Interactions between estradiol, BDNF and dendritic spines in promoting memory.

Several lines of evidence have converged to indicate that memory formation involves plasticity of dendritic spines in the medial prefrontal cortex (PFC) and the hippocampus. Memory varies with estrogen levels throughout the lifespan of the female. Generally, increased levels of estrogen are related to greater dendritic spine density on pyramidal cells in the PFC and the hippocampus and to improved memory function. Brain-derived neurotrophic factor (BDNF) is a growth factor which increases dendritic spines and enhances memory function. Estrogens increase BDNF levels in the PFC and the hippocampus. In the present review we provide evidence that estradiol and BDNF may work in concert to enhance cognition. In adult females, fluctuations in recognition memory following ovariectomy and estradiol replacement, during the estrous cycle, in pregnancy and with aging are accompanied by similar changes in circulating estradiol, BDNF levels and spine density alterations in the PFC and the hippocampus. In addition, both estradiol and BDNF induce spine plasticity via rapid membrane effects and slower transcriptional regulation via the CREB pathway. Moreover, estradiol increases BDNF levels through action on nuclear receptors. While the exact mechanism(s) for the influence of estrogens and BDNF on memory remain unclear, this combination may provide the basis for new and more effective strategies for treating age-related and neurodegenerative memory loss.

Estrogen-induced memory enhancements are blocked by acute bisphenol A in adult female rats: role of dendritic spines.

Acute effects of bisphenol (BPA), an environmental chemical, on estradiol (17α or ß-E2)-dependent recognition memory and dendritic spines in the medial prefrontal cortex and hippocampus were investigated in adult female rats. Ovariectomized rats received BPA 30 min before or immediately after a sample trial (viewing objects), and retention trials were performed 4 h later. Retention trials tested discrimination between old and new objects (visual memory) or locations (place memory). When given immediately after the sample trial, BPA, 1-400 µg/kg, did not alter recognition memory, but 1 and 40 µg/kg BPA, respectively, blocked 17ß-E2-dependent increases in place and visual memory. When ovariectomized rats were tested with 17α-E2, 1 µg/kg BPA blocked place memory, but up to 40 µg did not block visual memory. BPA, given to cycling rats at 40 µg/kg, blocked visual, but not place, memory during proestrus when 2 h intertrial delays were given. Spine density was assessed at times of memory consolidation (30 min) and retention (4 h) after 17ß-E2 or BPA + 17ß-E2. In prefrontal cortex, BPA did not alter E2-dependent increases. In the hippocampus, BPA blocked E2 increases in basal spines at 4 h and was additive with E2 at 30 min. Thus, these novel data show that doses of BPA, below the current Environmental Protection Agency safe limit of 50 µg/kg, rapidly alter neural functions dependent on E2 in adult female rats.

Prenatal cocaine exposure increases anxiety, impairs cognitive function and increases dendritic spine density in adult rats: influence of sex.

Cocaine exposure during pregnancy can impact brain development and have long-term behavioral consequences. The present study examined the lasting consequences of prenatal cocaine (PN-COC) exposure on the performance of cognitive tasks and dendritic spine density in adult male and female rats. From gestational day 8 to 20, dams were treated daily with 30 mg/kg (ip) of cocaine HCl or saline. At 62 days of age, offspring were tested consecutively for anxiety, locomotion, visual memory and spatial memory. PN-COC exposure significantly increased anxiety in both sexes. Object recognition (OR) and placement (OP) tasks were used to assess cognitive function. Behavioral tests consisted of an exploration trial (T1) and a recognition trial (T2) that were separated by an inter-trial delay of varying lengths. Male PN-COC subjects displayed significantly less time investigating new objects or object locations during T2 in both OR and OP tasks. By contrast, female PN-COC subjects exhibited impairments only in OR and only at the longest inter-trial delay interval. In addition, gestational cocaine increased dendritic spine density in the prefrontal cortex and nucleus accumbens in both genders, but only females had increased spine density in the CA1 region of the hippocampus. These data reveal that in-utero exposure to cocaine results in enduring alterations in anxiety, cognitive function and spine density in adulthood. Moreover, cognitive deficits were more profound in males than in females.

Chronic stress and neural function: accounting for sex and age.

Cognitive responses to stress follow the temporally dependent pattern originally established by Selye (1) wherein short-term stressors elicit adaptive responses whereas continued stress (chronic) results in maladaptive changes--deleterious effects on physiological systems and impaired cognition. However, this pattern for cognitive effects appears to apply to only half the population (males) and, more specifically, to young, adult males. Females show different cognitive responses to stress. In contrast to impaired cognition in males after chronic stress, female rodents show enhanced performance on the same memory tasks after the same stress. Not only cognition, but anxiety, shows sex-dependent changes following chronic stress--stress is anxiolytic in males and anxiogenic in females. Moreover, behavioral responses to chronic stress are different in developing as well as aging subjects (both sexes) as compared to adults. In aged rats, chronic stress enhances recognition memory in both sexes, does not alter spatial memory, and anxiety effects are opposite to young adults. When pregnant dams are exposed to chronic stress, at adulthood the offspring display yet different consequences of stress on anxiety and cognition, and, in contrast to adulthood when the behavioral effects of stress are reversible, prenatal stress effects appear enduring. Changing levels of estradiol in the sexes over the lifespan appear to contribute to the differences in response to stress. Thus, theories of stress dependent modulations in CNS function--developed solely in male models, focused on peripheral physiological processes and tested in adults--may require revision when applied to a more diverse population (age- and sex-wise) at least in relation to the neural functions of cognition and anxiety. Moreover, these results suggest that other stressors and neural functions should be investigated to determine whether age, sex and gonadal hormones also have an impact.

Dietary phytoestrogens enhance spatial memory and spine density in the hippocampus and prefrontal cortex of ovariectomized rats.

Long-term maintenance of ovariectomized rats (9 weeks) on chow containing high phytoestrogen levels (Purina LabDiet 5001) as compared to chow with minimal phytoestrogens (Harlan 2016 Teklad) was associated with better performance of the spatial memory task, object placement, increased dendritic spine density in CA1 and prefrontal cortex pyramidal neurons, and higher uterine weights. Object recognition memory, anxiety on an elevated plus maze and body weight were unaffected by phytoestrogen levels in the diet.

Ovariectomized rats show decreased recognition memory and spine density in the hippocampus and prefrontal cortex.

Effects of ovariectomy (OVX) on performance of the memory tasks, Object Recognition (OR) and Object Placement (OP), and on dendritic spine density in pyramidal neurons in layer II/III of the prefrontal cortex and the CA1 and CA3 regions of the hippocampus were determined. OVX was associated with a significant decline in performance of the memory tasks as compared to intact rats beginning at 1 week post OVX for OR and 4 weeks post OVX for OP. Golgi impregnation at 7 weeks post OVX showed significantly lower spine densities (17-53%) in the pyramidal neurons of the medial prefrontal cortex and the CA1, but not the CA3, region of the hippocampus in OVX compared to intact rats. These results suggest that cognitive impairments observed in OVX rats may be associated with morphological changes in brain areas mediating memory.

Prevention of stress-induced morphological and cognitive consequences.

Atrophy and dysfunction of the human hippocampus is a feature of aging in some individuals, and this dysfunction predicts later dementia. There is reason to believe that adrenal glucocorticoids may contribute to these changes, since the elevations of glucocorticoids in Cushing's syndrome and during normal aging are associated with atrophy of the entire hippocampal formation in humans and are linked to deficits in short-term verbal memory. We have developed a model of stress-induced atrophy of the hippocampus of rats at the cellular level, and we have been investigating underlying mechanisms in search of agents that will block the atrophy. Repeated restraint stress in rats for 3 weeks causes changes in the hippocampal formation that include suppression of 5-HT1A receptor binding and atrophy of dendrites of CA3 pyramidal neurons, as well as impairment of initial learning of a radial arm maze task. Because serotonin is released by stressors and may play a role in the actions of stress on nerve cells, we investigated the actions of agents that facilitate or inhibit serotonin reuptake. Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day) had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning. Because corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or corticosterone, and that the final common path may involve interactive effects between serotonin and glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus. We discuss the implications of these findings for treating cognitive impairments and the risk for dementia in the elderly.

Tianeptine treatment induces regionally specific changes in monoamines.

Tianeptine is an atypical tricyclic antidepressant that facilitates serotonin (5-HT) reuptake. Tianeptine (10 mg/kg) or saline was administered intraperitoneally to male rats daily for 4 days. Monoamine levels were measured in micropunches of discrete brain nuclei that are implicated in mood and cognition. In addition, the rates of 5-HT and norepinephrine (NE) accumulation were determined by the pargyline method. Few changes were noted in the 5-HT system. 5-HT levels were increased by short-term tianeptine in the CA3 region of hippocampus, and 5-hydroxyindoleacetic acid (5-HIAA) was increased in the ventromedial nucleus of hypothalamus, while 5-HT turnover was decreased in preoptic area (POA). In addition, short-term tianeptine treatment increased NE levels in POA, parietal sensory cortex (SCTX) and dorsal raphe (DR), and decreased NE in dentate gyrus. NE turnover was also decreased in DR, SCTX and parietal motor cortex. These data suggest that the short-term neural and behavioral actions of tianeptine may be attributable, in part, to alterations of the norepinephrine system.

Estrogen-induction of dendritic spines in ventromedial hypothalamus and hippocampus: effects of neonatal aromatase blockade and adult GDX.

Treatment of male rats at birth with an aromatase inhibitor (Letrazole), followed by adult gonadectomy GDX, led to an increase in dendritic spine density on ventromedial hypothalamic neurons (VMN) when treated with estrogen as compared to a decrease when vehicle animals were given estrogen. In contrast, estrogen-treatment increased dendritic spine density on CA1 pyramidal neurons regardless of neonatal treatment. In addition, in CA1 there was a significant difference between the two estrogen groups. These results suggest that estrogen induction of dendritic spines in the VMN and CA1 is dependent on organizational effects of gonadal steroids.

Gonadal steroids and neuronal plasticity. Studies in the adult rat hypothalamus.

In this chapter, recent studies on gonadal steroid-induced neural plasticity in the adult rat hypothalamus have been described. Neurons in the VMN and DMN are capable of rapid, reversible structural alterations in response to a changing hormonal environment. Given the importance of the VMN in mediating lordosis in female rats, the present studies suggest that hormonally induced morphological changes in the VMN may be necessary for the manifestation of lordosis. This possibility is supported by the 5,7-DHT studies which indicate that the induction of dendritic spines on VMN neurons may somehow decrease the threshold of E needed to elicit lordosis. Moreover, the sex differences in hormonal requirements for lordosis in 5,7-DHT-treated rats are probably the result of organizational effects of gonadal steroids. Our data support the idea that activational effects can only be superimposed on existing brain circuitry to a certain degree. Finally, the neuronal plasticity seen in the hypothalamus may be an important physiological mechanism by which gonadal steroid feedback mediates reproductive and behavioral function.

The effects of aging and hormonal manipulation on amyloid precursor protein APP695 mRNA expression in the rat hippocampus.

In the rat hippocampus, neuronal morphology and survival are profoundly affected by adrenal steroids, and synaptic plasticity can be modulated by the ovarian sex steroids estrogen and progesterone. beta-amyloid peptides, which accumulate in neuritic plaques and are derived from the amyloid precursor protein (APP), have been shown to be both trophic and toxic for hippocampal neurons. Of the various APP isoforms, APP695 is the predominant form found in rat brain and the APP695 mRNA is abundantly expressed in the hippocampus. In order to investigate the hypothesis that APP may serve as a mediator of the steroid effects, we have monitored the hippocampal expression of APP695 mRNA by in situ hybridization, with aging and with steroid manipulation. In aged female rats we observed a decrease in the level of APP695 mRNA relative to young female rats, while no such age difference was evident in male rats. Physiological, surgical and pharmacological manipulation of glucocorticoids appeared to have no effect on APP695 mRNA levels in the hippocampus. Treatment of young, ovariectomized female rats with estrogen and progesterone, resulted in an increase in hippocampal APP695 expression compared to untreated, ovariectomized controls.

Creating a participant text: writing, multiple voices, narrative multiplicity.

This article uses the ideas of social constructionism to explore how families change by investigating the way our perceptions of ourselves in relation to others are formed through language. The idea that language has the inherent potential to generate a reply has strongly influenced our thinking. We propose that the reply to others is shaped by our initial reply to ourselves in inner conversation. Interaction moves back and forth from inner conversation to conversation with others, from monologue to dialogue, becoming the "stuff" of new narratives. The particular focus on language in this article is on how adding writing to the session conversation produces a "participant text," a therapeutic narrative that is composed of the voices of the family and the therapists. These voices, often newly discovered or invented, allow our narrative discourse to expand and multiply. Using this approach with individuals, couples, and families from different socioeconomic levels, we have worked with mourning, divorcing couples, recovery from abuse, marital conflict, parenting dilemmas, and physical illness.

Short-term fluoxetine treatment alters monoamine levels and turnover in discrete brain nuclei.

The effects of short-term fluoxetine administration on monoamine levels and turnover were assessed in discrete brain nuclei. Adult male rats received fluoxetine HCl (10 mg/kg) or saline injections intraperitoneally for 4 days and monoamine levels determined by high performance liquid chromatography. The major metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), was decreased by fluoxetine treatment in the ventromedial hypothalamic nucleus (VMN), the lateral hypothalamic area and the CA1 region of the hippocampus. Fluoxetine treatment significantly increased serotonin (5-HT) levels in the VMN but did not change 5-HT levels in any other area examined. Norepinephrine (NE) levels were higher in fluoxetine-treated rats in the dorsomedial hypothalamic nucleus, dorsal raphe nucleus and parietal motor cortex (MCTX). 5-HT and NE turnover were also determined by the pargyline method. Fluoxetine treatment decreased 5-HT turnover in the VMN and increased 5-HT turnover in the median raphe. NE turnover was decreased in the preoptic area, the MCTX and parietal sensory cortex by fluoxetine administration. These results demonstrate that brain areas with similar 5-HT innervation respond differently to fluoxetine administration and fluoxetine, which selectively alters 5-HT uptake, also affects NE levels and turnover in several brain nuclei.

Effect of 5,7-dihydroxytryptamine, ovariectomy and gonadal steroids on serotonin receptor binding in rat brain.

Quantitative autoradiography was used to assess alterations in serotonin (5-HT) receptor binding in the hypothalamus and hippocampus following denervation with 5,7-dihydroxytryptamine (5,7-DHT), ovariectomy (OVX) and gonadal steroid manipulation. Seven days after 5,7-DHT injection, 5-HT1a receptor density was significantly increased in the ventromedial hypothalamic nucleus (VMN) of intact but not OVX female rats. Under these conditions 5-HT1b receptor density was unchanged in any brain region examined and 5-HT transporter binding was decreased in all 5,7-DHT injected animals. In addition, there was a significant interaction between OVX and 5,7-DHT for both the 5-HT1a receptor and the 5-HT transporter in the VMN, such that OVX inhibited the 5,7-DHT-induced increase in 5-HT1a receptors and attenuated the 5,7-DHT-induced decrease in 5-HT transporter binding. In a separate experiment the effect of gonadal steroid manipulation on 5-HT receptor binding was assessed. In female OVX rats, 5-HT1a receptor density was unchanged by estrogen or estrogen and progesterone administration. In male rats, castration significantly decreased 5-HT1a receptor density in the medial preoptic area. Estrogen and progesterone administration to female OVX rats increased the density of 5-HT1b receptors in the VMN, as compared to estrogen alone. The relationship of these results to the role of 5-HT in mediating lordosis behavior is discussed.

Alterations of serotonin receptor binding in the hypothalamus following acute denervation.

Quantitative autoradiography was used to determine the effect of acute serotonergic denervation with 5,7-dihydroxytryptamine (5,7-DHT) or serotonin 5HT1a and 5-HT1b receptors in male rats. Seven days after intrahypothalamic 5,7-DHT injection there was a significant increase in the density of 5HT1a receptors in the ventromedial and dorsomedial hypothalamic nuclei (VMN and DMN) of male rats. In adjacent sections. 5-HT1b receptors were significantly increased only in the VMN. No changes in receptor density were observed in the lateral hypothalamic area or hippocampus even though binding of [3H]paroxetine, which labels the presynaptic transporter site, was significantly decreased in all evaluated brain regions in 5,7-DHT-treated animals. In addition to demonstrating that 5-HT1a and 5-HT1b receptors are differentially regulated in different brain areas, these results show that in the brain regions examined both 5-HT1a and 5-HT1b receptors are primarily post-synaptic.

5,7-DHT facilitated lordosis: effects of 5-HT agonists.

The role of 5-HT (serotonin) in regulating lordosis was investigated by combining peripheral administration of the 5-HT agonists 8-OH-DPAT (8-hydroxy-2-[di-N-propylamino]tetralin) or TFMPP (1-[m-trifluoromethylphenyl]piperazine), with intrahypothalamic application of the 5-HT neurotoxin 5,7-DHT (5,7-dihydroxytryptamine). The 5-HT1A agonist, 8-OH-DPAT, significantly inhibited lordosis in 5,7-DHT-treated and non-treated rats. TFMPP, an agonist at 5-HT1B and 5-HT1C receptors, significantly facilitated lordosis in 5,7-DHT-treated and non-treated rats. Our results show that both inhibitory and facilitatory influences of hypothalamic 5-HT on lordosis, are modulated via postsynaptic receptors.

5,7-Dihydroxytryptamine and gonadal steroid manipulation alter spine density in ventromedial hypothalamic neurons.

Golgi impregnation was used to examine changes in dendritic spine density in the ventromedial hypothalmic nucleus (VMN) of intact and gonadectomized (GDX) rats treated with 5,7-dihydroxytryptamine (5,7-DHT) and/or estrogen. In intact rats of both sexes 5,7-DHT injection resulted in a large increase in dendritic spine density in the VMN. The combination of 5,7-DHT and estrogen treatment in GDX females resulted in a further increase in dendritic spine density. In male rats gonadectomy increased dendritic spine density on VMN neurons, and estrogen treatment partially reversed this effect. When GDX males were treated with 5,7-DHT and estrogen, there was no effect on dendritic spine density. These results complement a previous study in which it was demonstrated that dendritic spine density in the VMN was greatest during proestrus and after estrogen administration to ovariectomized females. The relevance of these findings to gonadal-steroid-mediated lordosis is discussed.

GABAergic-serotonergic interactions in regulating lordosis.

The GABAB agonist, baclofen, causes a dose-dependent decrease in lordosis, and this effect is attenuated following hypothalamic serotonin, (5-HT) lesions. Baclofen administration is associated with decreased 5-HT activity in the medial preoptic (mPOA) and ventromedial nuclei and enhanced 5-HT activity in the midbrain central gray, and with enhanced norepinephrine activity in the mPOA. Interactions between gamma-aminobutyric acid (GABA) and 5-HT may, therefore, be important for the activation of lordosis.