Myelin mechanisms of brain synaptic dysfunction in breast cancer therapy survivors. Breast cancer therapy, particularly chemotherapy involving doxorubicin (DOX), negatively impacts brain health, leading to cognitive deficits in over 75% of survivors. These cognitive difficulties encompass learning, memory, executive function, and psychomotor speed, affecting daily functioning. Chemotherapy disrupts neuronal metabolism, myelin formation, and neuroplasticity. While the functional detriments associated with DOX-chemotherapy are clinically obvious, the very nature of chemotherapy-induced changes in myelin-related synaptic health across the brain remains elusive. Recent research has observed that structural integrity (measured by diffusion fraction of anisotropy) and N-acetylaspartate (NAA) are both reduced bilaterally in the posterior cingulate gyrus of breast chemotherapy patients, and total creatine (tCr) is abnormally reduced in these same areas. Separate studies performed in breast cancer survivors also report that (i) the cingulate cortex shows reduced function during task and at rest and (ii) myelin fractions are lower in the cingulate’s interconnecting white matter (e.g., cingulum bundle, prefrontal, thalamic radiations). Given the primal role the cingulate cortex plays in cognition, these findings indicate that myelin-related synaptic dysfunction may play a mechanistic role in cancer therapy induced cognitive impairments. Investigating this further is a necessary step to the development of preventive and regenerative interventions. Despite the understanding that activity-dependent myelination is a known mechanism of adult brain plasticity that is reported to restore function in other conditions of aplastic myelination, this knowledge cannot be implemented in breast chemotherapy patients until more is known about treatment’s effects on synaptic health. The overall objective of this proposal is to investigate the alterations in synaptic health that occur in breast cancer survivors to inform possible future mitigation strategies. Our central hypothesis posits that cognitive impairments post-chemotherapy correlate with reduced NAA and myelination loss, which in turn leads to lasting deficits. The study plans to measure molecular markers of synaptic health, myelination integrity, and neurocognitive function in a longitudinal study of DOX-treated breast cancer patients to understand these relationships and elucidate possible future mitigation strategies. Our aims include: (1) Characterize synaptic dysfunction across brain networks of cognition post-cancer treatment; (2) Characterize myelination health across brain networks of cognition; and (3) Investigate the association between myelinrelated synaptic dysfunction and cognitive function. Overall, this research aims to shed light on the mechanisms behind cognitive impairments in breast cancer survivors.