Faculty Bibliography

Animals must distinguish external stimuli from self-generated sensory input to guide appropriate behaviors. A recent study elucidates a cellular mechanism by which zebrafish perform this distinction while maintaining sensitivity to external environmental signals.

Down Syndrome Cell Adhesion Molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), while abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.

Brain growth charts and age-normed brain templates are essential resources for researchers to eventually contribute to the care of individuals with atypical developmental trajectories. The present work generates age-normed brain templates for children and adolescents at one-year intervals and the corresponding growth charts to investigate the influences of age and ethnicity using a common pediatric neuroimaging protocol. Two accelerated longitudinal cohorts with the identical experimental design were implemented in the United States and China. Anatomical magnetic resonance imaging (MRI) of typically developing school-age children (TDC) was obtained up to three times at nominal intervals of 1.25 years. The protocol generated and compared population- and age-specific brain templates and growth charts, respectively. A total of 674 Chinese pediatric MRI scans were obtained from 457 Chinese TDC and 190 American pediatric MRI scans were obtained from 133 American TDC. Population- and age-specific brain templates were used to quantify warp cost, the differences between individual brains and brain templates. Volumetric growth charts for labeled brain network areas were generated. Shape analyses of cost functions supported the necessity of age-specific and ethnicity-matched brain templates, which was confirmed by growth chart analyses. These analyses revealed volumetric growth differences between the two ethnicities primarily in lateral frontal and parietal areas, regions which are most variable across individuals in regard to their structure and function. Age- and ethnicity-specific brain templates facilitate establishing unbiased pediatric brain growth charts, indicating the necessity of the brain charts and brain templates generated in tandem. These templates and growth charts as well as related codes have been made freely available to the public for open neuroscience (https://github.com/zuoxinian/CCS/tree/master/H3/GrowthCharts).

Meditation is a type of mental training commonly applied in clinical settings and also practiced for general well-being. Brain functional connectivity (FC) patterns associated with meditation have revealed its brain mechanisms. However, the variety of FC methods applied has made it difficult to identify brain communication patterns associated with meditation. Here we carried out a coordinate-based meta-analysis to get preliminary evidence of meditation effects on changing brain network interactions. Fourteen seed-based, voxel-wise FC studies reported in 13 publications were reviewed; 10 studies with seeds in the default mode network (DMN) were meta-analyzed. Seed coordinates and the effect sizes in statistically significant regions were extracted, based on 170 subjects in meditation groups and 163 subjects in control groups. Seed-based d-mapping was used to analyze meditation versus control FC differences with DMN seeds. Meditation was associated with increased connectivity within DMN and between DMN and somatomotor network and with decreased connectivity between DMN and frontoparietal network (FPN) as well as ventral attention network (VAN). The pattern of decreased within-DMN FC and increased between-network FC (FPN and DAN with DMN) was more robust in highly experienced meditators compared to less experienced individuals. The identified neural network interactions may also promote meditation's effectiveness in clinical interventions for treating physical and mental disorders.

In the above published article there was an error in the abstract, the sentence should read as follows: "Meditation was associated with decreased connectivity within DMN and between DMN and somatomotor network and with increased connectivity between DMN and frontoparietal network (FPN) as well as ventral attention network (VAN)." The authors apologise for this error.

Following the publication of the article, it was noted that the last column in Table 1, the total % should have read 5/8 (62.5) for the 'Epilepsy' row, and not 5.7 (71.4). This has now been amended in the HTML and PDF of the original article.

Fluorouracil (5-FU) remains a first-line chemotherapeutic agent for colorectal cancer. However, a subset of colorectal cancer patients who have defective mismatch-repair (dMMR) pathway show resistance to 5-FU. Here, we demonstrate that the efficacy of 5-FU in dMMR colorectal cancer cells is largely dependent on the DNA base excision repair (BER) pathway. Downregulation of APE1, a key enzyme in the BER pathway, decreases IC₅₀ of 5-FU in dMMR colorectal cancer cells by 10-fold. Furthermore, we discover that the facilitates chromatin transcription (FACT) complex facilitates 5-FU repair in DNA via promoting the recruitment and acetylation of APE1 (AcAPE1) to damage sites in chromatin. Downregulation of FACT affects 5-FU damage repair in DNA and sensitizes dMMR colorectal cancer cells to 5-FU. Targeting the FACT complex with curaxins, a class of small molecules, significantly improves the 5-FU efficacy in dMMR colorectal cancer in vitro (∼50-fold decrease in IC₅₀) and in vivo xenograft models. We show that primary tumor tissues of colorectal cancer patients have higher FACT and AcAPE1 levels compared with adjacent nontumor tissues. Additionally, there is a strong clinical correlation of FACT and AcAPE1 levels with colorectal cancer patients' response to chemotherapy. Together, our study demonstrates that targeting FACT with curaxins is a promising strategy to overcome 5-FU resistance in dMMR colorectal cancer patients.