Biology subjects

Daniel, J. M.

Publications and source records attributed to Daniel, J. M..

3 recordsLinked to original sources

bioRxiv2024

The benefits of estradiol on cognitive aging in rats are independent from its effects on cardiometabolic health

Research in preclinical models of menopause indicates that exogenously administered estrogens positively impact cognitive aging. However, clinical evidence indicates that the effects of estrogen therapy on cognition are inconsistent and may be modulated by pre-existing cardiometabolic conditions. The extent to which cardiometabolic health affects the cognitive outcomes of estrogen therapy remains unclear. This study aimed to determine whether variations in cardiometabolic health, both prior to and resulting from different estradiol treatment regimens, are related to the ability of estradiol to improve the cognitive aging trajectory in ovariectomized Long-Evans rats. Cognitive function and health status were assessed at 10 months of age after which rats were ovariectomized and administered vehicle or various estradiol treatments. Rats were assessed again at 18 (middle age) and 22 (old age) months. Cognition was evaluated using a spatial memory radial-maze task. Health status was determined through body composition (dual-energy X-ray absorptiometry), glucose tolerance testing, and blood pressure (tail-cuff plethysmography). Results demonstrated that both continuous ongoing estradiol treatment and a previous 40-day estradiol exposure (terminated long before testing) significantly improved the cognitive aging trajectory from middle to old age. However, only continuous estradiol treatment had positive impacts on health measures; previous estradiol treatment provided no benefits to aging cardiometabolic systems. In contrast, a delayed estradiol treatment (initiated months after ovariectomy) provided no benefits for cognition but provided health benefits. Results indicated that estradiol impacts on cognition in healthy aging rats are separate from and not secondary to its effects on cardiometabolic health.

animal behavior and cognition↗

bioRxiv2022

History of previous midlife estradiol treatment permanently alters interactions of brain insulin-like growth factor-1 signaling and hippocampal estrogen synthesis to enhance cognitive aging in a rat model of menopause

Across species, including humans, elevated levels of brain estrogen receptor (ER) are associated with enhanced cognitive aging even in the absence of circulating estrogens. In rodents, short-term estrogen treatment--such as that commonly used in the menopausal transition--results in long-term increases in levels of ER in the hippocampus, leading to enhanced memory long after termination of estrogen treatment. However, mechanisms by which increased levels of brain ER enhances cognitive aging remain unclear. Here we show that in the hippocampus, insulin-like growth factor-1 (IGF-1)--which can activate ER via ligand-independent mechanisms--requires concomitant synthesis of brain-derived neuroestrogens to phosphorylate ER via MAPK signaling, ultimately resulting in enhanced memory. In a rat model of menopause involving long-term ovarian hormone deprivation, hippocampal neuroestrogen activity decreases, altering IGF-1 activity and resulting in impaired memory. However, this process is reversed by short-term estradiol treatment. Forty-days of estradiol exposure following ovariectomy results in maintenance of neuroestrogen levels that persist beyond the period of hormone treatment, allowing for continued interactions between IGF-1 and neuroestrogen signaling, elevated levels of hippocampal ER, and ultimately enhanced memory. Collectively, results demonstrate that short-term estradiol use following loss of ovarian function has long-lasting effects on hippocampal function and memory by dynamically regulating cellular mechanisms that promote activity of ER in the absence of circulating estrogens. Translational impacts of these findings suggest lasting cognitive benefits of short-term estrogen use near menopause and highlight the importance of hippocampal ER--independent from the role of circulating estrogens--in regulating memory in aging females. Significance statementDeclines in ovarian hormones following menopause coincide with increased risk of cognitive decline. Due to potential health risks, current recommendations are that menopausal estrogen therapy be limited to a few years. Long-term consequences for the brain and memory of this short-term midlife estrogen therapy are unclear. Here, in a rodent model of menopause, we determined mechanisms by which short-term midlife estrogen exposure can enhance hippocampal function and memory with cognitive benefits and molecular changes enduring long after termination of estrogen exposure. Our model indicates long-lasting benefits of maintaining hippocampal estrogen receptor function in the absence of ongoing estrogen exposure and suggests potential strategies for combating age-related cognitive decline.

neuroscience↗

bioRxiv2021

Previous estradiol treatment during midlife maintains transcriptional regulation of memory-related proteins by ERα in the hippocampus in a rat model of menopause

Previous midlife estradiol treatment, like continuous treatment, improves memory and results in lasting increases in hippocampal levels of estrogen receptor (ER) and ER-dependent transcription in ovariectomized rodents. We hypothesized that previous and continuous midlife estradiol act to specifically increase levels of nuclear ER, resulting in transcriptional regulation of proteins that mediate estrogen effects on memory. Ovariectomized middle-aged rats received estradiol or vehicle capsule implants. After 40 days, rats initially receiving vehicle received another vehicle capsule (Vehicle). Rats initially receiving estradiol received either another estradiol (Continuous Estradiol) or a vehicle (Previous Estradiol) capsule. One month later, hippocampal genes and proteins were analyzed. Continuous and previous estradiol increased levels of nuclear, but not membrane or cytosolic ER and had no effect on Esr1. Continuous and previous estradiol impacted gene expression and/or protein levels of mediators of estrogenic action on memory including ChAT, BDNF, and PSD-95. Findings demonstrate a long-lasting role for hippocampal ER as a transcriptional regulator of memory following termination of previous estradiol treatment in a rat model of menopause.

neuroscience↗