The recognition of pain generates negative emotion. In contrast, relief of pain is rewarding. Opioids are commonly used for medical pain relief, but opioids are addictive and can cause physical dependence. The G protein‐coupled inwardly‐rectifying potassium (GIRK) channels, which are activated via signal transduction cascade starting with opioid receptors, are also associated with both of dependence and pain relief. Moreover, a genome‐wide association study suggested genetic polymorphisms close to the cyclic AMP responsive element binding protein (CREB) gene were associated with severity of substance dependence as well as analgesia. Here, we focus on the molecules associated with positive and negative emotions and pain control.

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Pain is “an aversive sensory and emotional experience” (the International Association for the Study of Pain) . Recent brain imaging and neurophysiological studies revealed that the networks underlying pain experience are sub‐divided into three main systems : thalamocortical, anterior cingulate‐insular cortex, and parabrachio‐amygdaloid systems. Concerning the pain‐associated emotion, the anterior cingulate‐insular cortex system is more involved in cognitively perceived negative emotion, While the parabrachio‐amygdaloid system is more linked with the “sentient” subconscious emotion which is more important in the defensive/survival function of the pain. Importantly, these systems undergo robust plasticity in chronic pain, which in turn modulates pain sensitivity, thus forming a total aversive experience of pain.

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Pain experience is strongly affected by emotions, and especially, negative emotions cause more painful perception. And as mechanisms of linking to chronic pain, negative emotions are also important factors. We have been gradually studying the association between negative emotions and painful perception, and we will review these relationship by using clinical symptoms and neuroimaging data. Our studies have been approved by the Hiroshima University ethics committee.

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Autism spectrum disorder (ASD) is recognized as one of the major neuropsychiatric disorders defined as social deficits, repetitive behavior and lack of communication skills. Since the word “spectrum” means “a condition that is not restricted to a specific set of values but can vary, without steps, across a continuum”, patients with ASD showed broad and various phenotypes. Although the past bulk RNAseq studies have succeeded to identify converged pathways, genes, and networks in ASD, these outcomes may reflect the results of major cell‐type alternation but not in minor cell‐type one. Here we introduce a recent technique, single cell RNA‐sequence (scRNA‐seq) , which enables to analyze at a single‐cell resolution. The scRNA‐seq sheds light on minor cell‐types that may be an important factor for ASD pathogenesis. The single cell analysis with bioinformatics, combined with genome editing tools, will become a key player to understand heterogeneous psychiatric disorders, such as ASD.

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The increasing evidence suggests that oxidative stress findings have emerged in recent bioenergetics studies of autism spectrum disorders (ASD) . According to previous research, oxidative stress findings have potential as a clinical target for ASD. A link between ASD and oxidative stress will be explored in the research upcoming.

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It remains unclear how molecular mechanisms contribute to high rates of attention deficit hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) in autism spectrum disorder (ASD) . Considering that adverse childhood experiences (ACEs) are correlated with the symptoms of ADHD and PTSD, and the individuals with ASD tend to experience stressful events in childhood, we hypothesize that ACEs may develop ADHD and PTSD in the individuals with ASD. In this review article, we discuss the associations between ACEs and ADHD/PTSD symptoms in the individuals with ASD focusing on the serotonin transporter gene, SLC6A4, as the shared causative agent.

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Differences in the effects between single‐dose and repeated administrations of oxytocin on autism spectrum disorder (ASD) suggest a time‐course change in efficacy. However, the possibility cannot be examined without a repeatable, objective, and quantitative assessments of the ASD core symptoms. The author and colleagues comprehensively examined our single‐site exploratory and multi‐site confirmatory, double‐blind, placebo‐controlled trials of six weeks intranasal oxytocin in men with ASD. The outcome was statistical representative values of the objectively quantified facial expression intensity during a semi‐structured social interaction in Autism Diagnostic Observation Schedule (ADOS) . The quantitative facial expression analyses on data‐sets from two independent randomized trials successfully find and confirm the therapeutic effect of repeated intranasal administrations of oxytocin on autistic feature in facial expressions during social interaction. Furthermore, for the first time, our study demonstrated a time‐course change in the efficacy : a deterioration during repetitive administration phase and a preservation during post‐treatment phase. Together with our recent study in a combination of clinical and animal studies regarding neurochemical mechanisms of deterioration of oxytocin’s efficacy, the findings are expected to promote further development of optimization of objective, quantitative, and repeatable outcome measure for autistic social deficits and to establish optimized regimen of oxytocin treatment on ASD.

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Dendritic spines, the postsynaptic compartments at excitatory synapses, are capable of changing their shape and size to modulate synaptic transmission. The actin cytoskeleton and a variety of actin‐binding proteins play a critical role in the dynamics of dendritic spines. Abnormalities of spine dynamics are implicated in several psychiatric disorders. Class I myosins are monomeric motor proteins that move along actin filaments using the energy of ATP hydrolysis. Of these class I myosins, myosin Id has been reported to be expressed in neurons, whereas its subcellular localization in neurons remained unknown. The linkage analysis suggests that myosin Id is a potential risk gene for autism spectrum disorder (ASD) . Here, we investigated the subcellular localization of myosin Id and determined the domain responsible for it. We found that myosin Id is enriched in the dendritic spines of primary hippocampal neurons. The mutant form lacking the TH1 domain is less distributed in dendritic spines than is the full‐length form. Taken together, our findings reveal that myosin Id localizes in dendritic spines through the TH1 domain. These results provide the first clues to understand the role of this molecule in the development and pathophysiology of ASD.

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Roundabout (Robo) is one of the axon guidance molecules which has been identified to be expressed in layers Ⅱ/Ⅲ, Ⅴ and Ⅵ in the developing neocortex. Studies have shown that reduced expression of Robo1 is associated with developmental disorders including autism and dyslexia, suggesting that the expression levels of Robo1 is crucial for neuronal differentiation and higher brain function. Over recent years, the roles of Robo1 in the developing neocortex has been examined using molecular and genetic approaches, highlighting its importance in the differentiation of cortical neurons and the formation of the cerebral cortical circuit. Suppression of Robo1 expression in the upper‐layer pyramidal neurons reveal migration delay and ectopic localization of these neurons, where Robo1‐suppressed neurons fail to establish the characteristic inside‐out neuronal distribution. Morphologically, Robo1‐suppressed neurons exhibit changes in their dendritic patterns, especially in the number of apical neurites. In this review, we will present an overview of the function of Robo1 in the developing neocortex and update our knowledge concerning the mechanisms by which a single receptor gene mediates pleiotropic roles in cortical circuit formation.

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