1), but also indicate changes in the regulation of eating for palatability.
Considering the abnormal OT signalling in autism and the fact that OT decreases feeding for energy and feeding for palatability, the third Specific Aim addressed whether VPA rats exhibit heightened sensitivity to exogenously administered OT, a peptide known for its anorexigenic properties. Intraperitoneal OT treatment was found to reduce episodic intake of palatable diets as well as post-energy deprivation intake of ‘bland’ chow; however, the dose needed to generate hypophagia was lower in VPAs than in controls. c-Fos immunohistochemistry revealed that the lower OT dose found to be anorexigenic in VPA rats, was sufficient to affect brain activation in a manner typical for hypophagia, whereas in healthy control rats, it did not induce significant c-Fos changes.
Importantly, OT is involved also in the process of avoidance of toxic foods, i.e., it facilitates the development of a conditioned taste aversion (CTA). Therefore, the goal of the Specific Aim 4, was to assess whether VPA animals display atypical taste aversion acquisition. It was found that VPAs failed to develop aversion to a standard dose of LiCl that induces a CTA in healthy non-ASD controls. In line with the outcome of the behavioural study, the immunohistochemical analysis revealed lower c-Fos-OT colocalization in the PVN in VPAs and a less pronounced broader CTA circuit c-Fos response in ASD animals compared to controls after LiCl treatment.
Taken together, evidence presented in this thesis shows that ASD is associated with abnormal appetite in VPA rats and it offers an insight into the neural basis of this phenomenon. The VPA animals show a slight decrease in intake of standard ‘bland’ chow, an elevated drive to consume palatable tastants, and resistance to taste aversion. These anomalies in feeding behaviours are underpinned by distinct changes in brain activation and gene expression patterns, as well as altered sensitivity to anorexigenic properties of OT, a neuropeptide known to affect other symptoms of ASD, from social deficits to anxiety.||