Final Report Summary - SOCIALBRAIN (The young social brain at work: from neurobiology to innovative pharmacotherapies for autism spectrum disorders)
SCIENTIFIC BACKGROUND
Autism spectrum disorders (ASD) are among the most severe psychiatric disorders in childhood in terms of prevalence, outcome, impact on families and cost to society. Social dysfunctions are a core, disabling symptom of ASD. Since the neurobiology of social behavior is largely unknown, there are no drugs available to treat social dysfunctions in ASD.
PROJECT OBJECTIVES
The general aim of this project was to shed light on the neural underpinnings of normal and aberrant social behavior at young age, by investigating the neurobiology of social behavior in laboratory animals, in physiological and impaired conditions. In particular, this project focused on the most characteristic social activity displayed by young mammals: social play behavior. Social play is highly pleasurable and is essential for proper development, both in young rats and human children. Importantly, social play is highly impaired in ASD children. Although the neurobiology of social play is largely unknown, neurotransmitters involved in positive emotions and motivations, such as endogenous opioids, endocannabinoids and dopamine, positively modulate social play. On this basis, the specific objectives of this project were: 1. identify the neural circuits of social play in young rats; 2. investigate whether drugs that increase social play ameliorate experimentally-induced impairments in social behavior in rat models of social dysfunction that strongly resemble ASD.
DESCRIPTION OF THE MAIN RESULTS ACHIEVED
The studies performed in the first and second year of the project have revealed important roles for cannabinoid, opioid, dopaminergic, noradrenergic and serotonergic neurotransmission in social play. This is in keeping with the rewarding properties of social play, as these neurotransmitter systems have been widely implicated in the positive subjective properties of food, sex and drugs. In-depth analysis of the underlying neural substrates has identified the nucleus accumbens as a site of action for the stimulating effects of mu-opioid receptor agonists on social play behavior. Furthermore, analysis of immediate early gene expression patterns after social play revealed activation of limbic corticostriatal pathways during social play. Based on these data, pharmacological inactivation studies have subsequently confirmed the importance of the prelimbic cortex, medial orbitofrontal cortex and nucleus accumbens core for social play.
The studies performed in the third year of the project showed that early embryonic exposure to valproic acid in rats provides a good model for specific aspects of ASD and is a valuable tool to explore potential pharmacological targets for this disease. In particular, we found that rats prenatally exposed to valproic acid have a behavioral phenotype that resembles both the core and associated symptoms displayed by ASD patients: deficits in social communication, altered social interaction and stereotyped behavior, together with increased anxiety, and deficits in cognitive processes. Interestingly, most of these behavioral alterations appear already at early developmental age. An in-depth analysis of the substrates underlying the altered behavioral profile displayed by rats prenatally exposed to valproic acid revealed that these animals show changes in the brain endocannabinoid system, in brain cholesterol metabolism, in glia components and in gut-nerve-microbiome-brain interaction. The studies performed in the last year of the project showed that drugs acting on the endocannabinoid system can correct several behavioral impairments displayed by adolescent and adult rats prenatally exposed to valproic acid, thus providing preclinical support to the potential use of these compounds in ASD.
CONCLUSIONS AND POTENTIAL IMPACT
By focusing on social dysfunctions as a crucial phenotype in ASD, this project investigated neurobiological aspects of ASD that cannot be studied in humans, in order to 1. understand the abnormal social behaviors that characterize ASD; 2. provide novel drug targets to treat social dysfunctions in ASD. By using a multidisciplinary approach that encompasses behavioral, biochemical and anatomical levels of analysis, this project has provided important knowledge on the brain areas and neurotransmitter systems underlying social play behavior, that is the most characteristic social behavior displayed by young mammals and is highly impaired in ASD. This project also tested the intriguing possibility that drugs that increase social play behavior remediate experimentally-induced impairments in social behavior in a validated rodent model of social dysfunction. This proposal will have the following impact: 1) elucidating the neural organization of social play in adolescent rats will help to understand the neurobiology of social behavior in children; 2) investigating the effects of drugs that increase social play in rat models of abnormal social behavior will provide novel pharmacological targets to treat social dysfunctions.
Contact: viviana.trezza@uniroma3.it
Autism spectrum disorders (ASD) are among the most severe psychiatric disorders in childhood in terms of prevalence, outcome, impact on families and cost to society. Social dysfunctions are a core, disabling symptom of ASD. Since the neurobiology of social behavior is largely unknown, there are no drugs available to treat social dysfunctions in ASD.
PROJECT OBJECTIVES
The general aim of this project was to shed light on the neural underpinnings of normal and aberrant social behavior at young age, by investigating the neurobiology of social behavior in laboratory animals, in physiological and impaired conditions. In particular, this project focused on the most characteristic social activity displayed by young mammals: social play behavior. Social play is highly pleasurable and is essential for proper development, both in young rats and human children. Importantly, social play is highly impaired in ASD children. Although the neurobiology of social play is largely unknown, neurotransmitters involved in positive emotions and motivations, such as endogenous opioids, endocannabinoids and dopamine, positively modulate social play. On this basis, the specific objectives of this project were: 1. identify the neural circuits of social play in young rats; 2. investigate whether drugs that increase social play ameliorate experimentally-induced impairments in social behavior in rat models of social dysfunction that strongly resemble ASD.
DESCRIPTION OF THE MAIN RESULTS ACHIEVED
The studies performed in the first and second year of the project have revealed important roles for cannabinoid, opioid, dopaminergic, noradrenergic and serotonergic neurotransmission in social play. This is in keeping with the rewarding properties of social play, as these neurotransmitter systems have been widely implicated in the positive subjective properties of food, sex and drugs. In-depth analysis of the underlying neural substrates has identified the nucleus accumbens as a site of action for the stimulating effects of mu-opioid receptor agonists on social play behavior. Furthermore, analysis of immediate early gene expression patterns after social play revealed activation of limbic corticostriatal pathways during social play. Based on these data, pharmacological inactivation studies have subsequently confirmed the importance of the prelimbic cortex, medial orbitofrontal cortex and nucleus accumbens core for social play.
The studies performed in the third year of the project showed that early embryonic exposure to valproic acid in rats provides a good model for specific aspects of ASD and is a valuable tool to explore potential pharmacological targets for this disease. In particular, we found that rats prenatally exposed to valproic acid have a behavioral phenotype that resembles both the core and associated symptoms displayed by ASD patients: deficits in social communication, altered social interaction and stereotyped behavior, together with increased anxiety, and deficits in cognitive processes. Interestingly, most of these behavioral alterations appear already at early developmental age. An in-depth analysis of the substrates underlying the altered behavioral profile displayed by rats prenatally exposed to valproic acid revealed that these animals show changes in the brain endocannabinoid system, in brain cholesterol metabolism, in glia components and in gut-nerve-microbiome-brain interaction. The studies performed in the last year of the project showed that drugs acting on the endocannabinoid system can correct several behavioral impairments displayed by adolescent and adult rats prenatally exposed to valproic acid, thus providing preclinical support to the potential use of these compounds in ASD.
CONCLUSIONS AND POTENTIAL IMPACT
By focusing on social dysfunctions as a crucial phenotype in ASD, this project investigated neurobiological aspects of ASD that cannot be studied in humans, in order to 1. understand the abnormal social behaviors that characterize ASD; 2. provide novel drug targets to treat social dysfunctions in ASD. By using a multidisciplinary approach that encompasses behavioral, biochemical and anatomical levels of analysis, this project has provided important knowledge on the brain areas and neurotransmitter systems underlying social play behavior, that is the most characteristic social behavior displayed by young mammals and is highly impaired in ASD. This project also tested the intriguing possibility that drugs that increase social play behavior remediate experimentally-induced impairments in social behavior in a validated rodent model of social dysfunction. This proposal will have the following impact: 1) elucidating the neural organization of social play in adolescent rats will help to understand the neurobiology of social behavior in children; 2) investigating the effects of drugs that increase social play in rat models of abnormal social behavior will provide novel pharmacological targets to treat social dysfunctions.
Contact: viviana.trezza@uniroma3.it