Published papers

The homozygous Bronx waltzer (bv) mouse, which shows hearing impairment, also exhibits anxiety accompanied by a reduction in cortical parvalbumin (PV)-positive GABAergic interneurons. Recently, a mutation in splicing factor Ser/Arg repetitive matrix 4 (Srrm4) was found in bv mice. However, the cellular consequences of the Srrm4 mutation for anxiety remain unknown. Here, we tested our hypothesis that bv mutant primarily affects interneurons through a cell-intrinsic pathology that leads to a reduction of interneurons and consequently causes anxiety. We found that the anxiety becomes apparent at 6 weeks of age in bv/bv mice. However, in situ hybridization revealed that Srrm4 is not expressed in interneurons, but rather dominates in pyramidal neurons. In addition, the PV-positive GABAergic interneurons were not reduced in number in the bv/bv cortex when anxiety became evident. However, electrophysiological abnormality of GABAergic transmission from interneurons was concomitantly present. Pharmacological blockage of GABAA receptors revealed increased excitability in bv/bv mice, although no gross change occurred in the expression of an Srrm4-downstream gene, Kcc2, which regulates chloride flux upon GABAergic transmission. These findings suggest that the bv-associated Srrm4 mutation mainly involves post-synaptic GABAergic transmission in the central nervous system, which may be associated with the anxiety phenotype in bv/bv mice.

Background: Shifting enables flexible switch between tasks or mental sets. It is a component of the executive function that plays critical roles in human behaviour control. However, shifting ability in individuals with intellectual disability (ID) has not been well clarified because of the use of intellectually demanding tasks in previous studies. The present study invented a novel shifting task with minimal intellectual demands and aimed to clarify the characteristics of shifting in adolescents with ID. Methods: Adolescents with ID (n = 21) and chronological-age-matched (n = 10) and mental-age-matched controls (n = 33) performed a novel shifting task with simple rule switching (i.e. change in direction). Analyses focused on the switch cost or the increase in the reaction time associated with rule switching. Results: Two subtypes of adolescents with ID were found with respect to the switch cost: one that lacks it and another with an increased switch cost. The lack of a switch cost was unique to the subgroup adolescents with ID and was not indicated in the control group. Conclusions: The present study indicated that shifting in adolescents with ID does not depend solely on their intellectual function and is highly heterogeneous. This finding further implies that executive functions, including shifting, must be evaluated separately from their intellectual functions.

Defining the morphological disorders causing neurodegenerative diseases is an unresolved problem. In this study, we propose a statistical−physical approach to quantify neurite morphology and evaluate the pathological states induced by Alzheimer's disease (AD). We analyzed the two-dimensional morphologies of neurites of in vitro-cultured human induced-pluripotent stem cell-derived neurons, reprogrammed from both a healthy person and a patient with AD, using discrete chordal Loewner evolution. For the numerically calculated Loewner driving forces, detrended fluctuation analysis was performed, and the morphological characteristics of the neurites were quantified using short-range and long-range scaling exponents. The day in vitro (DIV)-dependent behaviors of the scaling exponents and the associated neurite-type categorizations suggested that differences between healthy and AD neurites can be observed from the early stage (DIV3) of their development. Notably, AD neurites have less long-range autocorrelations than healthy neurites, particularly in the earlier stages (DIV3-10). Immunofluorescence-staining results suggested that these differences precede significant expressions of β-amyloid and phosphorylated tau, which are known as biological factors causing AD. We expect that these results will lead to a theoretical interpretation of the neurogenerative disease, providing the physical properties of individual neurites with different morphologies.

Patients with major depressive disorder (MDD) exhibit several clinical symptoms including difficulties in flexible thinking. Flexible thinking mainly relies on a cognitive ability called shifting; however, the mechanisms underlying shifting in patients with MDD have not yet been clarified. Therefore, we conducted a preliminary intervention study to clarify the association between depression and shifting ability. We examined the hemodynamic responses in the frontal regions during the shifting task using functional near-infrared spectroscopy (fNIRS) in 21 patients with MDD who were treated using high-frequency repetitive transcranial magnetic stimulation (rTMS). Behavioral performance on the shifting task did not change between pre- and posttreatments, whereas patients who responded well to rTMS treatment showed a significant decrease in hemodynamic responses posttreatment. On the other hand, the poor responders did not show significant changes in the hemodynamic responses between pre- and posttreatments. These results suggest that the good responders were successfully remedied with rTMS treatment and did not need effortful activity in frontal regions for shifting, which made their brain activity more efficient.