Dopamine and Oxytocin Interactions Underlying Behaviors: Potential Contributions to Behavioral Disorders

Dopamine is an important neuromodulator that exerts widespread effects on the central nervous system (CNS) function. Disruption in dopaminergic neurotransmission can have profound effects on mood and behavior and as such is known to be implicated in various neuropsychiatric behavioral disorders including autism and depression. The subsequent effects on other neurocircuitries due to dysregulated dopamine function have yet to be fully explored. Due to the marked social deficits observed in psychiatric patients, the neuropeptide, oxytocin is emerging as one particular neural substrate that may be influenced by the altered dopamine levels subserving neuropathologic‐related behavioral diseases. Oxytocin has a substantial role in social attachment, affiliation and sexual behavior. More recently, it has emerged that disturbances in peripheral and central oxytocin levels have been detected in some patients with dopamine‐dependent disorders. Thus, oxytocin is proposed to be a key neural substrate that interacts with central dopamine systems. In addition to psychosocial improvement, oxytocin has recently been implicated in mediating mesolimbic dopamine pathways during drug addiction and withdrawal. This bi‐directional role of dopamine has also been implicated during some components of sexual behavior. This review will discuss evidence for the existence dopamine/oxytocin positive interaction in social behavioral paradigms and associated disorders such as sexual dysfunction, autism, addiction, anorexia/bulimia, and depression. Preliminary findings suggest that whilst further rigorous testing has to be conducted to establish a dopamine/oxytocin link in human disorders, animal models seem to indicate the existence of broad and integrated brain circuits where dopamine and oxytocin interactions at least in part mediate socio‐affiliative behaviors. A profound disruption to these pathways is likely to underpin associated behavioral disorders. Central oxytocin pathways may serve as a potential therapeutic target to improve mood and socio‐affiliative behaviors in patients with profound social deficits and/or drug addiction.     

Efficacy of behavioral interventions for reducing problem behavior in persons with autism: An updated quantitative synthesis of single-subject research

Problem or challenging behaviors are highly prevalent among persons with autism and bring along major risks for the individual with autism and his/her family. In order to reduce the problem behavior, several behavioral interventions are used. We conducted a quantitative synthesis of single-subject studies to examine the efficacy of behavioral interventions for reducing problem behavior in persons with autism. Two hundred and thirteen studies representing 358 persons with autism met the inclusion criteria and were included in the statistical analyses. Overall, we found that behavioral interventions were on average effective in reducing problem behavior in individuals with autism, but some interventions were significantly more effective than others. The results further showed that the use of positive (nonaversive) behavioral interventions was increasing over time. The behavioral interventions were on average equally effective regardless of the type of problem behavior that was targeted. Interventions preceded by a functional analysis reduced problem behavior significantly more than interventions not preceded by a functional analysis. Finally, treatment and experimental characteristics, but not participant characteristics, were statistically significant moderators of the behavioral treatment effectiveness.     

Sexual Behavior in Adults with Autism

A survey of the sexual behavior of 89 adults with autism living in group homes in North Carolina found that the majority of individuals were engaging in some form of sexual behavior. Masturbation was the most common sexual behavior. However, person-oriented sexual behaviors with obvious signs of arousal were also present in one third of the sample. The relationship between sexual behavior and demographic variables and other types of behaviors is explored. Information regarding group home sexuality policies and procedures are described.     

Developmental Effects of Oxytocin Neurons on Social Affiliation and Processing of Social Information

Hormones regulate behavior either through activational effects that facilitate the acute expression of specific behaviors or through organizational effects that shape the development of the nervous system thereby altering adult behavior. Much research has implicated the neuropeptide oxytocin (OXT) in acute modulation of various aspects of social behaviors across vertebrate species, and OXT signaling is associated with the developmental social deficits observed in autism spectrum disorders (ASDs); however, little is known about the role of OXT in the neurodevelopment of the social brain. We show that perturbation of OXT neurons during early zebrafish development led to a loss of dopaminergic neurons, associated with visual processing and reward, and blunted the neuronal response to social stimuli in the adult brain. Ultimately, adult fish whose OXT neurons were ablated in early life, displayed altered functional connectivity within social decision-making brain nuclei both in naive state and in response to social stimulus and became less social. We propose that OXT neurons have an organizational role, namely, to shape forebrain neuroarchitecture during development and to acquire an affiliative response toward conspecifics.SIGNIFICANCE STATEMENT Social behavior is developed over the lifetime of an organism and the neuropeptide oxytocin (OXT) modulates social behaviors across vertebrate species, and is associated with neuro-developmental social deficits such as autism. However, whether OXT plays a role in the developmental maturation of neural systems that are necessary for social behavior remains poorly explored. We show that proper behavioral and neural response to social stimuli depends on a developmental process orchestrated by OXT neurons. Animals whose OXT system is ablated in early life show blunted neuronal and behavioral responses to social stimuli as well as wide ranging disruptions in the functional connectivity of the social brain. We provide a window into the mechanisms underlying OXT-dependent developmental processes that implement adult sociality.     

The EL mouse: a natural model of autism and epilepsy

Purpose: Autism is a multifactorial disorder that involves impairments in social interactions and communication, as well as restricted and repetitive behaviors. About 30% of individuals with autism develop epilepsy by adulthood. The EL mouse has long been studied as a natural model of multifactorial idiopathic generalized epilepsy with complex partial seizures. Because epilepsy is a comorbid trait of autism, we evaluated the EL mouse for behaviors associated with autism. Methods: We compared the behavior of EL mice to age‐matched control DDY mice, a genetically related nonepileptic strain. The mice were compared in the open field and in the light–dark compartment tests to measure activity, exploratory behavior, and restricted and repetitive behaviors. The social transmission of food preference test was employed to evaluate social communication. Home‐cage behavior was also evaluated in EL and DDY mice as a measure of repetitive activity. Key Findings: We found that EL mice displayed several behavioral abnormalities characteristic of autism. Impairments in social interaction and restricted patterns of interest were evident in EL mice. Activity, exploratory behavior, and restricted behavior were significantly greater in EL mice than in DDY mice. EL mice exhibited impairment in the social transmission of food preference assay. In addition, a stereotypic myoclonic jumping behavior was observed in EL mice, but was not seen in DDY mice. It is of interest to note that seizure activity within 24 h of testing exacerbated the autistic behavioral abnormalities found in EL mice. Significance: These findings suggest that the EL mouse expresses behavioral abnormalities similar to those seen in persons with autism. We propose that the EL mouse can be utilized as a natural model of autism and epilepsy.     

Brief report: Behavioral adjustment of siblings of children with autism

Existing research studies have shown mixed results relating to the impact upon children of having a sibling with a disability. However, siblings of children with autism may be more at risk than siblings of children with other disabilities. In the present study, data were gathered on 22 siblings of children with autism. These children were rated by their mothers as having more behavior problems and fewer prosocial behaviors than a normative sample. Analysis of variables predicting sibling behavioral adjustment revealed that boys with siblings who have autism, and also those younger than their sibling with autism, engaged in fewer prosocial behaviors. Psychological adjustment of mothers (stress) and the child with autism (behavior problems) were not predictive of sibling behavioral adjustment.     

Inhibition within the nucleus tractus solitarius (NTS) ameliorates environmental exploration deficits due to cerebellum lesions in an animal model for autism

Clinical observations suggest that abnormalities within the cerebellum and/or the cerebellum--cholinergic forebrain connections may be key to explain the severe behavioral deficits and increases in seizures seen in autism. In order to explore functional relationships between brain areas implicated in many of the core behavioral features of autism, experiments utilizing animal models for specific autism-like behaviors have increased in recent years. In the current study, we used a rodent model for the autism-like behavior of environment exploration deficits to examine the role of the cerebellum and its connectivity to the forebrain. In addition, due to the possible common neural pathways between seizures and autism-like behaviors, we explored the possibility for limiting autism-like behaviors via antiseizure brainstem and cerebellar circuitry. In two experiments, adult male rats showed a significant decrease in exploration behavior following developmental cerebellar suction lesions (experiment 1) or i.c.v. saporin injections specifically targeting Purkinje cells, but not after the addition of saporin-induced cholinergic forebrain lesions (experiment 2). In both experiments, the anticonvulsant treatment of inhibition of the medullary nucleus tractus solitarius (NTS) restored exploration behavior to control levels. These findings suggest that specific neuronal populations within the cerebellum are responsible for mediating exploration behavior, and these neuronal populations are similar to the circuitry involved in limbic motor seizures in that they are sensitive to brainstem inhibition. Furthermore, these results suggest this connection could be utilized in order to control behavioral deficits seen in autism with treatments, such as vagal nerve stimulation, which are effective against pharmaco-resistant seizures.     

A New Neurobehavioral Model of Autism in Mice: Pre- and Postnatal Exposure to Sodium Valproate

Autism symptoms, including impairments in language development, social interactions, and motor skills, have been difficult to model in rodents. Since children exposed in utero to sodium valproate (VPA) demonstrate behavioral and neuroanatomical abnormalities similar to those seen in autism, the neurodevelopmental effects of this antiepileptic agent were examined in mice following its pre- or postnatal administration. Exposed pups were evaluated in a battery of neurodevelopmental procedures designed to assess VPA-induced retardation (wherein a behavior fails to mature on schedule), regression (wherein a behavior does mature on time but then deteriorates), or intrusions (wherein normal behaviors are overshadowed by stereotypic or self-injurious behaviors). The resulting observations were interpreted in the context of this new strategy to model autism.     

Animal models of restricted repetitive behavior in autism

Restricted, repetitive behavior, along with deficits in social reciprocity and communication, is diagnostic of autism. Animal models relevant to this domain generally fall into three classes: repetitive behavior associated with targeted insults to the CNS; repetitive behavior induced by pharmacological agents; and repetitive behavior associated with restricted environments and experience. The extant literature provides potential models of the repetitive behavioral phenotype in autism rather than attempts to model the etiology or pathophysiology of restricted, repetitive behavior, as these are poorly understood. This review focuses on our work with deer mice which exhibit repetitive behaviors associated with environmental restriction. Repetitive behaviors are the most common category of abnormal behavior observed in confined animals and larger, more complex environments substantially reduce the development and expression of such behavior. Studies with this model, including environmental enrichment effects, suggest alterations in cortical-basal ganglia circuitry in the development and expression of repetitive behavior. Considerably more work needs to be done in this area, particularly in modeling the development of aberrant repetitive behavior. As mutant mouse models continue to proliferate, there should be a number of promising genetic models to pursue.     

Evidence of a Distinct Behavioral Phenotype in Young Boys With Fragile X Syndrome and Autism

ObjectiveHow does the behavioral expression of autism in fragile X syndrome (FXS + Aut) compare with idiopathic autism (iAut)? Although social impairments and restricted, repetitive behaviors are common to these variants of autism, closer examination of these symptom domains may reveal meaningful similarities and differences. To this end, the specific behaviors comprising the social and repetitive behavioral domains in young children with FXS + Aut and iAut were profiled.MethodTwenty-three male subjects 3 to 5 years old with FXS + Aut were matched by age to a group of 38 boys with iAut. Repetitive behavior was assessed using the Repetitive Behavior Scales-Revised. Social behavior was evaluated using Autism Diagnostic Observation Schedule social item severity scores.ResultsRates of stereotypy, self-injury, and sameness behaviors did not differ between groups, whereas compulsive and ritual behavior scores were significantly lower for subjects with FXS + Aut compared with those with iAut. Those with FXS + Aut scored significantly lower (less severe) than the iAut group on five Autism Diagnostic Observation Schedule measurements of social behavior: gaze integration, quality of social overtures, social smile, facial expressions, and response to joint attention.ConclusionsThe behavioral phenotype of FXS + Aut and iAut are most similar with respect to lower-order (motoric) restricted, repetitive behaviors and social approach, but differ in more complex forms of restricted, repetitive behaviors and some social response behaviors. These findings highlight the phenotypic heterogeneity of autism overall and its unique presentation in an etiologically distinct condition.     

Efficacy of behavioral interventions for reducing problem behavior in persons with autism: a quantitative synthesis of single-subject research

The efficacy of behavioral interventions for problem behavior in persons with autism was reviewed. One hundred and seventeen published articles representing 181 individuals with autism were examined. Articles were selected from 15 journals. Participant, treatment, and experimental variables were evaluated. Three effect sizes were calculated for each article. Behavioral treatments are effective in reducing problematic behaviors in individuals with autism. Type of target behavior and type of treatment did not moderate the average effect of treatment. As measured by percentage of zero data (PZD), three variables were predictive of behavioral suppression beyond that accounted for by behavioral topography and treatment type. Reliability of observation and number of treatment data points were positively related to PZD scores. Treatments based on experimental functional analysis (EFA) produced higher average PZD scores than treatments that did not include an EFA. The implications of the findings, study limitations, and suggestions for future research are discussed.     

Symptom severity and challenging behavior in children with ASD

The prevalence of challenging behaviors in the autism spectrum disorders (ASD) population is often assumed to be high but relatively little research has actually been published on it. Furthermore, challenging behaviors are likely to impede progress in evidence-based treatment programs, such as early intensive behavioral intervention (EIBI). Little or no previous research has evaluated the prevalence of various topographies of challenging behavior in a population of children with ASD receiving EIBI services, nor evaluated the relationship between such behaviors and the severity of ASD symptoms. Using data from the ASD–DC and the ASD–BPC in 84 children with autism receiving EIBI services, the current study conducted a regression analysis of relations between endorsement of challenging behaviors and ASD symptom severity. Results indicated that 94% of the sample reported the presence of challenging behavior, stereotypical behaviors were the most commonly reported, and that the presence of challenging behavior was predicted by ASD severity.     

The teratology of autism

Autism spectrum disorders affect behaviors that emerge at ages when typically developing children become increasingly social and communicative, but many lines of evidence suggest that the underlying alterations in the brain occur long before the period when symptoms become obvious. Studies of the behavior of children in the first year of life demonstrate that symptoms are often detectable in the first 6 months. The environmental factors known to increase the risk of autism have critical periods of action during embryogenesis. Minor malformations that occur frequently in people with autism are known to arise in the same stages of development. Anomalies reported from histological studies of the brain are consistent with an early alteration of development. Congenital syndromes with high rates of autism include somatic that originate early in the first trimester. In addition, it is possible to duplicate a number of anatomic and behavioral features characteristic of human cases by exposing rat embryos to a teratogenic dose of valproic acid at the time of neural tube closure.     

Analysis of Social Interactions as Goal-Directed Behaviors in Children with Autism

An ecological psychology framework that considers the intentions of the child within the child's own social context was used to study the complexity of social interactions of 16 children with autism or Down syndrome. Children were observed in their homes and behaviors were recorded. Records were then analyzed by dividing behavior based on the children's own goals. Goal-directed behaviors were then categorized. Statistical analyses revealed similar social contexts and opportunities to receive bids from others for both groups. Differences in the frequencies and complexities of children's behaviors depended on behavioral intent. Socially intended behaviors were less frequent, less self-initiated, and less complex in children with autism. These findings are discussed as problems of attention and executive function, because social behaviors were more likely to occur secondarily, within the context of another ongoing behavior.     

Autism: The Point of View from Fragile X Studies

The relationship between the fragile X syndrome (FXS) and autism is reviewed. Shortly after the FXS was first described, it was noted that certain behaviors commonly found in afflicted individuals resemble certain features of autism. Research concerning a possible relationship between these conditions is summarized. The outcome of this research indicates that FXS is not a common cause of autism, although the number of individuals with FXS who meet diagnostic criteria for autism is higher than can be accounted for by chance. The major focus of this paper highlights that FXS is a well-defined neurogenetic disease that includes a cognitive behavioral phenotype, and has both a known biological cause and an increasing well-delineated pathogenesis. Autism is a behaviorally defined syndrome whose syndromic boundaries and biological causes are not known. These profound differences complicate comparisons and causal discussions. However, the behavioral neurogenetic information available about FXS suggests certain pathways for future research directed at elucidating the syndrome of autism.     

The relationship between sleep and behavior in autism spectrum disorder (ASD): a review

Although there is evidence that significant sleep problems are common in children with autism spectrum disorder (ASD) and that poor sleep exacerbates problematic daytime behavior, such relationships have received very little attention in both research and clinical practice. Treatment guidelines to help manage challenging behaviors in ASD fail to mention sleep at all, or they present a very limited account. Moreover, limited attention is given to children with low-functioning autism, those individuals who often experience the most severe sleep disruption and behavioral problems. This paper describes the nature of sleep difficulties in ASD and highlights the complexities of sleep disruption in individuals with low-functioning autism. It is proposed that profiling ASD children based on the nature of their sleep disruption might help to understand symptom and behavioral profiles (or vice versa) and therefore lead to better-targeted interventions. This paper concludes with a discussion of the limitations of current knowledge and proposes areas that are important for future research. Treating disordered sleep in ASD has great potential to improve daytime behavior and family functioning in this vulnerable population.     

Behavioral assessment and treatment of self-injurious behavior in autism

Self-injurious behaviors (SIB) are common in individuals who have autism and related developmental disabilities. When an individual engages in SIB, these behaviors frequently become the primary treatment target because of the potential for injury. A thorough behavioral assessment aimed at determining the function of the behaviors is the first step to developing a treatment plan. This article presents a brief background of SIB and a discussion of the behavioral assessment and treatment of these behaviors to familiarize readers with the behavioral perspective on SIB in individuals who have autism and other developmental disabilities.     

Advances in behavioral genetics: mouse models of autism

Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.     

Dynamic limbic networks and social diversity in vertebrates: From neural context to neuromodulatory patterning

Vertebrate animals exhibit a spectacular diversity of social behaviors, yet a variety of basic social behavior processes are essential to all species. These include social signaling; discrimination of conspecifics and sexual partners; appetitive and consummatory sexual behaviors; aggression and dominance behaviors; and parental behaviors (the latter with rare exceptions). These behaviors are of fundamental importance and are regulated by an evolutionarily conserved, core social behavior network (SBN) of the limbic forebrain and midbrain. The SBN encodes social information in a highly dynamic, distributed manner, such that behavior is most strongly linked to the pattern of neural activity across the SBN, not the activity of single loci. Thus, shifts in the relative weighting of activity across SBN nodes can conceivably produce almost limitless variation in behavior, including diversity across species (as weighting is modified through evolution), across behavioral contexts (as weights change temporally) and across behavioral phenotypes (as weighting is specified through heritable and developmental processes). Individual neural loci may also express diverse relationships to behavior, depending upon temporal variations in their functional connectivity to other brain regions (“neural context”). We here review the basic properties of the SBN and show how behavioral variation relates to functional connectivity of the network, and discuss ways in which neuroendocrine factors adjust network activity to produce behavioral diversity. In addition to the actions of steroid hormones on SBN state, we examine the temporally plastic and evolutionarily labile properties of the nonapeptides (the vasopressin- and oxytocin-like neuropeptides), and show how variations in nonapeptide signaling within the SBN serve to promote behavioral diversity across social contexts, seasons, phenotypes and species. Although this diversity is daunting in its complexity, the search for common “organizing principles” has become increasingly fruitful. We focus on multiple aspects of behavior, including sexual behavior, aggression and affiliation, and in each of these areas, we show how broadly relevant insights have been obtained through the examination of behavioral diversity in a wide range of vertebrate taxa.     

Early and adult hippocampal TGF-β1 overexpression have opposite effects on behavior

TGF-β1 is an anti-inflammatory cytokine that is augmented in the brain of autistic patients and that can affect brain development. In this work, we studied the effects of overexpressing TGF-β1 in the dentate gyrus of adult or young mice on behavior. TGF-β1 overexpression during postnatal development led to a long-term decrease in social interaction and to long-term increases in self-grooming and depression-related behaviors. Our analysis shows that these behavioral changes correlate with the long-term downregulation of TGF-β1 and IL-6 expression in the dentate gyrus, as well as to decreases in the mRNA levels of the synaptic protein neuroligin 3 and in the number of Reelin-positive neurons in the dentate gyrus. In contrast, chronic expression of TGF-β1 during adulthood led to transient opposite effects on these behaviors. These results show a central role of hippocampal TGF-β1 in the programming and modulation of social interaction, repetitive behavior and depression-related behavior. Finally, our data suggest a role of hippocampal TGF-β1 and early-life neuroinflammation in the development of the behavioral alterations observed in autism spectrum disorders.