Abstract
BackgroundThe social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients. ASD prevalence is higher in boys, but increasing evidence suggests underdiagnosis and undertreatment in girls. We showed that stress-induced motivational anhedonia is relieved by repeated treatment with fenofibrate (FBR), a peroxisome proliferator-activated receptor α (PPARα) agonist. Here, we used the valproic acid (VPA) model of ASD in rats to examine male and female phenotypes and assess whether FBR administration from weaning to young adulthood relieved social impairments.MethodsMale and female rats exposed to saline or VPA at gestational day 12.5 received standard or FBR-enriched diet from postnatal day 21 to 48–53, when behavioral tests and ex vivo neurochemical analyses were performed. Phosphorylation levels of DARPP-32 in response to social and nonsocial cues, as index of dopamine D1 receptor activation, levels of expression of PPARα, vesicular glutamatergic and GABAergic transporters, and postsynaptic density protein PSD-95 were analyzed by immunoblotting in selected brain regions.ResultsFBR administration relieved social impairment and perseverative behavior in VPA-exposed male and female rats, but it was only effective on female stereotypies. Dopamine D1 receptor signaling triggered by social interaction in the nucleus accumbens shell was blunted in VPA-exposed rats, and it was rescued by FBR treatment only in males. VPA-exposed rats of both sexes exhibited an increased ratio of striatal excitatory over inhibitory synaptic markers that was normalized by FBR treatment.LimitationsThis study did not directly address the extent of motivational deficit in VPA-exposed rats and whether FBR administration restored the likely decreased motivation to operate for social reward. Future studies using operant behavior protocols will address this relevant issue.ConclusionsThe results support the involvement of impaired motivational mechanisms in ASD-like social deficits and suggest the rationale for a possible pharmacological treatment. Moreover, the study highlights sex-related differences in the expression of ASD-like symptoms and their differential responses to FBR treatment.
Highlights
The social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients
Behavioral effects of FBR administration to ASD-like rats In order to verify the presence of social impairments in the valproic acid (VPA) offspring and the effects of FBR treatment, we firstly employed the three-chamber test
Neurochemical effects of FBR administration in ASD-like rats In order to study the neurochemical mechanisms underpinning the impairment in social behavior exhibited by VPA rats and the effects of FBR administration, we focused on the NAc shell (NAcS), a key brain region in the neural circuitry mediating the motivational component of reward behavior [28, 29]
Summary
The social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients. The social motivational theory has suggested that ASD subjects fail to entertain peer relationships because of the lack of reward feelings from social stimuli (social motivation deficit or social anhedonia) [3] In support of this theory, a number of neuroimaging, electrophysiological, and neurochemical data have provided evidence for disrupted rewardseeking tendencies in ASD, emphasizing the involvement of the motivational component of reinforcement processing, and the underlying brain circuitry that includes the ventral striatum, and the nucleus accumbens (NAc) [4]. If proven right, this interpretation would offer a novel potential target for the core symptom domain of social impairments that still lacks effective treatments
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
