External self-representations improve self-awareness in a child with autism.

We have previously suggested that the social symptoms of autism spectrum disorder (ASD) could be caused in part by a dysfunctional mirror neuron system (MNS). Since the recursive activity of a functioning MNS might enable the brain to integrate visual and motor sensations into a coherent body schema, the deficits in self-awareness often seen in ASD might be caused by the same mirror neuron dysfunction. CL is an autistic adolescent who is profoundly fascinated with his reflection, looking in mirrors at every opportunity. We demonstrate that CL's abnormal gait improves significantly when using a mirror for visual feedback. We also show that both the fascination and the happiness that CL derives from looking at a computer-generated reflection diminish when a delay is introduced between the camera input and screen output. We believe that immediate, real-time visual feedback allows CL to integrate motor sensations with external visual ones into a coherent body schema that he cannot internally generate, perhaps due to a dysfunctional MNS.

Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival.

Huntington's disease (HD) is caused by an autosomal dominant polyglutamine expansion mutation of Huntingtin (HTT). HD patients suffer from progressive motor, cognitive, and psychiatric impairments, along with significant degeneration of the striatal projection neurons (SPNs) of the striatum. HD is widely accepted to be caused by a toxic gain-of-function of mutant HTT. However, whether loss of HTT function, because of dominant-negative effects of the mutant protein, plays a role in HD and whether HTT is required for SPN health and function are not known. Here, we delete Htt from specific subpopulations of SPNs using the Cre-Lox system and find that SPNs require HTT for motor regulation, synaptic development, cell health, and survival during aging. Our results suggest that loss of HTT function in SPNs could play a critical role in HD pathogenesis.

Dynamically Timed Stimulation of Corticolimbic Circuitry Activates a Stress-Compensatory Pathway.

BACKGROUND: The prefrontal cortex plays a critical role in regulating emotional behaviors, and dysfunction of prefrontal cortex-dependent networks has been broadly implicated in mediating stress-induced behavioral disorders including major depressive disorder. METHODS: Here we acquired multicircuit in vivo activity from eight cortical and limbic brain regions as mice were subjected to the tail suspension test (TST) and an open field test. We used a linear decoder to determine whether cellular responses across each of the cortical and limbic areas signal movement during the TST and open field test. We then performed repeat behavioral testing to identify which brain areas show cellular adaptations that signal the increase in immobility induced by repeat TST exposure. RESULTS: The increase in immobility observed during repeat TST exposure is linked to a selective functional upregulation of cellular activity in infralimbic cortex and medial dorsal thalamus, and to an increase in the spatiotemporal dynamic interaction between these structures. Inducing this spatiotemporal dynamic using closed-loop optogenetic stimulation is sufficient to increase movement in the TST in stress-naive mice, while stimulating above the carrier frequency of this circuit suppressed movement. This demonstrates that the adaptations in infralimbic cortex-medial dorsal thalamus circuitry observed after stress reflect a compensatory mechanism whereby the brain drives neural systems to counterbalance stress effects. CONCLUSIONS: Our findings provide evidence that targeting endogenous spatiotemporal dynamics is a potential therapeutic approach for treating stress-induced behavioral disorders, and that dynamics are a critical axis of manipulation for causal optogenetic studies.

Intact Hedonic Responses to Sweet Tastes in Autism Spectrum Disorder.

The Sweet Taste Test (STT) is a standardized measure designed to index the ability to detect differences in sweet tastes (sweet taste sensitivity) and hedonic responses to sweet tastes (sweet taste liking). Profiles of response on the STT suggest enhanced hedonic responses to sweet tastes in psychiatric disorders characterized by dysfunctional reward processing systems, including binge-eating disorders and substance use disorders, and a putative mechanism governing STT responses is the brain opioid system. The present study examined STT responses in 20 adults with autism spectrum disorder (ASD) and 38 healthy control adults. There were no differences in sweet taste sensitivity or hedonic response to sweet tastes between the ASD and control groups. Within the ASD sample, ASD symptom severity was associated with sweet taste sensitivity, but not hedonic response to sweet taste. Results may ultimately shed light on brain opioid system functioning in ASD.

Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards.

BACKGROUND: There has been significant progress in identifying genes that confer risk for autism spectrum disorders (ASDs). However, the heterogeneity of symptom presentation in ASDs impedes the detection of ASD risk genes. One approach to understanding genetic influences on ASD symptom expression is to evaluate relations between variants of ASD candidate genes and neural endophenotypes in unaffected samples. Allelic variations in the oxytocin receptor (OXTR) gene confer small but significant risk for ASDs for which the underlying mechanisms may involve associations between variability in oxytocin signaling pathways and neural response to rewards. The purpose of this preliminary study was to investigate the influence of allelic variability in the OXTR gene on neural responses to monetary rewards in healthy adults using functional magnetic resonance imaging (fMRI). METHODS: The moderating effects of three single nucleotide polymorphisms (SNPs) (rs1042778, rs2268493 and rs237887) of the OXTR gene on mesolimbic responses to rewards were evaluated using a monetary incentive delay fMRI task. RESULTS: T homozygotes of the rs2268493 SNP demonstrated relatively decreased activation in mesolimbic reward circuitry (including the nucleus accumbens, amygdala, insula, thalamus and prefrontal cortical regions) during the anticipation of rewards but not during the outcome phase of the task. Allelic variation of the rs1042778 and rs237887 SNPs did not moderate mesolimbic activation during either reward anticipation or outcomes. CONCLUSIONS: This preliminary study suggests that the OXTR SNP rs2268493, which has been previously identified as an ASD risk gene, moderates mesolimbic responses during reward anticipation. Given previous findings of decreased mesolimbic activation during reward anticipation in ASD, the present results suggest that OXTR may confer ASD risk via influences on the neural systems that support reward anticipation.

Developmental trajectories of abuse--an hypothesis for the effects of early childhood maltreatment on dorsolateral prefrontal cortical development.

The United States has a high rate of child maltreatment, with nearly 12 in 1000 children being victims of abuse or neglect. Child abuse strongly predicts negative life outcomes, especially in areas of emotional and mental health. Abused children are also more likely than their peers to engage in violence and enter the juvenile justice system, as well as to become abusive parents themselves. Research has shown that child abuse and trauma can lead to decreased hippocampal volume, which could be indicative of abnormal hippocampal development. Hippocampal development appears to directly affect the development of the dorsolateral prefrontal cortex, a brain area responsible for emotion regulation, cognitive reappraisal, and general executive function. Therefore, I hypothesize that if child abuse results in abnormal hippocampal development, which leads to abnormal dorsolateral prefrontal cortex development, many of the correlated risk factors of child abuse, such as emotionally-laden parenting and unfavorable cognitive distortions regarding children's behaviors, may be in part caused by underdevelopment or abnormal functioning of the dorsolateral prefrontal cortex, as a function of the individual's own experiences with abuse during childhood. If this hypothesis is supported with future research, more targeted, successful, and cost-effective prevention and treatment protocols could ensue. For instance, programs that have been empirically shown to increase the activity of the dorsolateral prefrontal cortex, such as cognitive behavioral therapy, could be effective in decreasing the incidence of intergenerational transfer of abuse.

A biochemical rationale for the interaction between gastrointestinal yeast and autism.

Autism is a disorder characterized by difficulty with social interactions, difficulty expressing empathy and intimacy and, in many cases, mild to severe language and learning deficits. Current estimates suggest autism now affects approximately one in 88 children, with rates increasing rapidly, making autism one of the most common and devastating developmental disorders. This trend is especially alarming considering that a cause for this disorder has yet to be discovered, nor are there successful biological treatments. Here a possible biochemical etiology is proposed for a certain spectrum of autism based on a reaction between propionic acid and ammonia released by Candida albicans in the gastrointestinal tract. A reaction between ammonia and propionic acid should result in the production of beta-alanine, a chemical similar in composition to gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter which has been shown to be present in higher quantities in autistic patients. Assuming beta-alanine is able to cross the blood-brain barrier, beta-alanine would be used in the brain as a partial antagonist, blocking the receptor sites for GABA, thus facilitating the production of more GABA to achieve equilibrium. An excess of GABA has been proposed as a possible contributor to autism. Further research should be conducted with this hypothesis to determine whether the chemical reaction in the human body between propionic acid and ammonia does in fact produce a chemical structurally and functionally similar to beta-alanine, as well as how this product affects the brain. Positive conclusions from this follow-on research could result in a preventative screening test for sensitivity to propionic acid and gastrointestinal yeast, thus slowing the progression of this type of autism. A more targeted treatment for children already diagnosed with autism could also result.