In this review, we focus on “sperm aging” in order to understand the etiology of neurodevelopmental disorders such as autism spectrum disorder, which have been on the rise in recent years. Sperm cells not only supply half of the genome as the origin of life, but can also transmit additional information by introducing epigenetic changes (“epi‐mutations”) such as DNA methylation, histone modification, and microRNAs. In fact, using mice as a model, we have elucidated the molecular mechanisms by which sperm DNA hypomethylation, which occurs as the father ages, affects the brain development of the offspring in the next generation. Understanding how epi‐mutations in sperm cause diseases and disorders in the next generation will contribute to the development of new treatments and prevention methods for neurodevelopmental disorders.

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Current advances of single‐cell resolution analyses such as “single‐cell RNA sequencing (scRNA‐seq) ”, followed by chromatin structure (chromatin accessibility) analysis by “ATAC‐seq”, cell membrane (surface) protein analysis by “CITE‐seq”, and “gene expression analysis with spatial gene expression information on the tissue sections” enable us to realize multimodal omics analysis for neurodevelopmental and neuropsychiatric disorders. Combined with other methods such as 3D brain organoids, these techniques have discovered a better understanding of in vivo gene functions and pathophysiology of human brain diseases. These techniques have been explained the previously unknown molecular and cellular‐specific mechanism of neuropsychiatric and neurodevelopmental disorders. In this review, we introduce the latest findings of autism spectrum disorder (autism) and novel coronavirus infection (COVID‐19) from the single‐cell analysis.

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Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety‐related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC→pPVT neurons and increased inhibitory input drive from low‐threshold‐spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC→pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific medial prefrontal cortex excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience.

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is mainly characterized by impairment of sociability, deficits of communication, and restricted/repeated behaviors and interests. Parents and caregivers of patients with ASD need understanding and skills that correspond to the characteristics of the patient. Genetic and environmental causes of ASD have been investigated, but the pathophysiology and treatment of ASD have not yet been thoroughly defined. In this article, we focus on activating the mammalian/mechanistic target of rapamycin (mTOR) signaling pathway that is one of pathophysiology in hereditary disease with ASD. We introduce the animal studies and clinical studies associated with the mTOR signaling pathway including the results of our studies. Furthermore, we describe the effect of early intervention for patients with ASD and prospects for the future ASD research. No potential conflicts of interest were disclosed.

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Discrepancies in the efficacy between single‐dose and repeated administrations of oxytocin on autism spectrum disorder (ASD) indicate a time‐course change in efficacy. However, the hypothesis cannot be tested without a repeatable, objective, and quantitative measurement of the core symptoms of ASD. The author’s research group comprehensively examined our single‐site exploratory (n=18, crossover) and multi‐site confirmatory (n=106, parallel‐group) , 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 from two independent clinical trials successfully detect and verify the therapeutic effect of repeated administrations of intranasal oxytocin on autistic feature in facial expressions during social interaction. Furthermore, for the first time, the recent 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 studies regarding neural and molecular 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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Depression is a disorder that is prone to relapse and recurrence, and a therapeutic strategy is needed after acute treatment. Especially in treatment‐resistant depression, the establishment of continuous / maintenance therapy (hereinafter referred to as maintenance therapy) to prevent relapse / recurrence is an urgent issue. Repetitive transcranial magnetic stimulation (rTMS) is a non‐invasive technique that stimulates the cerebral cortex and modifies its excitability, and has been demonstrated to be effective in treatment‐resistant depression from several clinical trials and meta‐analyses to date. A meta‐analysis of the long‐term effects of rTMS therapy has shown that maintenance rTMS therapy is useful as a treatment option to prevent relapse and recurrence after acute rTMS therapy. The authors’ group delivered 6 weeks of acute rTMS therapy to patients with treatment‐resistant depression and introduced 12 months of maintenance rTMS therapy for 2 patients in remission and reported the usefulness of maintenance rTMS therapy. Finally, we give an overview of a multicenter, prospective, non‐randomized longitudinal study to aim at standardizing and insuring maintenance rTMS therapy, which is currently under preparation.

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One of the pathophysiologies of depression is the neuroplasticity hypothesis, and rTMS is precisely a physical therapy that exerts its therapeutic effects by neuromodulating the neuroplasticity of brain networks. Previous studies have suggested that GABA, NMDA, AMPA, and BDNF are involved in the therapeutic mechanism of rTMS at the molecular level. At the neuroimaging level, functional connectivity between the DLPFC and subgenual anterior cingulate cortex, within the default mode network and central executive network, and between the left DLPFC and striatum as measured by resting‐state functional MRI are thought to be involved. In this article, the neurobiological mechanisms of rTMS for depression, including the findings of rTMS research conducted by the author, and the future direction and prospects of rTMS are discussed.

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The dopamine hypothesis has been proposed as the pathophysiology of schizophrenia（SZ）, and drug discovery has been based on this hypothesis. About 30% of SZ patients do not respond to dopamine D2 receptor blockers and are considered to have treatment‐resistant schizophrenia（TRS）. The DA hypothesis has limitations in explaining the pathogenesis of TRS, and the glutamate（Glu）hypothesis has been proposed as a comprehensive new hypothesis. Recently, magnetic resonance spectroscopy（¹H‐MRS）has been used to measure the concentrations of Glu neurometabolites, suggesting abnormalities in the Glu nervous system in SZ. The Glu hypothesis is expected to clarify the pathogenesis of TRS and develop new therapeutic agents.

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Patients with schizophrenia present cognitive impairment in addition to positive and negative symptoms. Cognitive impairment of schizophrenia (CIS) is a distinct symptom, and is independent of motivation or general intelligence. Cognitive domains affected in schizophrenia include verbal learning memory, verbal fluency, attention, and executive function. Since CIS influences functional outcomes, pharmacotherapy and psychosocial approaches have been tested to enhancement cognition. However, the effect sizes of these treatments have been small, and side effects and/or the need of considerable human resources poses major challenges. For these reasons, non‐invasive brain stimulation methods, e. g., transcranial direct current stimulation (tDCS) , are attracting interest as a feasible and safe treatment. In this paper, we provide an overview of tDCS and its ability to alleviate CIS.

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