One in 8 women in the US will be diagnosed with breast cancer. Currently, doxorubicin is one of the most effective chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed, and executive functioning. Currently, no interventions for CICD have been approved by the US Food and Drug Administration. I show here that a 14-day treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor successfully reverses long-term CICD following a therapeutic doxorubicin dosing schedule in female mice, as assessed by the puzzle box test and novel object/place recognition test. Long-term CICD was associated with a decreased expression of the postsynaptic protein PSD95, but no decrease in the presynaptic protein synaptophysin, in the hippocampus. I did not detect a significant decrease in mitochondrial function or morphology in brain synaptosomes, myelination in the cingulate cortex using Black Gold II staining, or changes in astrocyte reactivity as assessed by anti-GFAP immunofluorescence staining. Using advanced imaging techniques and single-nucleus RNA sequencing, I demonstrate that doxorubicin-induced changes are associated with decreased microglial ramification and alterations in the microglia transcriptome that suggest a neurodegenerative microglia phenotype closely resembling stage 1 disease-associated microglia (DAMs). HDAC6 inhibition completely reversed these doxorubicin-induced alterations, indicating a restoration of microglial homeostasis. These results suggest that a stage 1 DAM-like microglia phenotype and decreased postsynaptic integrity contribute to long-term CICD. Moreover, HDAC6 inhibition shows promise as an efficacious pharmaceutical intervention to alleviate CICD and improve quality of life of breast cancer survivors.
","abstract_html":"<p>One in 8 women in the US will be diagnosed with breast cancer. Currently, doxorubicin is one of the most effective chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed, and executive functioning. Currently, no interventions for CICD have been approved by the US Food and Drug Administration. I show here that a 14-day treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor successfully reverses long-term CICD following a therapeutic doxorubicin dosing schedule in female mice, as assessed by the puzzle box test and novel object/place recognition test. Long-term CICD was associated with a decreased expression of the postsynaptic protein PSD95, but no decrease in the presynaptic protein synaptophysin, in the hippocampus. I did not detect a significant decrease in mitochondrial function or morphology in brain synaptosomes, myelination in the cingulate cortex using Black Gold II staining, or changes in astrocyte reactivity as assessed by anti-GFAP immunofluorescence staining. Using advanced imaging techniques and single-nucleus RNA sequencing, I demonstrate that doxorubicin-induced changes are associated with decreased microglial ramification and alterations in the microglia transcriptome that suggest a neurodegenerative microglia phenotype closely resembling stage 1 disease-associated microglia (DAMs). HDAC6 inhibition completely reversed these doxorubicin-induced alterations, indicating a restoration of microglial homeostasis. These results suggest that a stage 1 DAM-like microglia phenotype and decreased postsynaptic integrity contribute to long-term CICD. Moreover, HDAC6 inhibition shows promise as an efficacious pharmaceutical intervention to alleviate CICD and improve quality of life of breast cancer survivors.</p>","abstract_has_math":false,"creators":["McAlpin, Blake","0000-0002-6539-8406
"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Cobi J. Heijnen, Ph.D.","M. Neal Waxham, Ph.D.","Robert Dantzer, D.V.M., Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-05-01T07:00:00Z","date_published":"2022-05-01T07:00:00Z","updated_at":"2026-07-24T05:48:59Z","subjects":["chemotherapy-induced cognitive dysfunction","chemobrain","HDAC6 inhibition","microglia","single-nucleus RNA sequencing","chemofog","snRNA-seq","synaptic integrity","PSD95","Medical Neurobiology","Medicine and Health Sciences","Neurosciences","Oncology","Other Chemicals and Drugs","Other Neuroscience and Neurobiology","Translational Medical Research"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1160","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Cobi J. Heijnen, Ph.D.","M. Neal Waxham, Ph.D.","Robert Dantzer, D.V.M., Ph.D."]},{"key":"dc:creator","label":"Author","values":["McAlpin, Blake","0000-0002-6539-8406
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"]},{"key":"dc:title","label":"Title","values":["Hdac6 Inhibition Reverses Long-Term Doxorubicin-Induced Cognitive Dysfunction By Restoring Microglia Homeostasis"]}]}],"canonical_facts":{"dc:contributor":["Cobi J. Heijnen, Ph.D.","M. Neal Waxham, Ph.D.","Robert Dantzer, D.V.M., Ph.D."],"dc:creator":["McAlpin, Blake","0000-0002-6539-8406
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"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1160"],"dc:subject":["chemotherapy-induced cognitive dysfunction","chemobrain","HDAC6 inhibition","microglia","single-nucleus RNA sequencing","chemofog","snRNA-seq","synaptic integrity","PSD95","Medical Neurobiology","Medicine and Health Sciences","Neurosciences","Oncology","Other Chemicals and Drugs","Other Neuroscience and Neurobiology","Translational Medical Research"],"dc:title":["Hdac6 Inhibition Reverses Long-Term Doxorubicin-Induced Cognitive Dysfunction By Restoring Microglia Homeostasis"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:48:59Z"}