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Previous investigations of estradiol's effects on learning and memory yielded equivocal results. This study was designed to determine whether these inconsistencies were due to dose-dependent effects of estradiol on different memory processes. Ovariectomized female rats were injected daily with estradiol benzoate (EB; 0.32, 1.00, or 5.00 [micro]g) or vehicle. Approximately 3 hr after injection, rats were run on a hippocampus-dependent working/reference memory version of the radial arm maze. Total number of working (WME), reference, and combined working/reference memory errors were scored. Compared with vehicle, 1.00 or 5.00 [micro]g EB (high physiological) impaired performance by increasing the number of WME, whereas 0.32 [micro]g EB (low physiological) facilitated performance by decreasing the number of WME. Taken together, these data demonstrate a dose-dependent effect of EB on working memory.

The present study investigated the role of endogenous opioids in the expression of defensive behaviors (DBs) and the suppression of cell proliferation (CP) in the dentate gyms (DG) induced by exposure to predator odor, trimethyl thiazoline (TMT). Adult male rats were injected with either naltrexone (an opioid antagonist, 5 mg/kg) or saline 30 min before exposure to either TMT or a control odor. Behavior was scored for the first 15 min of odor exposure. Bromodeoxyuridine (BrdU, 200 mg/kg) was then injected, and the rats were perfused 1 hr later. Exposure to TMT increased the expression of DBs and suppressed the number of proliferating cells in the DG. Pretreatment with naltrexone attenuated the effects of TMT on DB expression but did not attenuate the effects of TMT on CP. In addition, naltrexone administration suppressed CP in the absence of TMT. These results demonstrate a dissociation between DBs and regulation of CP in the DG.

Chronic restraint stress causes significant dendritic atrophy of CA3 pyramidal neurons that reverts to baseline within a week. Therefore, the authors assessed the functional consequences of this atrophy quickly (within hours) using the Y maze. Experiments 1-3 demonstrated that rats relied on extrinsic, spatial cues located outside of the Y maze to determine arm location and that rats with hippocampal damage (through kainic acid, colchicine, or trimethyltin) had spatial memory impairments. After the Y maze was validated as a hippocampally relevant spatial task, Experiment 4 showed that chronic restraint stress impaired spatial memory performance on the Y maze when rats were tested the day after the last stress session and that tianeptine prevented the stress-induced spatial memory impairment. These data are consistent with the previously demonstrated ability of tianeptine to prevent chronic stress-induced atrophy of the CA3 dendrites.

To correlate pain-related phenotyping for central nervous system sensitization in endometriosis-associated pain with mental health outcomes during the COVID-19 pandemic, the prospective Endometriosis and Pelvic Pain Interdisciplinary Cohort (ClinicalTrials.gov #NCT02911090) was linked to the COVID-19 Rapid Evidence Study of a Provincial Population-Based Cohort for Gender and Sex (RESPPONSE) dataset. The primary outcomes were depression (PHQ-9) and anxiety (GAD-7) scores during the pandemic. The explanatory variables of interest were the Central Sensitization Inventory (CSI) score (0–100) and endometriosis-associated chronic pain comorbidities/psychological variables before the pandemic. The explanatory and response variables were assessed for correlation, followed by multivariable regression analyses adjusting for PHQ-9 and GAD-7 scores pre-pandemic as well as age, body mass index, and parity. A higher CSI score and a greater number of chronic pain comorbidities before the pandemic were both positively correlated with PHQ-9 and GAD-7 scores during the pandemic. These associations remained significant in adjusted analyses. Increasing the CSI score by 10 was associated with an increase in pandemic PHQ-9 by .74 points (P < .0001) and GAD-7 by .73 points (P < .0001) on average. Each additional chronic pain comorbidity/psychological variable was associated with an increase in pandemic PHQ-9 by an average of .63 points (P = .0004) and GAD-7 by .53 points (P = .0002). Endometriosis patients with a history of central sensitization before the pandemic had worse mental health outcomes during the COVID-19 pandemic. As a risk factor for mental health symptoms in the face of major stressors, clinical proxies for central sensitization can be used to identify endometriosis patients who may need additional support.

Pregnancy and mothering result in a number of hormonal, neurological, and behavioral changes that are necessary to ensure reproductive success. With subsequent reproductive experience (multiparity and mothering), further neurological and behavioral changes may result. Recent research has shown that previous motherhood enhances both hippocampus‐dependent learning and memory and long‐term potentiation (LTP); together with decreases in hippocampus volumes during pregnancy it is suggested that the hippocampus is affected by pregnancy and/or mothering. The present experiment aimed to investigate the effect of reproductive experience (nulli, primi‐, and multiparity and mothering) on dendritic morphology in the CA1 and CA3 regions of the hippocampus. Brains were stained with a modified version of the single‐section Golgi impregnation technique, and dendritic length, number of branch points, and spine density was analyzed for apical and basal regions of CA1 and CA3 pyramidal neurons. Primiparity and/or mothering resulted in dendritic remodeling in both the CA1 and CA3 hippocampal regions, and multiparity resulted in enhanced spine density in the basal CA1 region, which was positively correlated with number of male pups in a litter. These findings point to the effect of reproductive experience and offspring on plasticity in the hippocampus, an area not traditionally associated with motherhood. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2006

High‐level estradiol enhances cell proliferation in the dentate gyrus of adult female rats within 4 h of administration and then suppresses cell proliferation within 48 h via an adrenal steroid‐dependent mechanism (Ormerod et al., [2003b] J Neurobiol 55:247–260). Here, we investigate whether the estradiol‐induced enhancement in progenitor cell proliferation is mediated through estrogen receptors (ERSs) using the selective ER antagonist ICI 182,780 (ICI). Ovariectomized Sprague‐Dawley rats were given two subcutaneous injections of either vehicle + vehicle (VEH; 0.1 ml sesame oil); VEH+ICI (500 µg); estradiol benzoate (EB; 10 µg)+VEH; or EB +ICI. The cell synthesis marker, 5‐bromo‐2′‐deoxyuridine (200 mg/kg) was administered 4 h later. Animals were perfused 24 h after BrdU injection and cell proliferation was assessed following immunohistochemical processing of the tissue. Relative to VEH, EB increased cell proliferation by approximately 50%. This EB‐induced increase was partially blocked by ICI 182,780 treatment, and ICI 182,780 treatment alone enhanced cell proliferation. Our results demonstrate that estradiol enhances cell proliferation in the dentate gyrus of adult female rats by activating estrogen receptors. Drug Dev. Res. 66:142–149, 2006. © 2006 Wiley‐Liss, Inc.

To determine whether exposure to fox odor alters granule neuron production, we examined proliferating cells and their progeny in the dentate gyrus of adult male rats exposed to trimethyl thiazoline, a component of fox feces. Additionally, to determine whether this effect is adrenal hormone‐mediated, we examined animals exposed to fox odor after bilateral adrenalectomy and replacement with low levels of the endogenous glucocorticoid corticosterone. Stereologic analyses of the number of 5‐bromo‐2′deoxyuridine (BrdU) ‐labeled cells revealed that exposure to fox odor but not other, nonthreatening, odors (mint or orange) rapidly decreased the number of proliferating cells in the dentate gyrus. This effect is dependent on a stress‐induced rise in adrenal hormones; exposure to fox odor resulted in an increase in circulating corticosterone levels and prevention of this increase (by means of adrenalectomy plus low‐dose corticosterone replacement) eliminated the suppression of cell proliferation. Examination at longer survival times revealed that the decrease in the number of new granule cells in fox odor‐exposed animals was transient; a difference was still detectable at 1 week after BrdU labeling but not at 3 weeks. In both fox and sham odor‐exposed animals, many new cells acquired morphologic and biochemical characteristics of mature granule neurons. The majority of these cells expressed a marker of immature granule neurons (TuJ1) by 1 week after BrdU labeling and markers of mature granule neurons (calbindin, NeuN) by 3 weeks after labeling. These findings suggest that stressful experiences rapidly diminish cell proliferation by increasing adrenal hormone levels, resulting in a transient decrease in the number of adult‐generated immature granule neurons. J. Comp. Neurol. 437:496–504, 2001. © 2001 Wiley‐Liss, Inc.

The present experiments investigated the effects of pregnancy on performance in the Morris water maze and on hippocampal volume. In the first study, pregnant rats (in between the first and second trimester) outperformed nonpregnant rats on the Morris water maze on 1 day of testing. In the second study, rats were tested in a working memory variation of the maze in which the spatial location of the platform varied. Pregnant females traveled shorter distances than nonpregnant females during the first two trimesters, but performed worse than nonpregnant females during the third trimester. Latency measures showed a similar profile. Group differences in performance were not related to changes in swim speed. However, changes in performance in pregnant females may be related to estrogen, progesterone, and/or corticosterone levels during pregnancy, with low levels of estradiol and high levels of progesterone being associated with better performance. There were no significant differences between pregnant and nonpregnant animals on any of the brain measures, although pregnant animals tended to have a smaller hippocampus than nonpregnant animals. These results indicate that pregnancy can affect performance, possibly related to the hormonal changes that accompany pregnancy.

The granule cell population of the dentate gyrus is produced predominantly during the postnatal period in rats. Previous studies have shown that experimental increases in the levels of adrenal steroids suppress the proliferation of granule cell precursors during the first postnatal week, the time of maximal neurogenesis in the dentate gyrus. These findings raise the possibility that stressful experiences that elevate adrenal steroid levels may inhibit the production of granule neurons, and thus alter the development of the dentate gyrus. To test this possibility, we exposed naive rat pups to the odors of a known predator, adult male rats, and examined both plasma corticosterone levels and the number of 3H-thymidine labeled cells in the dentate gyrus. A single exposure of rat pups to adult male rat odor elevated corticosterone levels immediately and diminished the number of 3H-thymidine labeled cells in the granule cell layer by 24 h later. These results suggest that stressful experiences suppress the production of granule neurons in the developing dentate gyrus.