Role of perinatal testosterone in programming behavioral and astrocyte responses to early life chemotherapy

Abstract. Astrocytes play an essential role in early brain development, and sex differences in the maturation of cortical astrocytes and their function have been described. While the role of astrocytes in early perinatal brain development is a rapidly developing field, significant knowledge gaps remain. This application will test the novel hypothesis that the perinatal testosterone surge in males alters astrocyte calcium signaling, which renders males vulnerable to cognitive deficits induced by environmental exposures. Long-term cognitive deficits are common amongst survivors of childhood acute lymphoblastic leukemia (ALL). These deficits largely affect executive function (e.g., attention, impulse control) and memory. To improve quality of life for leukemia survivors, there is a pressing need to better understand the underlying neurobiological changes that link early life cancer+chemotherapy to cognitive deficits. To address this question, we have developed a more translationally relevant mouse model that involves administration of a leukemia cell line (L1210) and a cycle of chemotherapy (methotrexate, vincristine, leucovorin) between postnatal day 19 (P19) and P33. We observe persistent deficits in learning, recognition memory and executive function and have identified a link to glial dysregulation with chemotherapy exposure. Of note, we observe a strong sex difference, such that female animals exposed to early life cancer+chemotherapy are relatively resilient to executive function deficits as compared to males. Our preliminary data highlight a robust transcriptional response in female astrocytes from the prefrontal cortex (PFC) that is absent in male astrocytes. Pathway analyses identify genes related to Gq-coupled G protein-coupled receptor (GPCR) signaling, calcium (Ca2+) mobilization and inhibitory gliotransmission as significantly changed in females. Our findings of a strong sex difference in astrocyte responses to early life cancer+chemotherapy exposure represent a robust readout with which to test our hypothesis. Manipulating the impact of the P1 testosterone surge, combined with astrocyte specific gene expression and calcium imaging, and advanced operant behavioral testing will provide a unique opportunity to dissect astrocytic contributions to cognitive dysfunctions at molecular, cellular and functional levels of evaluation, in both normal development and in response to challenge. Advancing knowledge around sex differences in astrocyte developmental biology has broad implications for furthering understanding of neurodevelopmental disorders and/or responses to early life adversity, both of which show sex biases.