1.Research overview
It is generally believed that children improve and learn sports, music, foreign languages, and other subjects more quickly than adults. The saying, “The soul of a child is worth a hundredfold” has become a real phenomenon in brain growth. Children's brains undergo a special “critical period,” during which neural circuits are intensively remodeled in response to individual experiences, and the neural circuits tend to be preserved as individual characteristics until adulthood. On the other hand, it has been pointed out that children raised in a stressful environment, such as bullying or abuse, exhibit emotional and social behaviors similar to neurodevelopmental disorders (e.g., autistic spectrum disorder). Our laboratory aims to clarify the mechanisms by which the brain flexibly acquires functions, thereby contributing to the improvement of brain.
2.Research theme
Childhood experiences impact vision. When the experience of seeing is disturbed, a significant loss of visual acuity (amblyopia) occurs. Amblyopia should be treated during the critical period when neural circuits are highly plastic, which is difficult to improve beyond this period. However, there are still many unknowns as to how the critical period appears in children's brains and why it does not appear in adult brains. How do differences in a child’s environment and experiences affect the formation and function of neural circuits? In our laboratory, we use a variety of experimental approaches, ranging from molecules to neurons, from circuits function to animal behavior, and aim to clarify how children's brain development is influenced not only by genetic factors but also by environmental factors (see below).
3.Research findings and perspective (for researchers)
The critical period is first observed in the primary sensory cortex of the cerebrum and then expands to the higher association areas that integrate various brain functions as the child grows. Recently, analysis of neurodevelopmental disorders has proposed the “sensory-first” theory: abnormal information processing in the primary sensory cortex triggers abnormalities that spread to the higher association cortex. For example, visual abnormalities during the developmental period are thought to lead to reduced face recognition and eye contact, and eventually to emotional and social disorders. However, the mechanisms through which sensory abnormalities give rise to emotional and social disorders remain elucidated.
We have demonstrated that Otx2, a homeodomain transcription factor well-known for its role in embryonic head formation, is also utilized during postnatal brain development (Cell, 2008; Dev. Growth Differ., 2009; J. Neurosci., 2012; Sci. Rep., 2017). Otx2 homeoproteins act as "experience messengers" that transmit information about an individual's experience to neural circuits as they migrate to key neurons (often covered with chondroitin sulfate). Importantly, the experience-dependent transfer of this homeoprotein regulates the critical period. Manipulating the amount of Otx2 in the target neurons of mice can induce the onset or offset of the critical period. For example, it can induce the critical period in adult mice.
Human Otx2 mutations have been associated with developmental delays, autism spectrum disorder (ASD), bipolar disorder, and depression. Understanding the role of Otx2 transport may help us better comprehend these neurodevelopmental and psychiatric disorders. Therefore, we comprehensively searched for Otx2 target genes (ChIP-seq, RNA-seq, and RIP-seq) and identified a group of genes associated with psychiatric disorders and autism risk factors (Dev. Biol. 2013; Front. Neurosci. 2017; Dev. Growth Differ. 2018; Front. Dev. Biol. 2021). For instance, Nipbl, the causative gene of Cornelia de Lange syndrome (CdLS) and ASD, acts with Otx2 to regulate chromatin. Over a thousand common target genes have been identified. The novel actin polymerization factor Cotl1 is involved in the visual superiority and hypersensibility observed in ASD. Our new techniques for visualizing single-cell-derived circuits (Front. Neural Circuits, 2020) and behavioral patterns using the deep learning tool DeepLabCut will clarify how the brain develops in children, not only due to genetic factors, but also due to environmental factors, and how individual circuits affect behavior.
