A potential mechanistic role for neuroinflammation in reward processing impairments in autism spectrum disorder

Abstract

Accumulating evidence suggests that autism spectrum disorder (ASD) may be conceptualized within a framework of reward processing impairments. The "Social Motivation Theory of Autism" posits that reduced motivation to interact with people and decreased pleasure derived from social interactions may derail typical social development and contribute to the emergence of core social communication deficits in ASD. Neuroinflammation may disrupt the development of mesolimbic dopaminergic systems that are critical for optimal functioning of social reward processing systems. This neuroinflammation-induced disturbance of mesolimbic dopaminergic functioning has been substantiated using maternal immune activation rodent models whose offspring show aberrant dopaminergic corticostriatal function as well as behavioral characteristics of ASD model systems. Preclinical findings are in turn supported by clinical evidence of increased mesolimbic neuroinflammatory responses in individuals with ASD. This review summarizes evidence for reward processing deficits and neuroinflammatory impairments in ASD and examines how immune inflammatory dysregulation may impair the development of dopaminergic mesolimbic circuitry in ASD. Finally, future research directions examining neuroinflammatory effects on reward processing in ASD are proposed.

The Dopamine Hypothesis of Autism Spectrum Disorder Revisited: Current Status and Future Prospects

“…Nevertheless, the observations regarding the general dysfunction of the reward circuitry in individuals with ASD [13], along with the positive results of OXT administration in murine models [28,29], prompted the use of OXT as a therapeutic means in individuals with ASD. While some trials showed a promising beneficial effect of OXT on social behavior via modulation of the reward pathway [33][34][35], several meta-analyses failed to demonstrate a clear-cut benefit of OXT over placebo in alleviating autistic core symptoms [36][37][38].…”

“…The need for novel therapeutics remains acute as knowledge of new molecular targets has yet to be translated into clinical practice [62]. However, as new insights into the dopamine signaling anomalies in ASD stem from animal models [70][71][72][73][74][75], as well as neuroimmune theoretical frameworks [13,76,77], novel treatment approaches emerge.…”

“…The SMT of ASD has gained ever-increasing endorsement over the last years [10, 11], leading Abrams et al [12] to theorize that the brain’s reward system dysfunction provides “a stable brain signature of ASD.” Indeed, accumulating evidence suggests that ASD may be conceptualized within a framework of reward processing impairments [13]. Given its role as a reward attribution node, the mesolimbic circuit is regarded as a critical region in a recently proposed unified circuit for social behavior [14].…”

Dopaminergic Gene Dosage in Autism versus Developmental Delay: From Complex Networks to Machine Learning approaches

“…Research on putative causal aspects that conduct to the different manifestations of ASD remains a priority. The role of dopaminergic neurotransmission and its involvement in the causal pathway of ASD deserves attention in this regard (Ayano, 2016;Greene, Walsh, Mosner, & Dichter, 2018;Pavăl, 2017). For example, disruptions in the nigrostriatal pathway, classically linked to motor functions, has been proposed as a potential contributing cause of some motor repetitive behaviours in ASD whereas disturbances in the mesocorticolimbic pathway, involved in reward and cognitive related functions, may lead to social cognitive an affective impairments, (Fernández, Mollinedo-Gajate, & Peñagarikano, 2018;Supekar et al, 2018).…”

Microbiota‐gut‐brain axis as a regulator of reward processes

“…There has been an increasing emphasis on the contribution of factors outside the brain in regulating central processes. Indeed, a growing body of research focuses on the ability of both the endocrine and the immune system on modulating reward processes (Adam & Epel, 2007;Anisman et al, 1996;Goeders, 2002;Greene et al, 2019;Montesinos et al, 2016;Ye et al, 2001). Over the past decade a new player has emerged as another key factor in sculpting reward circuits across the lifespan, namely, the gut microbiome, which encompasses the trillions of bacteria in our gut.…”