Abnormality in GABAergic postsynaptic transmission associated with anxiety in Bronx waltzer mice with an Srrm4 mutation.

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.

Repetitive transcranial magnetic stimulation decreased effortful frontal activity for shifting in patients with major depressive disorder.

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.

Quantifying scaling exponents for neurite morphology of in vitro-cultured human iPSC-derived neurons using discrete Loewner evolution: A statistical-physical approach to the neuropathology in Alzheimer's disease.

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 ß-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.

Executive dysfunction in medication-naïve children with ADHD: A multi-modal fNIRS and EEG study.

OBJECTIVE: Children with attention deficit hyperactivity disorder (ADHD) exhibit deficits in executive function. Since there are no clear biomarkers for the disorder, this study aimed to investigate the neurophysiological biomarkers for deficits in executive function in children with ADHD using functional near-infrared spectroscopy (fNIRS) and electroencephalography. METHODS: Twenty patients diagnosed with ADHD and 19 typically developing children (TDC; 8-11 years old) were included. Event related potentials (ERPs) were recorded using an electroencephalogram (EEG) and oxygenated hemoglobin concentrations (Oxy-Hb) were recorded using fNIRS during a colored Go/NoGo task, simultaneously. Latencies and amplitudes of NoGo-N2 and NoGo/Go-P3 tasks were measured using EEG. RESULTS: Children with ADHD showed significantly decreased Oxy-Hb in the right frontal cortex as well as longer NoGo-P3 latencies and a decreased NoGo/Go-P3 amplitude. There was a significant positive correlation between the Oxy-Hb and NoGo/Go-P3 amplitude. CONCLUSIONS: These results suggest that children with ADHD experience executive dysfunction. Hemodynamic and electrophysiological findings during the Go/NoGo task might be useful as a biomarker of executive function. SIGNIFICANCE: These findings have key implications for understanding the pathophysiology of deficits in executive function in ADHD.

Reduced Nogo-P3 in adults with developmental coordination disorder (DCD).

Nogo-N2 is associated with the premotor cognitive process that precedes motor response (e.g., conflict monitoring), whereas Nogo-P3 is related to the inhibition of the actual motor response. We examined the influence of motor clumsiness of developmental coordination disorder (DCD) on components of the event-related potential in a Go/Nogo task. Participants were healthy adults (N = 81) that were classified into control and DCD groups based on the Movement Assessment Battery for Children Second Edition. We manipulated the difficulty in stopping a response by varying the frequency of Nogo stimuli in a response task into rare (20%) and frequent (80%) conditions, and Nogo-N2 and Nogo-P3 were calculated from electroencephalograms (EEGs) during the Go/Nogo tasks. The commission error rate in the rare condition was significantly higher in the DCD group than in the control group, indicating that motor clumsiness decreases task performance. There were no differences in Nogo-N2 between DCD and control groups. However, Nogo-P3 in the rare condition was reduced in the DCD group compared to the control group. These results suggest that the influence of motor clumsiness is limited to the cognitive process after the initiation of the actual motor response.

A cross-species socio-emotional behaviour development revealed by a multivariate analysis.

Recent progress in affective neuroscience and social neurobiology has been propelled by neuro-imaging technology and epigenetic approach in neurobiology of animal behaviour. However, quantitative measurements of socio-emotional development remains lacking, though sensory-motor development has been extensively studied in terms of digitised imaging analysis. Here, we developed a method for socio-emotional behaviour measurement that is based on the video recordings under well-defined social context using animal models with variously social sensory interaction during development. The behaviour features digitized from the video recordings were visualised in a multivariate statistic space using principal component analysis. The clustering of the behaviour parameters suggested the existence of species- and stage-specific as well as cross-species behaviour modules. These modules were used to characterise the behaviour of children with or without autism spectrum disorders (ASDs). We found that socio-emotional behaviour is highly dependent on social context and the cross-species behaviour modules may predict neurobiological basis of ASDs.

Peer attachment formation by systemic redox regulation with social training after a sensitive period.

Attachment formation is the most pivotal factor for humans and animals in the growth and development of social relationships. However, the developmental processes of attachment formation mediated by sensory-motor, emotional, and cognitive integration remain obscure. Here we developed an animal model to understand the types of social interactions that lead to peer-social attachment formation. We found that the social interaction in a sensitive period was essential to stabilise or overwrite the initially imprinted peer affiliation state and that synchronised behaviour with others based on common motivations could be a driver of peer social attachment formation. Furthermore, feeding experience with supplementation of ubiquinol conferred peer social attachment formation even after the sensitive period. Surprisingly, the experience of feeding beyond the cage window was also effective to reduce the required amount ubiquinol, suggesting that peri-personal space modulation may affect socio-emotional cognition and there by lead to attachment formation.

Familiarity perception call elicited under restricted sensory cues in peer-social interactions of the domestic chick.

Social cognitive mechanisms are central to understanding developmental abnormalities, such as autistic spectrum disorder. Peer relations besides parent-infant or pair-bonding interactions are pivotal social relationships that are especially well developed in humans. Cognition of familiarity forms the basis of peer socialization. Domestic chick (Gallus gallus) studies have contributed to our understanding of the developmental process in sensory-motor cognition but many processes remain unknown. In this report, we used chicks, as they are precocial birds, and we could therefore focus on peer interaction without having to consider parenting. The subject chick behavior towards familiar and unfamiliar reference peers was video-recorded, where the subject and the reference were separated by either an opaque or transparent wall. Spectrogram and behavior correlation analyses based on principal component analysis, revealed that chicks elicited an intermediate contact call and a morphologically different distress call, more frequently towards familiar versus unfamiliar chicks in acoustic only conditions. When both visual and acoustic cues were present, subject chicks exhibited approaching and floor pecking behavior, while eliciting joyful (pleasant) calls, irrespective of whether reference peers were familiar or unfamiliar. Our result showed that chicks recognized familiarity using acoustic cues and expressed cognition through modified distress calls. These finding suggests that peer affiliation may be established by acoustic recognition, independent of visual face recognition, and that eventually, both forms of recognition are integrated, with modulation of acoustic recognition.

[Development and neural basis of social behavior].

We have developed a multi variate analysis of social communication behavior which allows for discriminating the emotional state of an agent interacting with other agents (Bouquet method). Domestic chick or common marmoset was reared under socially isolated conditions, later tested for its development of communication behavior with peers by Bouquet, and compared with that of animals reared under grouping conditions. We found the existence of high sensitive period for social interaction, given less experience, developing less affiliated behavior. From chick model, a couple of neuronal difference was observed between two groups, amygdale core central cell size, MRI volumetric measure in mesolimbic area, and gene expression patter including brain type tryptophan hydroxylase in nucleus accumbens. The isolated chick behavior changed better to be socially affiliated by taking SSRI/SNRI or Ubiquinol (the reduced form of CoQ10) together with social interaction experience after the sensitive period. Finally, we could discriminate the behavior of Asperger syndrome children (n = 7) from that of the typically developed siblings (n = 6) during the clinical interview by applying Bouquet method.