Middleton, C. | bioRxiv Science

bioRxiv2026

A critical role for the murine anterior insula in male social avoidance after early life maltreatment.

Maltreatment in children and adolescents poses a major public health crisis as a primary factor for the development of adult psychiatric disorders. However effective treatments for symptoms resulting from early life maltreatment are lacking, in part due to a lack of understanding of how neural circuits are disrupted in adulthood after childhood and adolescent abuse. We used a novel model of developmental maltreatment (early adolescent chronic social defeat stress, eaCSDS) in C57/B6J mice to examine behavioral and circuit-level effects in the adult anterior insula (AI). We combined chemogenetics, whole brain c-fos imaging and multi-site LFP to investigate the role of the AI and related circuitry in adult behavioral dysfunction after early life maltreatment. Behavioral analysis in adult animals reveals that males, but not females, show robust generalized social avoidance after social defeat in early adolescence. Chemogenetic silencing of AI neurons in males, but not females, reduces social avoidance in adulthood after eaCSDS. In males, whole brain c-fos imaging and multi-site LFP recordings further reveal circuit-level disruptions in connectivity to AI, implicating AI dysregulation as a driver of adult male social avoidance after adolescent maltreatment. Together these findings reveal AI as a novel circuits-level target whose activity normalization may reduce fear-based symptoms of adolescent maltreatment in adulthood specifically in males.

neuroscience↗

bioRxiv2024

Pan-cancer Analysis of Homologous Recombination Deficiency in Cell Lines

Homologous Recombination Deficiency (HRD) drives genomic instability in multiple cancer types and renders tumors vulnerable to certain DNA damaging agents such as PARP inhibitors. Thus, HRD is emerging as an attractive biomarker in oncology. A variety of in silico methods are available for predicting HRD; however, few of these methods have been applied to cell lines in a comprehensive manner. Here we utilized two of these methods, "CHORD" and "HRDsum" scores, to predict HRD for 1,332 cancer cell lines and 84 non-cancerous cell lines. Cell lines with biallelic mutations in BRCA1 or BRCA2, which encode key components of the homologous recombination pathway, showed the strongest HRD predictions, validating the two methods in cell lines. A small subset of BRCA1/2-wildtype cell lines were also classified as HRD, several of which showed evidence of epigenetic BRCA1 silencing. Similar to HRD in patient samples, HRD in cell lines was associated with p53 loss, was mutually exclusive with microsatellite instability and occurred most frequently in breast and ovarian cancer types. In addition to validating previously identified associations with HRD, we leveraged cell line-specific datasets to gain new insights into HRD and its relation to various genetic dependency and drug sensitivity profiles. We found that in cell lines, HRD was associated with sensitivity to PARP inhibition in breast cancer, but not at a pan-cancer level. By generating large-scale, pan-cancer datasets on HRD predictions in cell lines, we aim to facilitate efforts to improve our understanding of HRD and its utility as a biomarker. SIGNIFICANCE STATEMENTHomologous Recombination Deficiency (HRD) is common in cancer and can be exploited therapeutically, as it sensitizes cells to DNA damaging agents. Here we scored over 1,300 cancer cell lines for HRD using two different bioinformatic approaches, thereby enabling large-scale analyses that provide insight into the etiology and features of HRD.

cancer biology↗