The effects of chemotherapy during childhood on early maternal bonding and adult social and cognitive functioning in laboratory mice

The impact of cancer and its intensive treatments, like chemotherapy and radiotherapy, on the developing brain is overwhelming. Survivors often struggle with cognitive issues that impact attention, memory, and executive functions. Emotional challenges like anxiety, depression, and symptoms of post-traumatic stress are also widespread. As survival rates continue to rise, leading to a growing number of survivors, there is an urgent need for the medical and research community to create evidence-based services and interventions. This PhD thesis uses mouse models to provide a comprehensive investigation into the long-term neurodevelopmental and behavioral consequences of prenatal irradiation and childhood chemotherapy, focusing on their impact on higher-order brain functions and the potential influencing role of parental relationships.

The first study investigates the effects of prenatal irradiation in adult mice, revealing that exposure during a critical period of neurogenesis leads to a range of higher-order dysfunctions. These include impaired working memory, altered fear responses, and signs of perseverative behavior. Electrophysiological, fMRI, and immunohistological studies indicate that these behavioral changes are rooted in disrupted hippocampal synaptic plasticity, cerebral hyperconnectivity and altered neurotransmitter activity.

Studies 2 and 3 explore the long-lasting impact of central nervous system prophylactic methotrexate (MTX) treatment, a chemotherapeutic drug commonly used in childhood leukemia, on brain development and neurocognition. These studies reveal that early MTX exposure alters maternal care, disrupts gene expression related to myelin and neuroinflammation, and leads to a range of adult behavioral changes including increased anxiety-like behavior and impaired spatial learning and cognitive flexibility. Notably, study 3 also shows that the presence of an additional nurturing mother can partially or fully mitigate these adverse effects, highlighting the potential role of early social experiences in resilience.

The last study extends this investigation by examining the combined effects of systemic MTX treatment and maternal separation. The results suggest that while maternal separation aggravates some negative outcomes like reduced average weight, it surprisingly mitigates others, such as anxiety-like behavior, social interaction, and spatial memory. Maternal separation also increased adult social dominance.

Overall, the PhD thesis underscores the multifaceted and enduring impact of early-life cancer treatment on brain development and cognitive functioning. It also emphasizes the potential influencing role of parental relationships, offering valuable insights into the long-term care and treatment strategies for childhood cancer survivors.