Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats

We hypothesize that beneficial effects of estradiol on cognitive performance diminish with age and time following menopause due to a progressive decline in basal forebrain cholinergic function. This study tested whether galanthamine, a cholinesterase inhibitor used to treat memory impairment associated with Alzheimer's disease, could enhance or restore estradiol effects on cognitive performance in aged rats that had been ovariectomized in middle-age. Rats were ovariectomized at 16–17 months of age. At 21–22 months of age rats began receiving daily injections of galanthamine (5 mg/day) or vehicle. After one week, half of each group also received 17ß-estradiol administered subcutaneously. Rats were then trained on a delayed matching to position (DMP) T-maze task, followed by an operant stimulus discrimination/reversal learning task. Treatment with galanthamine + estradiol significantly enhanced the rate of DMP acquisition and improved short-term delay-dependent spatial memory performance. Treatment with galanthamine or estradiol alone was without significant effect. Effects were task-specific in that galanthamine + estradiol treatment did not significantly improve performance on the stimulus discrimination/reversal learning task. In fact, estradiol was associated with a significant increase in incorrect responses on this task after reversal of the stimulus contingency. In addition, treatments did not significantly affect hippocampal choline acetyltransferase activity or acetylcholine release. This may be an effect of age, or possibly is related to compensatory changes associated with long-term cholinesterase inhibitor treatment. The data suggest that treating with a cholinesterase inhibitor can enhance the effects of estradiol on acquisition of a DMP task by old rats following a long period of hormone deprivation. This could be of particular benefit to older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment. Potential mechanisms for these effects are discussed.     

Shifts in preferred learning strategy across the estrous cycle in female rats

The current status of the effects of ovarian steroids on learning and memory remains somewhat unclear, despite a large undertaking to evaluate these effects. What is emerging from this literature is that estrogen, and perhaps progesterone, influences learning and memory, but does so in a task-dependent manner. Previously, we have shown that ovariectomized rats given acute treatments of estrogen acquire allocentric or "place" tasks more easily than do rats deprived of estrogen, but acquire egocentric or "response" learning tasks more slowly than do those deprived of hormone, suggesting that estrogen treatment may bias the strategy a rat is able to use to solve tasks. To determine if natural fluctuations in ovarian hormones influence cognitive strategy, we tested whether strategy use fluctuated across the estrous cycle in reproductively intact female rats. We found that in two tasks in which rats freely choose the strategy used to solve the task, rats were more likely to use place strategies at proestrous, that is, when ovarian steroids are high. Conversely, estrous rats were biased toward response strategies. The data suggest that natural fluctuations in ovarian steroids may bias the neural system used and thus the cognitive strategies chosen during learning and memory.     

Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin

Ghrelin is a peptide hormone produced and secreted from the stomach. Hypothalamic injection of the peptide increases food intake but it is not known if the peptide affects other brain regions. We measured several behavioral parameters such as anxiety (elevated plus maze), memory retention (step down test), and food intake after injections of different doses of the peptide in the hippocampus, amygdala, and dorsal raphe nucleus (DRN). The injection of ghrelin in the hippocampus and DRN significantly and dose dependently increased food intake in relation to controls rats, while injections into the amygdala did not affect the food intake. We also show for the first time that ghrelin clearly and dose dependently increases memory retention in the hippocampus, amygdala, and DRN. Moreover, ghrelin at different potencies induced anxiogenesis in these brain structures while the highest dose of 3 nmol/microl was effective in all of them. The comparison of sensitivity of each brain structure indicates a specific role of them for each of the behaviors studied. The results provide new insight in to the anatomical substrate and the functional role of extrahypothalamic ghrelin targets in the CNS.     

The development and stability of estrogen-modulated spatial navigation strategies in female rats

Adult female rats with high levels of circulating estradiol are biased to use a place strategy to solve an ambiguous spatial navigation task and those with low levels are biased to use a response strategy. We examined the development of this hormonal modulation of strategy use by training juvenile female rats on an ambiguous navigation task and probing them for strategy use at postnatal day (PD) 16, 21, or 26, after administration of 17 β-estradiol or oil 48 and 24 h prior to testing. We found that rats could use either strategy successfully by PD21 but that estradiol did not bias rats to use a place strategy until PD26. In order to evaluate the stability of this effect over multiple navigation experiences, we retested oil-treated juveniles three times during adulthood. On the first adult navigation experience, rats were significantly more likely to use the same navigation strategy they used as juveniles, regardless of current estrous cycle phase. On the second and third adult tests, after rats had more experience with the task, previous navigation experience did not predict strategy use. Rats in proestrus were significantly more likely to use a place strategy while rats in estrus and diestrus did not appear to have a group bias to use either strategy. These results suggest that estradiol can modulate spatial navigation strategy use before puberty but that this effect interacts with previous navigation experience. This study sheds light on when and under what circumstances estradiol gains control over spatial navigation behavior in the female rat.     

Long-term tryptophan administration enhances cognitive performance and increases 5HT metabolism in the hippocampus of female rats

Summary. It has been shown in various studies that increase in serotonergic neurotransmission is associated with increased memory consolidation whereas low brain 5HT impairs memory performance. In the first phase of our study we found that tryptophan (TRP) administration for 6 weeks increased plasma TRP and whole brain TRP, 5HT and 5HIAA levels. Many brain regions are involved in the learning process but particularly the hippocampus is known to have key role in learning and memory. The present study was therefore designed to investigate the effects of TRP loading particularly on hippocampal 5HT metabolism and cognitive performance in rats. TRP-treated rats demonstrated spatial enhancement as evidenced by a significant decrease in time to find the hidden food reward in radial arm maze test (RAM). The important finding of the present study was the greater increase in the 5HT metabolism in hippocampus than in any other brain region of the TRP-treated rats. This increased 5HT metabolism in the hippocampus emphasizes the involvement of this region in memory process.     

The role of estradiol in adrenal insufficiency and its interaction with corticosterone on hydromineral balance

Estradiol (E2) plays an important role in controlling the homeostasis of body fluids. Several studies have reported the involvement of the hypothalamic pituitary adrenal axis (HPA) in the homeostatic control of hydromineral balance and the influence of estrogens on the modulation of this system. Nevertheless, until now, the physiological relevance of HPA axis activity on the hydromineral balance in females has not yet been fully elucidated. Therefore, the objective of the present study was to evaluate the effects of E2 (20 μg/animal) pretreatment on neuroendocrine and hydroelectrolyte changes induced by adrenalectomy (ADX) with or without glucocorticoid hormone replacement (corticosterone, CORT; 10 mg/kg) in ovariectomized rats (OVX). The results show that sodium appetite, natriuresis and the elevated plasma angiotensin II (ANG II) concentration induced by ADX were attenuated by E2 pretreatment. Additionally, a reduction of AT1 mRNA expression in the subfornical organ (SFO) and an increase in plasma atrial natriuretic peptide (ANP) concentrations by E2 pretreatment were observed. E2 pretreatment reversed the reduction in water intake induced by ADX in ADX CORT-replaced rats. Moreover, E2 pretreatment attenuated corticotropin releasing factor (CRF) mRNA expression in the paraventricular nucleus (PVN) induced by ADX. In contrast, E2 pretreatment increased CRF mRNA expression in the PVN in ADX CORT-replaced rats. Taken together, these results suggest that E2 has an important role in the modulation of behavioral and neuroendocrine responses involved in the maintenance of body fluid homeostasis in ADX rats with or without glucocorticoid replacement therapy.     

Peptides and aging: Their role in anorexia and memory

The rapid aging of the world's population has led to a need to increase our understanding of the pathophysiology of the factors leading to frailty and cognitive decline. Peptides have been shown to be involved in the pathophysiology of frailty and cognitive decline. Weight loss is a major component of frailty. In this review, we demonstrate a central role for both peripheral peptides (e.g., cholecystokinin and ghrelin) and neuropeptides (e.g., dynorphin and alpha-MSH) in the pathophysiology of the anorexia of aging. Similarly, peripheral peptides (e.g., ghrelin, glucagon-like peptide 1, and cholecystokinin) are modulators of memory. A number of centrally acting neuropeptides have also been shown to modulate cognitive processes. Amyloid-beta peptide in physiological levels is a memory enhancer, while in high (pathological) levels, it plays a key role in the development of Alzheimer's disease.     

Flavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studies

Evidence in support of the neuroprotective effects of flavonoids has increased significantly in recent years, although to date much of this evidence has emerged from animal rather than human studies. Nonetheless, with a view to making recommendations for future good practice, we review 15 existing human dietary intervention studies that have examined the effects of particular types of flavonoid on cognitive performance. The studies employed a total of 55 different cognitive tests covering a broad range of cognitive domains. Most studies incorporated at least one measure of executive function/working memory, with nine reporting significant improvements in performance as a function of flavonoid supplementation compared to a control group. However, some domains were overlooked completely (e.g. implicit memory, prospective memory), and for the most part there was little consistency in terms of the particular cognitive tests used making across study comparisons difficult. Furthermore, there was some confusion concerning what aspects of cognitive function particular tests were actually measuring. Overall, while initial results are encouraging, future studies need to pay careful attention when selecting cognitive measures, especially in terms of ensuring that tasks are actually sensitive enough to detect treatment effects.     

Neonatal asphyxia and hyperthermia and cognitive deficits in adult rats: Role of iron

We compared effects of a critical neonatal anoxia, applied in Wistar rats at body temperatures of 33, 37 and 39 °C, on memory performance in adulthood. Because hyperthermic–anoxic neonates suffer from hyperferremia an additional group of rats, exposed to anoxia at 39 °C, was injected with deferoxamine, a chelator of iron. At the age of 4 and 12 months all rats were examined in hole board, typical maze and Morris maze.     

The role of the supramammillary area of the hypothalamus in cognitive functions

The supramammillary area (SUM) of the hypothalamus has wide spread connection with numerous brain structures. It is known that the SUM can control the frequency of the hippocampal theta rhythm, which plays a role in the cognitive functions of the hippocampal formation. In order to examine the role of the specific cells of the SUM in learning and memory, selective cholinergic neurotoxic or excitotoxic lesioned rats of the SUM were tested for spatial memory on the Morris water maze (MWM) test. After the behavior tests, the expression of acetylcholinesterase (AChE) in the hippocampus was studied using the immunohistochemistry. In the MWM test, both lesion of the SUM with 192 IgG-saporin or ibotenic acid produced the impairment of spatial learning and memory. The expression of AChE immunreactive neurons in the hippocampal CA3 region was decreased after injections of 192 IgG-saporin into the SUM. These findings suggest that cholinoceptive cells of the SUM area may play a critical role in the process of learning and memory.     

Donepezil treatment restores the ability of estradiol to enhance cognitive performance in aged rats: Evidence for the cholinergic basis of the critical period hypothesis

Recent studies suggest that the ability of estradiol to enhance cognitive performance diminishes with age and/or time following loss of ovarian function. We hypothesize that this is due, in part, to a decrease in basal forebrain cholinergic function. This study tested whether donepezil, a cholinesterase inhibitor, could restore estradiol effects on cognitive performance in aged rats that had been ovariectomized as young adults. Rats were ovariectomized at 3 months of age, and then trained on a delayed matching to position (DMP) T-maze task, followed by a configural association (CA) operant condition task, beginning at 12-17 or 22-27 months of age. Three weeks prior to testing, rats started to receive either donepezil or vehicle. After one week, half of each group also began receiving estradiol. Acclimation and testing began seven days later and treatment continued throughout testing. Estradiol alone significantly enhanced DMP acquisition in middle-aged rats, but not in aged rats. Donepezil alone had no effect on DMP acquisition in either age group; however, donepezil treatment restored the ability of estradiol to enhance DMP acquisition in aged rats. This effect was due largely to a reduction in the predisposition to adopt a persistent turn strategy during acquisition. These same treatments did not affect acquisition of the CA task in middle-aged rats, but did have small but significant effects on response time in aged rats. The data are consistent with the idea that estrogen effects on cognitive performance are task specific, and that deficits in basal forebrain cholinergic function are responsible for the loss of estradiol effect on DMP acquisition in aged ovariectomized rats. In addition, the data suggest that enhancing cholinergic function pharmacologically can restore the ability of estradiol to enhance acquisition of the DMP task in very old rats following long periods of hormone deprivation. Whether donepezil has similar restorative effects on other estrogen-sensitive tasks needs to be explored.     

Effects of genistein in the maternal diet on reproductive development and spatial learning in male rats

Endocrine disruptors, chemicals that disturb the actions of endogenous hormones, have been implicated in birth defects associated with hormone-dependent development. Phytoestrogens are a class of endocrine disruptors found in plants. In the current study we examined the effects of exposure at various perinatal time periods to genistein, a soy phytoestrogen, on reproductive development and learning in male rats. Dams were fed genistein-containing (5 mg/kg feed) food during both gestation and lactation, during gestation only, during lactation only, or during neither period. Measures of reproductive development and body mass were taken in the male offspring during postnatal development, and learning and memory performance was assessed in adulthood. Genistein exposure via the maternal diet decreased body mass in the male offspring of dams fed genistein during both gestation and lactation, during lactation only, but not during gestation only. Genistein decreased anogenital distance when exposure was during both gestation and lactation, but there was no effect when exposure was limited to one of these time periods. Similarly, spatial learning in the Morris water maze was impaired in male rats exposed to genistein during both gestation and lactation, but not in rats exposed during only one of these time periods. There was no effect of genistein on cued or contextual fear conditioning. In summary, the data indicate that exposure to genistein through the maternal diet significantly impacts growth in male offspring if exposure is during lactation. The effects of genistein on reproductive development and spatial learning required exposure throughout the pre- and postnatal periods.     

Response probability and response time: a straight line, the Tagging/Retagging interpretation of short term memory, an operational definition of meaningfulness and short term memory time decay and search time

The functional relationship between correct response probability and response time is investigated in data sets from Rubin, Hinton and Wenzel, J Exp Psychol Learn Mem Cogn 25:1161–1176, 1999 and Anderson, J Exp Psychol [Hum Learn] 7:326–343, 1981. The two measures are linearly related through stimulus presentation lags from 0 to 594 s in the former experiment and for repeated learning of words in the latter. The Tagging/Retagging interpretation of short term memory is introduced to explain this linear relationship. At stimulus presentation the words are tagged. This tagging level drops slowly with time. When a probe word is reintroduced the tagging level has to increase for the word to be properly identified leading to a delay in response time. The tagging time is related to the meaningfulness of the words used—the more meaningful the word the longer the tagging time. After stimulus presentation the tagging level drops in a logarithmic fashion to 50% after 10 s and to 20% after 240 s. The incorrect recall and recognition times saturate in the Rubin et al. data set (they are not linear for large time lags), suggesting a limited time to search the short term memory structure: the search time for recall of unusual words is 1.7 s. For recognition of nonsense words the corresponding time is about 0.4 s, similar to the 0.243 s found in Cavanagh (1972).     

Effect of sevoflurane and halothane anesthesia on cognitive function and immune function in young rats

In the current study, we scrutinized the effect of sevoflurane and halothane on cognitive and immune function in young rats. The rats were divided into following groups: sevoflurane, halothane and sevoflurane + halothane groups, respectively. The rats were regularly treated with the pre-determined treatment. We also scrutinized the serum proinflammatory cytokines including IL-10, IL-4 and IL-2; brain level IL-1β; hippocampal neuronal apoptosis concentration were estimated. The water maze test was performed in rats for the estimation of cognitive ability. During the water maze test, on the 1st day the sevoflurane group showed the latency; sevoflurane and sevoflurane + halothane group demonstrated the declined latency gradually as compared to the control group rats after the 3 days. The latency of the control, halothane, sevoflurane + halothane group rats showed the reduced latency and also showed the reduced crossing circle times. The hippocampal neuron apoptosis was significantly increased in halothane and sevoflurane + halothane group as compared to control group rats, respectively. Control group rats demonstrated the increased neuron apoptosis. The proinflammatory cytokines including IL-10 and IL-4 was significantly higher in sevoflurane, halothane and sevoflurane + halothane group rats after anesthesia and the whole brain IL-1β was significantly decrease in the sevoflurane, halothane and sevoflurane + halothane as compared to control group. Sevoflurane can inhibit the anesthesia effect of halothane on the immune and cognitive function of rats.     

大鼠鞘内注射多巴胺受体激动剂与拮抗剂对痛及针刺镇痛的影响

在大鼠电刺激甩测痛模型上,应用鞘内注射（ｉｔ）多巴胺（ＤＡ）受体选择性激动剂与拮抗剂,分析大鼠脊髓ＤＡ受体亚型Ｄ１和Ｄ２在痛及针刺镇痛（ＡＡ）中的作用。结果显示,在正常清醒大鼠,ｉｔ Ｄ２受体选择性激动剂,Ｙ１７１５５５（ＬＹ）或Ｄ１／Ｄ２受体激动剂阿朴吗啡（ＡＰＯ）有镇痛作用（呈剂量依赖式增加）,并加强ＡＡ,而ｉｔ Ｄ１受体选择性激动剂ＳＫＦ３８３９３（ＳＫＦ）对痛及ＡＡ均无影响;ｉｔ Ｄ１受体     

Cyclic nucleotide phosphodiesterase of the olfactory membrane in rats: its distribution and possible connection with the estradiol receptor

In the rat olfactory tissue the existence of soluble and membrane-bound forms of cyclic nucleotide phosphodiesterase (PDE) with quite similar kinetic parameters was demonstrated (KM = 220 and 200 microM, VMaX = 10 and 7 nmoles cAMP/mg protein per minute, respectively). 17 beta-estradiol (10(-7)-10(-5) M) decreased the soluble PDE activity by 25%, whereas non-hydrolysable GTP analogue (Gpp (NHp)) abolished their effect. On the other hand, this analogue in a dose-dependent manner inhibited the specific binding of 3H-estradiol to cytosolic receptors. The data indicate possible functional interrelations between the cytosolic estradiol receptors, GTP-binding proteins and PDE in the olfactory tissue which is a target organ for steroid hormones.     

Roles of oxytocin in spatial learning and memory in the nucleus basalis of Meynert in rats

The present study was performed to explore the role of oxytocin (OT) in spatial learning and memory in the nucleus basalis of Meynert (NBM) of rats. The latency, distance and swimming path to find the platform were tested by Morris water maze and recorded by a video camera connected to a computer. Intra-NBM injections of 2 or 10 nmol of OT, but not 0.2 nmol of OT, induced significant increase on the latency of spatial learning. Rats receiving intra-NBM administrations of 2 or 10 nmol of OT showed a more random search pattern. There were no significant changes in the swimming speed in Morris water maze test after the injection of OT. Furthermore, the impaired effect of OT on the latency of spatial learning was blocked by intra-NBM injection of the selective OT antagonist Atosiban, indicating that the effect of OT was mediated by OT receptor in the NBM of rats. Moreover, there were no influences of OT or Atosiban on the retention performance in rats. The results suggest that OT plays an inhibitory role in spatial learning in the NBM; the effect is mediated by OT receptor.     

Estradiol treatment and its interaction with the cholinergic system: effects on cognitive function in healthy young women

The steroid hormone estradiol has been shown to modulate cognitive function in both animals and humans, and although the exact mechanisms associated with these effects are unknown, interactions with the cholinergic system have been proposed. We examined the neurocognitive effects of short-term estradiol treatment and its interaction with the cholinergic system using the muscarinic receptor antagonist scopolamine in healthy young women. Thirty-four participants (Mean age ± SD = 22.4 ± 4.4) completed baseline cognitive assessment and then received either 100 μg/day transdermal estradiol or transdermal placebo for 31 days. On days 28 and 31 of treatment, further cognitive assessment was performed pre- and 90 min post-scopolamine (0.4 mg) or placebo (saline) injection, under a randomized double-blind placebo-controlled design. Short-term estradiol treatment significantly enhanced spatial working memory with a trend for improvement in long-term verbal learning and memory. Overall, estradiol treatment did not protect against or attenuate the scopolamine-induced impairments in the cognitive domains assessed. Findings suggest that estrogen has minimal effects on cholinergic-mediated cognitive processes following short-term treatment. Effects of estradiol treatment may be dependent on age, dose of estradiol, integrity of cholinergic innervation and baseline endogenous estrogen levels, which may in part explain the inconsistent findings in the literature.     

High glucose blocks the effects of estradiol on human vascular cell growth: differential interaction with estradiol and raloxifene

Because diabetic women appear not to be protected by estrogen in terms of propensity to cardiovascular disease, we tested the possibility that chronic hyperglycemia modulates the effects of E(2) on vascular cell growth in vitro. Human endothelial cells (E304) and vascular smooth muscle cells (VSMC) were grown in normal glucose (5.5 mmol/l), high glucose (22 mmol/l) or high manitol (22 nmol/l; an osmotic control) for 7 days. In endothelial cells glucose per se stimulated DNA synthesis. However E(2)- (but not RAL-) stimulated [3H] thymidine incorporation was attenuated in the presence of high glucose. In parallel, E(2)-dependent MAP-kinase-kinase activity was blocked in the presence of high glucose. High glucose increased basal creatine kinase (CK) specific activity, but E(2)-stimulated CK was not significantly impaired in the presence of high glucose. In VSMC, high glucose prevented the inhibitory effect of high E(2) (but not of high RAL) concentrations on DNA synthesis. High glucose also prevented E(2)-induced MAP-kinase-kinase activity. In contrast, while high glucose augmented basal CK, the relative E(2)-induced changes were roughly equal in normal and high high glucose media. Hence, high glucose blocks several effects of E(2) on vascular cell growth, which are mediated, in part, via the MAP-kinase system and are likely contributors to E(2)'s anti-atherosclerotic properties. Since RAL's estrogen-mimetic effects on human vascular cell growth were independent of MAP-kinase activation and were not affected by hyperglycemia, the potential use of RAL to circumvent the loss of estrogen function induced by hyperglycemia and diabetes in the human vasculature should be further explored.     

Aquaporin-3 in keratinocytes and skin: its role and interaction with phospholipase D2

Aquaporin 3 (AQP3) is an aquaglyceroporin that transports water and glycerol and is expressed in the epidermis, among other epithelial tissues. We have recently shown that there is an association between this glycerol channel and phospholipase D2 (PLD2) in caveolin-rich membrane microdomains. While PLD2 is able to hydrolyze membrane phospholipids to generate phosphatidic acid, this enzyme also catalyzes, in the presence of primary alcohols, a transphosphatidylation reaction to produce a phosphatidylalcohol. We have proposed that AQP3 associated with PLD2 provides the physiological primary alcohol glycerol to PLD2 for use in the transphosphatidylation reaction to generate phosphatidylglycerol (PG). Further, we have proposed that PG functions as a signaling molecule to mediate early epidermal keratinocyte differentiation, and manipulation of this signaling module inhibits keratinocyte proliferation and enhances differentiation. In contrast, other investigators have suggested a proliferative role for AQP3 in keratinocytes. In addition, AQP3 knockout mice exhibit an epidermal phenotype, characterized by dry skin, decreased elasticity and delayed barrier repair and wound healing, which can be corrected by glycerol but not other humectants. AQP3 levels have also been found to be altered in human skin diseases. In this article the evidence supporting a role for AQP3 in the epidermis will be discussed.