Kelly, M. E. | Search bioRxiv

bioRxiv2023

Long-Term Oral Tamoxifen Administration Decreases Brain Derived Neurotrophic Factor in the Hippocampus of Female Long-Evans Rats

Tamoxifen is a selective estrogen receptor modulator (SERM) that is commonly used as an adjuvant drug therapy for estrogen receptor-positive breast cancers. While this drug is effective at reducing the rate of cancer recurrence, many patients report unwanted cognitive and affective side effects such as brain fog, confusion, memory impairment, anxiety, and depression. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We therefore used long-term ad lib consumption of medicated food pellets in adult female rats to model chronic tamoxifen exposure in a clinically-relevant way. Gonadally-intact adult female Long-Evans Hooded rats consumed tamoxifen medicated food pellets for approximately 12 weeks while control animals received standard chow. At the conclusion of the experiment, animals were euthanized, and blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography-tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry and quantified using background-subtracted optical densitometry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. Together, these findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure, and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients.

neuroscience↗

bioRxiv2021

Ipsilesional motor cortex activation with high-force unimanual handgrip contractions of the less-affected limb in participants with stroke

Stroke is a leading cause of severe disability that often presents with unilateral motor impairment. Conventional rehabilitation approaches focus on motor practice of the affected limb and aim to suppress brain activity in the contralesional hemisphere to facilitate ipsilesional hemispheric neuroplasticity subserving motor recovery. Previous research has also demonstrated that exercise of the less-affected limb can promote motor recovery of the affected limb through the interlimb transfer of the trained motor task, termed cross-education. One of the leading theories for cross-education proposes that the interlimb transfer manifests from ipsilateral cortical activity during unimanual motor tasks, and that this ipsilateral cortical activity results in motor related neuroplasticity giving rise to contralateral improvements in motor performance. Conversely, exercise of the less-affected limb promotes contralesional brain activity which is typically viewed as contraindicated in stroke recovery due to the interhemispheric inhibitory influence onto the ipsilesional hemisphere. High-force unimanual handgrip contractions are known to increase ipsilateral brain activation in control participants, but it remains to be determined if this would be observed in participants with stroke. Therefore, this study aimed to determine how parametric increases in handgrip force during repeated contractions with the less-affected limb impacts brain activity bilaterally in participants with stroke and in a cohort of neurologically intact controls. In this study, higher force contractions were found to increase brain activation in the ipsilesional/ipsilateral hemisphere in both groups (p = .002), but no between group differences were observed. These data suggest that high-force exercise with the less-affected limb may promote ipsilesional cortical plasticity to promote motor recovery of the affected-limb in participants with stroke.

neuroscience↗