Evidence for intrathymic and neuroimmune alterations in a mouse model of neglectrelated early life stressors

Abstract Environmental exposures during the impressionable early life period can influence biological and behavioral development. These exposures accumulate from birth and comprise the exposome, which impacts health and disease. Neglect is a major source of early life stress (ELS) and accounts for 80% of reported child abuse in the United States. Forms of neglect vary (e.g., physical, medical, emotional, nutritional) and with increased concerns for abuse during the COVID-19 pandemic, we require a deeper understanding of how ELS affects immune system programming/development. T cells undergo a stringent selection process in the thymus to achieve self-nonself discrimination capacity and can be identified based on double-positive (DP) or single-positive (SP) CD4/CD8 expression status. We utilize a maternal separation with early weaning paradigm to study the effects of ELS on anxiety/depressive behavior and intrathymic T cell distribution. Conditions of neglect-related stress were simulated based on scheduled dam-pup separation (physical neglect) and early weaning to a high carbohydrate diet (malnutrition). Pups were subjected to one of two distinct ELS conditions: (1) daily separation with early weaning (MSEW) or (2) early weaning alone (EW) at postnatal day (PD) 14. Control pups experienced no separation and were maintained on the dam’s milk to the standard wean date (PD21). Body metrics and tissues were collected at PD21. Behavioral phenotypes were assessed at PD28–35. The results demonstrated significant stress effects and revealed an altered distribution of thymocytes within DP and SP compartments. This study provides preliminary causal evidence and provokes questions about ELS-mediated consequences on T cell immunity. NIH/NIA T32 AG020494 NIH/NIMHD 5U54MD006882-10 UNTHSC MIG Dept. Intramural Grant