Gynecological surgery in adulthood imparts cognitive and brain changes in rats: A focus on hysterectomy at short-, moderate-, and long-term intervals after surgery.

Premenopausal hysterectomy is associated with a greater relative risk of dementia. We previously demonstrated cognitive impairments in adult rats six weeks after hysterectomy with ovarian conservation compared with intact sham-controls and other gynecological surgery variations. Here, we investigated whether hysterectomy-induced cognitive impairments are transient or persistent. Adult rats received sham-control, ovariectomy (Ovx), hysterectomy, or Ovx-hysterectomy surgery. Spatial working memory, reference memory, and anxiety-like behavior were tested either six-weeks post-surgery, in adulthood; seven-months post-surgery, in early middle-age; or twelve-months post-surgery, in late middle-age. Hysterectomy in adulthood yielded spatial working memory deficits at short-, moderate-, and long-term post-surgery intervals. Serum hormone levels did not differ between ovary-intact, but differed from Ovx, groups. Hysterectomy had no significant impact on healthy ovarian follicle or corpora lutea counts for any post-surgery timepoint compared with intact sham-controls. Frontal cortex, dorsal hippocampus, and entorhinal cortex were assessed for activity-dependent markers. In entorhinal cortex, there were alterations in FOSB and ΔFOSB expression during the early middle-age timepoint, and phosphorylated ERK1/2 levels at the adult timepoint. Collectively, results suggest a primary role for the uterus in regulating cognition, and that memory-related neural pathways may be modified following gynecological surgery. This is the first preclinical report of long-term effects of hysterectomy with and without ovarian conservation on cognition, endocrine, ovarian, and brain assessments, initiating a comprehensive framework of gynecological surgery effects. Translationally, findings underscore critical needs to decipher how gynecological surgeries, especially those involving the uterus, impact the brain and its functions, the ovaries, and overall aging from a systems perspective.

Evaluations of memory, anxiety, and the growth factor IGF-1R after post-surgical menopause treatment with a highly selective progestin.

Progestogens are a key component of menopausal hormone therapies. While some progestogens can be detrimental to cognition, there is preclinical evidence that progestogens with a strong progesterone-receptor affinity benefit some molecular mechanisms believed to underlie cognitive function. Thus, a progestin that maximizes progesterone-receptor affinity and minimizes affinities to other receptors may be cognitively beneficial. We evaluated segesterone-acetate (SGA), a 19-norprogesterone derivative with a strong progesterone-receptor affinity and no androgenic or estrogenic-receptor activity, hypothesizing that it would enhance cognition. Middle-aged rats underwent Sham or Ovariectomy (Ovx) surgery followed by administration of medroxyprogesterone-acetate (MPA; used as a positive control as we have previously shown MPA-induced cognitive deficits), SGA (low or high dose), or vehicle (one Sham and one Ovx group). Spatial working and reference memory, delayed retention, and anxiety-like behavior were assessed, as were memory- and hormone- related protein assays within the frontal cortex, dorsal hippocampus, and entorhinal cortex. Low-dose SGA impaired spatial working memory, while high-dose SGA had a more extensive detrimental impact, negatively affecting spatial reference memory and delayed retention. Replicating previous findings, MPA impaired spatial reference memory and delayed retention. SGA, but not MPA, alleviated Ovx-induced anxiety-like behaviors. On two working memory measures, IGF-1R expression correlated with better working memory only in rats without hormone manipulation; any hormone manipulation or combination of hormone manipulations used herein altered this relationship. These findings suggest that SGA impairs spatial cognition after surgical menopause, and that surgical menopause with or without progestin administration disrupts relationships between a growth factor critical to neuroplasticity.

Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer's disease: three key timepoints through middle-age in females.

The TgF344 rat model of Alzheimer's disease (AD) provides a comprehensive neuropathology presentation, with age-dependent development of tau tangles, amyloid-beta (A[Formula: see text]) plaques, neuronal loss, and increased gliosis. The behavioral trajectory of this model, particularly relating to spatial learning and memory, has yet to be fully characterized. The current experiment evaluated spatial working and reference memory performance, as well as several physiological markers of health, at 3 key age points in female TgF344-AD rats: 6-months, 9-months, and 12-months. At 6 months of age, indications of working and reference memory impairments were observed in transgenic (Tg) rats on the water radial-arm maze, a complex task that requires working and reference memory simultaneously; at 12 months old, Tg impairments were observed for two working memory measures on this task. Notably, no impairments were observed at the 9-month timepoint on this maze. For the Morris maze, a measure of spatial reference memory, Tg rats demonstrated significant impairment relative to wildtype (WT) controls at all 3 age-points. Frontal cortex, entorhinal cortex, and dorsal hippocampus were evaluated for A[Formula: see text]1-42 expression via western blot in Tg rats only. Analyses of A[Formula: see text]1-42 expression revealed age-dependent increases in all 3 regions critical to spatial learning and memory. Measures of physiological health, including heart, uterine, and body weights, revealed unique age-specific outcomes for female Tg rats, with the 9-month timepoint identified as critical for further research within the trajectory of AD-like behavior, physiology, and pathology.

Evaluating the Cognitive Impacts of Drospirenone, a Spironolactone-Derived Progestin, Independently and in Combination With Ethinyl Estradiol in Ovariectomized Adult Rats.

Oral contraceptives and hormone therapies require a progestogen component to prevent ovulation, curtail uterine hyperplasia, and reduce gynecological cancer risk. Diverse classes of synthetic progestogens, called progestins, are used as natural progesterone alternatives due to progesterone's low oral bioavailability. Progesterone and several synthetic analogs can negatively impact cognition and reverse some neuroprotective estrogen effects. Here, we investigate drospirenone, a spironolactone-derived progestin, which has unique pharmacological properties compared to other clinically-available progestins and natural progesterone, for its impact on spatial memory, anxiety-like behavior, and brain regions crucial to these cognitive tasks. Experiment 1 assessed three drospirenone doses in young adult, ovariectomized rats, and found that a moderate drospirenone dose benefited spatial memory. Experiment 2 investigated this moderate drospirenone dose with and without concomitant ethinyl estradiol (EE) treatment, the most common synthetic estrogen in oral contraceptives. Results demonstrate that the addition of EE to drospirenone administration reversed the beneficial working memory effects of drospirenone. The hippocampus, entorhinal cortex, and perirhinal cortex were then probed for proteins known to elicit estrogen- and progestin- mediated effects on learning and memory, including glutamate decarboxylase (GAD)65, GAD67, and insulin-like growth factor receptor protein expression, using western blot. EE increased GAD expression in the perirhinal cortex. Taken together, results underscore the necessity to consider the distinct cognitive and neural impacts of clinically-available synthetic estrogen and progesterone analogs, and why they produce unique cognitive profiles when administered together compared to those observed when each hormone is administered separately.

Surgical Menopause and Estrogen Therapy Modulate the Gut Microbiota, Obesity Markers, and Spatial Memory in Rats.

Menopause in human females and subsequent ovarian hormone deficiency, particularly concerning 17ß-estradiol (E2), increase the risk for metabolic dysfunctions associated with obesity, diabetes type 2, cardiovascular diseases, and dementia. Several studies indicate that these disorders are also strongly associated with compositional changes in the intestinal microbiota; however, how E2 deficiency and hormone therapy affect the gut microbial community is not well understood. Using a rat model, we aimed to evaluate how ovariectomy (OVX) and subsequent E2 administration drive changes in metabolic health and the gut microbial community, as well as potential associations with learning and memory. Findings indicated that OVX-induced ovarian hormone deficiency and E2 treatment had significant impacts on several health-affecting parameters, including (a) the abundance of some intestinal bacterial taxa (e.g., Bifidobacteriaceae and Porphyromonadaceae), (b) the abundance of microbial short-chain fatty acids (SCFAs) (e.g., isobutyrate), (c) weight/BMI, and (d) high-demand spatial working memory following surgical menopause. Furthermore, exploratory correlations among intestinal bacteria abundance, cognition, and BMI underscored the putative influence of surgical menopause and E2 administration on gut-brain interactions. Collectively, this study showed that surgical menopause is associated with physiological and behavioral changes, and that E2-linked compositional changes in the intestinal microbiota might contribute to some of its related negative health consequences. Overall, this study provides novel insights into interactions among endocrine and gastrointestinal systems in the post-menopausal life stage that collectively alter the risk for the development and progression of cardiovascular, metabolic, and dementia-related diseases.