In JoVE (1)

Other Publications (60)

Articles by Neil J. MacLusky in JoVE

Other articles by Neil J. MacLusky on PubMed

Neuroendocrine Function and Response to Stress in Mice with Complete Disruption of Glucagon-Like Peptide-1 Receptor Signaling1

Endocrinology. Feb, 2000  |  Pubmed ID: 28200996

ER-X: a Novel, Plasma Membrane-associated, Putative Estrogen Receptor That is Regulated During Development and After Ischemic Brain Injury

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Oct, 2002  |  Pubmed ID: 12351713

We showed previously in neocortical explants, derived from developing wild-type and estrogen receptor (ER)-alpha gene-disrupted (ERKO) mice, that both 17alpha- and 17beta-estradiol elicit the rapid and sustained phosphorylation and activation of the mitogen-activated protein kinase (MAPK) isoforms, the extracellular signal-regulated kinases ERK1 and ERK2. We proposed that the ER mediating activation of the MAPK cascade, a signaling pathway important for cell division, neuronal differentiation, and neuronal survival in the developing brain, is neither ER-alpha nor ER-beta but a novel, plasma membrane-associated, putative ER with unique properties. The data presented here provide further evidence that points strongly to the existence of a high-affinity, saturable, 3H-estradiol binding site (K(d), approximately 1.6 nm) in the plasma membrane. Unlike neocortical ER-alpha, which is intranuclear and developmentally regulated, and neocortical ER-beta, which is intranuclear and expressed throughout life, this functional, plasma membrane-associated ER, which we have designated "ER-X," is enriched in caveolar-like microdomains (CLMs) of postnatal, but not adult, wild-type and ERKO neocortical and uterine plasma membranes. We show further that ER-X is functionally distinct from ER-alpha and ER-beta, and that, like ER-alpha, it is re-expressed in the adult brain, after ischemic stroke injury. We also confirmed in a cell-free system that ER-alpha is an inhibitory regulator of ERK activation, as we showed previously in neocortical cultures. Association with CLM complexes positions ER-X uniquely to interact rapidly with kinases of the MAPK cascade and other signaling pathways, providing a novel mechanism for mediation of the influences of estrogen on neuronal differentiation, survival, and plasticity.

Gonadal Hormones Affect Spine Synaptic Density in the CA1 Hippocampal Subfield of Male Rats

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Mar, 2003  |  Pubmed ID: 12629162

The effects of androgen on the density of spine synapses on pyramidal neurons in the CA1 area of the hippocampus were studied in male rats. Gonadectomy (GDNX) had no significant effect on the number of CA1 pyramidal cells but reduced CA1 spine synapse density by almost 50% (to 0.468 +/- 0.018 spine synapses/microm(3)) compared with sham-operated controls (0.917 +/- 0.06 spine synapses/microm(3)). Treatment of GDNX rats with testosterone propionate (500 microg/d, s.c., 2 d) increased spine synapse density to levels (1.01 +/- 0.026 spine synapses/microm(3)) comparable with intact males. A similar increase in synapse density (1.013 +/- 0.05 spine synapses/microm(3)) was observed in GDNX animals after treatment with dihydrotestosterone (DHT) (500 microg/d, s.c., 2 d) but not after estradiol (10 microg/d, s.c., 2 d; 0.455 +/- 0.02 spine synapse/microm(3)). These data indicate that testosterone is important for maintenance of normal spine synapse density in the CA1 region of the male rat hippocampus. The comparable responses to testosterone and the non-aromatizable androgen DHT, coupled with the lack of response to estradiol, suggest that testosterone acts directly on hippocampal androgen receptors rather than indirectly via local estrogen biosynthesis.

Rapid Enhancement of Visual and Place Memory by Estrogens in Rats

Endocrinology. Jul, 2003  |  Pubmed ID: 12810538

Estrogenic effects on visual (object recognition) and place (object placement) memory were investigated. Ovariectomized (OVX) rats received acute sc injections 30 min before a sample trial (viewing objects), and 4 h later a recognition/retention trial was performed. During recognition/retention trials, discrimination between sample (old) and new objects (visual memory) or between objects in sample (old) and new locations (place memory) was tested. Subjects given 17alpha- or 17beta-estradiol or diethylstilbestrol (DES) 30 min before sample trials discriminated between objects or locations during recognition/retention trials whereas vehicle-treated, OVX rats did not. Estrogens were given a postsample trial to investigate whether enhancements were due to effects on memory processes or psychological/performance parameters. Hormones were given immediately after or 2 h after sample trials (delayed injections), and recognition/retention were tested 4 h after the sample trial. Both object and place discriminations were enhanced when estrogens were given immediately after sample trials, but not when injections were delayed. These results provide evidence that estrogen rapidly enhances visual and place memory. Moreover, posttraining injections suggest effects on mnemonic processes, consolidation, or encoding, not on performance parameters. Place memory enhancements required higher estrogen doses, both pre- and postsample trial. The rapid time course, stereospecificity of responses (alpha- and beta-estradiol are effective), and efficacy of various estrogens suggest interactions at other than classic estrogen alpha- or beta-receptors in mediating the effects. Thus, these results provide the first demonstration of rapid memory enhancements by estrogen and implicate nongenomic mechanisms, possibly an extranuclear receptor(s), in mediating the response.

Hippocampal Excitability Increases During the Estrous Cycle in the Rat: a Potential Role for Brain-derived Neurotrophic Factor

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Dec, 2003  |  Pubmed ID: 14684866

To test the hypothesis that induction of BDNF may contribute to changes in hippocampal excitability occurring during the female reproductive cycle, we examined the distribution of BDNF immunoreactivity and changes in CA1 and CA3 electrophysiology across the estrous cycle in rats. Hippocampal BDNF immunoreactivity increased on the day of proestrus as well as on the following morning (estrus), relative to metestrus or ovariectomized animals. Changes in immunoreactivity were clearest in mossy fiber axons of dentate gyrus granule cells, which contain the highest concentration of BDNF. Increased immunoreactivity was also apparent in the neuropil-containing dendrites of CA1 and CA3 neurons. Electrophysiological recordings in hippocampal slices showed robust cycle-dependent differences. Evoked responses of CA1 neurons to Schaffer collateral stimulation changed over the cycle, with larger maximum responses at both proestrus and estrus relative to metestrus. In area CA3, repetitive hilar stimuli frequently evoked multiple population spikes at proestrus and estrus but only rarely at other cycle stages, and never in slices of ovariectomized rats. Hyperexcitability in area CA3 at proestrus was blocked by exposure to the high-affinity neurotrophin receptor antagonist K252a, or an antagonist of the alpha7 nicotinic cholinergic receptor, whereas it was induced at metestrus by the addition of BDNF to hippocampal slices. These studies suggest that hippocampal BDNF levels change across the estrous cycle, accompanied by neurophysiological responses that resemble the effects of BDNF treatment. An estrogen-induced interaction of BDNF and alpha7 nicotinic receptors on mossy fibers seems responsible for estrous cycle changes in area CA3. Periovulatory changes in hippocampal function may, thus, involve estrogen-induced increases in BDNF expression.

Dehydroepiandrosterone Increases Hippocampal Spine Synapse Density in Ovariectomized Female Rats

Endocrinology. Mar, 2004  |  Pubmed ID: 14645116

This study tests the hypothesis that dehydroepiandrosterone (DHEA) stimulates formation of hippocampal CA1 spine synapses in ovariectomized rats. Subcutaneous injections of DHEA (1 mg/d for 2 d) increased CA1 spine synapse density by more than 50% compared with vehicle-injected animals. The effect of DHEA on CA1 synapse density was abolished by pretreatment with the nonsteroidal aromatase inhibitor, letrozole. DHEA treatment, with or without letrozole, had no detectable uterotrophic effect. These observations are consistent with the hypothesis that DHEA treatment may be capable of reversing the decline in hippocampal spine synapse density observed after loss of ovarian steroid hormone secretion. The blockade of the synaptic response to DHEA by letrozole, despite the lack of a uterotrophic response to this steroid, suggests that the hippocampal response to DHEA may be mediated via aromatization in the brain.

Androgens Increase Spine Synapse Density in the CA1 Hippocampal Subfield of Ovariectomized Female Rats

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Jan, 2004  |  Pubmed ID: 14724248

The effects of androgen on the density of spine synapses on pyramidal neurons in the CA1 area of the hippocampus were studied in ovariectomized (OVX) adult female rats. Treatment of OVX rats with testosterone propionate (TP; 500 microg/d, s.c., 2 d) significantly increased spine synapse density (from 0.661 +/- 0.016 spine synapse/microm3 in OVX rats to 1.081 +/- 0.018 spine synapse/microm3 after TP treatment). A smaller, but still statistically significant, increase in synapse density (0.955 +/- 0.029 spine synapse/microm3) was observed in OVX animals after treatment with the nonaromatizable androgen dihydrotestosterone (DHT; 500 microg/d, s.c., 2 d). Administration of 1 mg of letrozole, a powerful nonsteroidal aromatase inhibitor, 1 hr before the steroid injections almost completely blocked the synaptic response to testosterone, resulting in a mean synapse density (0.723 +/- 0.003 spine synapse/microm3) only slightly higher than in OVX control rats. By contrast, the response to DHT was unaffected by letrozole pretreatment. These data suggest that androgen secretion during the female reproductive cycle may contribute to cyclical changes in hippocampal synaptic density. They also indicate that androgen treatment may be as effective as estrogen replacement in reversing the decline in hippocampal CA1 spine synapses that follows loss of ovarian function. Induction of hippocampal synapse formation by androgen is not mediated entirely via intracerebral estrogen biosynthesis, however, because aromatase-independent mechanisms also significantly affect CA1 spine synapse density.

Acute and Chronic Effects of Hormone Replacement Therapy on the Cardiovascular System in Healthy Postmenopausal Women

The Journal of Clinical Endocrinology and Metabolism. Apr, 2004  |  Pubmed ID: 15070921

Previous studies have shown that conjugated estrogens and continuous medroxyprogesterone increases heart disease risk in healthy women. Little is known about the effects of the natural ovarian hormones estradiol and progesterone on cardiovascular function at rest and exercise. The purpose of this study was to investigate the short- and longer-term effects of a cyclic format of hormone replacement therapy (HRT) (1 mg estradiol daily with cyclic micronized progesterone, 200 mg for 10 d/month) on cardiovascular function at rest and during exercise in healthy, postmenopausal women. A double-blind, cross-over study was conducted in 31 patients. Peak oxygen uptake and ventilatory threshold in addition to submaximal cardiac output were determined. Peripheral measures of resting and peak ischemic blood flows were also determined. Measurements were made at baseline, after 4 h of estrogen/placebo exposure, and subsequently after 1, 2, and 3 months. The sequence of data collection was repeated after 6-wk washout. Oral estradiol with cyclic micronized progesterone increases peak ischemic peripheral blood flow chronically but fails to improve exercise tolerance and peak oxygen uptake. Similarly, submaximal central cardiovascular function is unaffected by HRT. This suggests that estradiol has a beneficial effect on peripheral blood flow, but this benefit offers little advantage in terms of peak exercise performance after 3 months of HRT.

Aromatase Inhibition, Testosterone, and Seizures

Epilepsy & Behavior : E&B. Apr, 2004  |  Pubmed ID: 15123030

The effect of testosterone on brain excitability is unclear. The excitatory aspect of testosterone's action in the brain may be due to its conversion to estrogen via aromatase. We report herein a 61-year-old man with temporal lobe epilepsy and sexual dysfunction due to low testosterone levels. Use of an aromatase inhibitor, letrozole, normalized his testosterone level and improved his sexual functioning. Letrozole, in addition to standard antiseizure medication, was also associated with improved seizure control. This was sustained and, further, was associated with seizure exacerbation after withdrawing letrozole, and subsequent seizure improvement after restarting it. During the course of treatment, his serum testosterone level increased, sex hormone-binding globulin decreased (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels increased, while serum estradiol levels remained undetectable. Letrozole may, therefore, have produced a central alteration in the testosterone/estrogen ratio, thereby impairing estrogen-mediated feedback control of the pituitary, resulting in the observed increase in circulating LH and FSH levels. This experience suggests that aromatase inhibitors should be further investigated as a beneficial treatment modality for male patients with epilepsy.

Sexually Dimorphic Effects of Prenatal Stress on Cognition, Hormonal Responses, and Central Neurotransmitters

Endocrinology. Aug, 2004  |  Pubmed ID: 15142991

Exposure to stress during gestation results in physiological and behavioral alterations that persist into adulthood. This study examined the effects of prenatal stress on the postnatal expression of sexually differentiated cognitive, hormonal, and neurochemical profiles in male and female rats. Pregnant dams were subjected to restraint stress three times daily for 45 min during d 14-21 of pregnancy. The offspring of control and prenatally stressed dams were tested for anxiety-related and cognitive behaviors, stress and gonadal steroid hormone levels, as well as monoamines and metabolite levels in selected brain regions. Postnatal testosterone levels (measured at 1 and 5 d) did not differ between controls and prenatally stressed animals. In adulthood, the serum corticosterone response to stress was attenuated in prenatally stressed females, eliminating the sex difference normally observed in this parameter. Prenatally stressed females exhibited higher anxiety levels, evidenced by longer open field entry latencies. Prenatal stress had no effect on object recognition memory, but eliminated the advantage normally seen in the male performance of a spatial memory task. Neurochemical profiles of prenatally stressed females were altered toward the masculine phenotype in the prefrontal cortex, amygdala, and hippocampus. Thus, prenatal stress altered subsequent cognitive, endocrine, and neurochemical responses in a sex-specific manner. These data reinforce the view that prenatal stress affects multiple aspects of brain development, interfering with the expression of normal behavioral, neuroendocrine, and neurochemical sex differences. These data have implications for the effects of prenatal stress on the development of sexually dimorphic endocrine and neurological disorders.

Effects of Dehydroepiandrosterone and Flutamide on Hippocampal CA1 Spine Synapse Density in Male and Female Rats: Implications for the Role of Androgens in Maintenance of Hippocampal Structure

Endocrinology. Sep, 2004  |  Pubmed ID: 15178643

The effects of androgens and the androgen antagonist, flutamide, on the density of dendritic spine synapses in the CA1 subfield of the hippocampus were studied in gonadectomized male and female rats. Treatment of orchidectomized male rats with dehydroepiandrosterone (DHEA; 2 d, 1 mg/d sc) increased the density of CA1 spine synapses observed 2 d later, by 106%, without significantly affecting ventral prostate weight. The hippocampal response to DHEA was unaffected by blockade of intracerebral estrogen biosynthesis using the aromatase inhibitor, letrozole. By contrast, flutamide alone (2 d; 5 mg/d, sc) increased CA1 spine synapse density by 66%, whereas in combination the effects of flutamide and DHEA were additive rather than inhibitory. Additive effects on CA1 synapse density were also observed in males using combinations of flutamide with 5alpha-dihydrotestosterone (2 d, 500 microg/d, sc). At the same doses, flutamide had no effect on prostate weight and completely blocked the effects on the prostate of treatment with 5alpha-dihydrotestosterone. Treatment of ovariectomized females with DHEA increased CA1 spine synapse density to a level similar to that observed in the male. As in males, flutamide in females increased CA1 spine synapse formation and further augmented the response to DHEA. These results demonstrate that flutamide and DHEA have positive effects on hippocampal CA1 spine synapse density in both sexes. They also suggest that conventional measures of androgen agonist or antagonist activity, exemplified by ventral prostate growth, may not be indicative of effects on hippocampal CA1 synaptogenesis.

Behavioral Training Interferes with the Ability of Gonadal Hormones to Increase CA1 Spine Synapse Density in Ovariectomized Female Rats

The European Journal of Neuroscience. Jun, 2004  |  Pubmed ID: 15182310

Estradiol benzoate (EB) has repeatedly been shown to increase hippocampal CA1 spine synapse density in ovariectomized female rats. Although this increase has been assumed to enhance memory, a direct link between increased spine synapse density and memory has not been demonstrated. Furthermore, while androgens, such as testosterone propionate (TP) and dihydrotestosterone (DHT), also increase spine synapse density in females, their effects on memory have yet to be investigated. In the present study, ovariectomized female rats were given two injections, 24 h apart, of sesame oil (control), 10 microg EB, 500 microg TP or 500 microg DHT. Forty-eight hours after the second injection, rats were tested in a 1-day spatial Morris water maze task and then immediately perfused for analysis of CA1 spine synapse density (using electron microscopy and unbiased stereology). In the spatial acquisition phase of testing, EB, but not TP or DHT, significantly impaired memory relative to controls. Hormone treatment did not affect spatial retention or performance in the non-spatial phase of testing. In contrast to previous work, spine synapse density was not increased by EB, TP or DHT. We therefore examined a new set of EB-treated females, only half of which were water maze tested. Consistent with previous work, EB significantly increased spine synapse density among behaviorally naïve females. In contrast, spine synapse densities did not differ among behaviorally tested control and EB females, although they were higher than behaviorally naïve controls. These data indicate that 1-day water maze testing can eliminate the hormone-induced increases in CA1 spine synapse density typically observed in behaviorally naïve females.

Estrogen and Alzheimer's Disease: the Apolipoprotein Connection

Endocrinology. Jul, 2004  |  Pubmed ID: 15198969

The 17alpha and 17beta Isomers of Estradiol Both Induce Rapid Spine Synapse Formation in the CA1 Hippocampal Subfield of Ovariectomized Female Rats

Endocrinology. Jan, 2005  |  Pubmed ID: 15486220

Previous studies have demonstrated that estradiol-17beta and estradiol-17alpha both induce short-latency effects on spatial memory in rats, estradiol-17alpha being at least as potent as its 17beta isomer. To determine whether the mechanisms underlying these behavioral responses might include effects on hippocampal synaptic plasticity, CA1 pyramidal spine synapse density (PSSD) was measured in ovariectomized rats within the first few hours after s.c. estrogen injection. PSSD increased markedly (by 24%) 4.5 h after the administration of 45 microg/kg estradiol-17beta. The PSSD response was significantly greater (44% above control) 30 min after estradiol-17beta injection and was markedly dose dependent; a 3-fold lower estradiol-17beta dose (15 microg/kg) did not significantly affect CA1 PSSD at either 30 min or 4.5 h. Estradiol-17alpha was a more potent inducer of PSSD than estradiol-17beta. Dose-response analysis determined an ED50 for the effect of estradiol-17alpha on PSSD of 8.92 +/- 1.99 microg/kg, with a maximal response at 15 microg/kg. These results demonstrate that high doses of estradiol induce rapid changes in CA1 PSSD. CA1 spine synapse formation appears to be more sensitive to estradiol-17alpha than to estradiol-17beta, paralleling previous data on the effects of these two steroids on spatial memory. Rapid remodeling of hippocampal synaptic connections may thus contribute to the enhancement of spatial mnemonic processing observed within the first few hours after estrogen treatment. The potency of estradiol-17alpha suggests that hormone replacement therapy using this steroid might be useful clinically in ameliorating the impact of low endogenous estrogen production on the development and progression of neurodegenerative disorders involving the hippocampus.

Similarities Between Actions of Estrogen and BDNF in the Hippocampus: Coincidence or Clue?

Trends in Neurosciences. Feb, 2005  |  Pubmed ID: 15667930

The principal ovarian estrogen, estradiol, and brain-derived neurotrophic factor (BDNF) have widespread effects on the CNS that have usually been studied independently. This article examines the similarities in the effects of estradiol and BDNF in the hippocampus, in light of the evidence that estradiol can induce BDNF expression, and recent data suggesting that structural and electrophysiological effects of estradiol in the hippocampus might be mediated by BDNF. The possible role of BDNF as a signaling molecule downstream of estrogen in the hippocampus has implications for our understanding of several cellular and behavioral hippocampal functions, including dendritic and synaptic plasticity, learning and cognitive behavior. Furthermore, disruption of the relationship between estrogen and BDNF could contribute to neurological and psychiatric disorders that have been associated with the hippocampus, such as Alzheimer's disease, depression and epilepsy.

Short-term Treatment with the Antidepressant Fluoxetine Triggers Pyramidal Dendritic Spine Synapse Formation in Rat Hippocampus

The European Journal of Neuroscience. Mar, 2005  |  Pubmed ID: 15813939

The pathomechanism of major depressive disorder and the neurobiological basis of antidepressant therapy are still largely unknown. It has been proposed that disturbed hippocampal activity could underlie some of the cognitive and vegetative symptoms of depression, at least in part because of loss of pyramidal cell synaptic contacts, a process that is likely to be reversed by antidepressant treatment. Here we provide evidence that daily administration of the antidepressant fluoxetine to ovariectomized female rats for 5 days induces a robust increase in pyramidal cell dendritic spine synapse density in the hippocampal CA1 field, with similar changes appearing in CA3 after 2 weeks of treatment. This rapid synaptic remodelling might represent an early step in the fluoxetine-induced cascade of responses that spread across the entire hippocampal circuitry, leading to the restoration of normal function in the hippocampus. Hippocampal synaptic remodelling might provide a potential mechanism to explain certain aspects of antidepressant therapy and mood disorders, especially those associated with changes in reproductive state in women, that cannot be reconciled adequately with current theories for depression.

Aromatase Inhibitors As Add-on Treatment for Men with Epilepsy

Expert Review of Neurotherapeutics. Jan, 2005  |  Pubmed ID: 15853482

Manipulation of neurosteroids to treat epilepsy has been an area of active research. The effect of testosterone on brain excitability and seizure threshold has been mixed; the estradiol metabolite of testosterone increases brain excitability, while the reduced metabolite of testosterone, 3alpha-androstanediol, decreases brain excitability, likely through an action at the gamma-amino butyric acid A receptor. Therefore, the metabolites of testosterone produce opposite effects on brain excitability in seizure models. Aromatase is the enzyme for the conversion of testosterone to 17beta-estradiol. Aromatase inhibitors could decrease brain excitability by decreasing local estradiol levels and therefore, could be beneficial for the treatment of epilepsy. Aromatase inhibitors are US Food and Drug Administration-approved and have a long history of safe use in menopausal women with breast cancer. This review presents the results of using anastrazole in an open-label, add-on manner in a small group of men with epilepsy in order to improve seizures. The results suggested some effect on reduction of seizures and no side effects. Testosterone levels did increase, but not to above the normal range. Letrozole used in a single case was also beneficial for seizures. It was concluded that aromatase inhibitors may be a useful adjunct to the treatment of epilepsy, but habituation to the treatment may be limiting. Many men with epilepsy have low testosterone, and aromatase inhibition may be helpful in restoring levels to normal. Modulation of reproductive hormones by aromatase inhibition as well as enhancement of the 3alpha-androstanediol pathway may be an avenue of epilepsy treatment that would not produce sedative side effects, which is often a limiting factor with standard antiseizure medications. A further interesting result is that elevated follicle stimulating hormone and luteal stimulating hormone levels were associated with seizure reduction, suggesting that they may be a biomarker for a beneficial effect of aromatase inhibition on brain excitability.

The Environmental Estrogen Bisphenol a Inhibits Estradiol-induced Hippocampal Synaptogenesis

Environmental Health Perspectives. Jun, 2005  |  Pubmed ID: 15929888

Bisphenol A (BPA) is an estrogenic chemical that is widely used in the manufacture of plastics and epoxy resins. Because BPA leaches out of plastic food and drink containers, as well as the BPA-containing plastics used in dental prostheses and sealants, considerable potential exists for human exposure to this compound. In this article we show that treatment of ovariectomized rats with BPA dose-dependently inhibits the estrogen-induced formation of dendritic spine synapses on pyramidal neurons in the CA1 area of the hippocampus. Significant inhibitory effects of BPA were observed at a dose of only 40 microg/kg, below the current U.S. Environmental Protection Agency reference daily limit for human exposure. Because synaptic remodeling has been postulated to contribute to the rapid effects of estrogen on hippocampus-dependent memory, these data suggest that environmental BPA exposure may interfere with the development and expression of normal sex differences in cognitive function, via inhibition of estrogen-dependent hippocampal synapse formation. It may also exacerbate the impairment of hippocampal function observed during normal aging, as endogenous estrogen production declines.

Seizure Susceptibility in Intact and Ovariectomized Female Rats Treated with the Convulsant Pilocarpine

Experimental Neurology. Nov, 2005  |  Pubmed ID: 16084511

Despite numerous neuroendocrinological studies of seizures, the influence of estrogen and progesterone on seizures and epilepsy remains unclear. This may be due to the fact that previous studies have not systematically compared distinct endocrine conditions and included all relevant controls. The goal of the present study was to conduct such a study using pilocarpine as chemoconvulsant. Thus, age and weight-matched, intact or ovariectomized rats were tested to determine incidence of status epilepticus and to study events leading to status. Intact female rats were sampled at each cycle stage (proestrus, estrus, metestrus, or diestrus 2). Convulsant was administered at the same time of day, 10:00-10:30 a.m. Statistical analysis showed that there was a significantly lower incidence of status on the morning of estrus, but differences were attenuated in older animals. Ovariectomized rats were distinct in their rapid progression to status. These results show that the incidence of status in female rats following pilocarpine injection, and the progression to pilocarpine-induced status, are influenced by reproductive state as well as age. The hormonal milieu present specifically on the morning of estrus appears to decrease susceptibility to pilocarpine-induced status, particularly at young ages. In contrast, the chronic absence of reproductive steroids that characterizes the ovariectomized rat leads to a more rapid progression to status. This dissociation between incidence vs. progression provides new insight into the influence of estrogen and progesterone on seizures.

Androgen Effects on Hippocampal CA1 Spine Synapse Numbers Are Retained in Tfm Male Rats with Defective Androgen Receptors

Endocrinology. May, 2006  |  Pubmed ID: 16439462

The effects of estradiol benzoate (EB), dihydrotestosterone (DHT), or the antiandrogen hydroxyflutamide on CA1 pyramidal cell dendritic spine synapses were investigated in adult male rats. To elucidate the contribution of the androgen receptor to the hormone-induced increase in hippocampal CA1 synapses, wild-type males were compared with males expressing the Tfm mutation, which results in synthesis of defective androgen receptors. Orchidectomized rats were treated with EB (10 microg/rat.d), DHT (500 mug/rat.d), hydroxyflutamide (5 mg/rat.d), or the sesame oil vehicle sc daily for 2 d and examined using quantitative electron microscopic stereological techniques, 48 h after the second injection. In wild-type males, DHT and hydroxyflutamide both induced increases in the number of spine synapses in the CA1 stratum radiatum, whereas EB had no effect. DHT almost doubled the number of synaptic contacts observed, whereas hydroxyflutamide increased synapse density by approximately 50%, compared with the vehicle-injected controls. Surprisingly, in Tfm males, the effects of EB, DHT, and hydroxyflutamide were all indistinguishable from those observed in wild-type animals. These observations demonstrate that Tfm male rats resemble normal males in having no detectable hippocampal synaptic response to a dose of EB that is highly effective in females. Despite the reduction in androgen sensitivity as a result of the Tfm mutation, hippocampal synaptic responses to both DHT and a mixed androgen agonist/antagonist (hydroxyflutamide) remain intact in Tfm males. These data are consistent with previous results suggesting that androgen effects on hippocampal spine synapses may involve novel androgen response mechanisms.

Neurologic Links Between Epilepsy and Depression in Women: is Hippocampal Neuroplasticity the Key?

Neurology. Mar, 2006  |  Pubmed ID: 16567737

Recent advances in our understanding of the actions of sex steroids on the brain and the pathophysiology of depression have provided a hypothetical framework that may functionally connect epilepsy, ovarian hormone levels, and depression. The hippocampus plays a critical role in both seizure activity and mood disorders, which suggests that pathology in this area of the brain might provide a link between epilepsy and depression. Recent findings support the view that neurogenesis is not the only factor that contributes to the pathomechanism of depression and antidepressant responses, which may involve other hippocampal cellular or molecular changes, or both. Specifically, remodeling of the hippocampal spine synapses may play a significant role in the neurobiology of depression and the effects of antidepressant therapy. Because the effects of estrogens on hippocampal synaptogenesis parallel those of antidepressants, loss of estrogen appears to be a critical contributor to the etiology of depressive disorders. The increased incidence of depression observed in women with epilepsy might therefore reflect a hormonal deficiency state because epilepsy is frequently associated with defects in reproductive function. In women with catamenial epilepsy, changes in gonadal steroid production are seen to link seizure frequency with reproductive state, emphasizing the importance of gonadal steroid levels not only in depression but also in seizure activity. Paradoxical features of epilepsy, i.e., seizure-induced increases in hippocampal neurotrophin expression and neurogenesis, suggest that the most important factor in the neurobiology of depression might be the extent to which the hippocampus can adapt appropriately to changes in the environment through alterations in hippocampal synaptic connectivity.

Aged Rats: Sex Differences and Responses to Chronic Stress

Brain Research. Dec, 2006  |  Pubmed ID: 16919611

Cognitive, as well as physiological, sex differences exist in young adult rats under both basal conditions and following chronic stress; however, few studies have examined whether sex differences remain in aged subjects and whether responses to stress are altered. We compared aged male and female Fischer 344 rats (21.5 months at testing) without stress and when given 21 days of restraint for 6 h/day on locomotion, anxiety-related behaviors, object recognition (non-spatial memory), object placement (spatial memory), body weight and serum steroid hormone levels. Control (unstressed) females had lower levels of estradiol and testosterone and higher corticosterone than males, and stress had no lasting effect on hormone concentrations. Females weighed less than males and showed less weight loss with stress. Locomotion measures on an open field were similar in the sexes and unaffected by stress. Anxiety-related behavior measures on the field showed that males were generally more anxious and that stress increased male, but decreased, female anxiety-related behaviors. In memory testing, exploration of objects was not different between the sexes, with or without stress, while stress increased exploration in both sexes during object recognition trials. Both males and females, regardless of treatment, discriminated between old and new objects at short, but not long, inter-trial delays. The typical advantage of young males for spatial memory performance was not observed in aged subjects on the object placement tasks. Stress-dependent enhancements in females and impairments in males for object placement are reported for young rats, but in aged rats, neither sex was altered by stress. Current data suggest that aging is associated with changes in the pattern of sex differences present in young adult rats in some behaviors and in the behavioral responses to stress.

The Influence of Gonadal Hormones on Neuronal Excitability, Seizures, and Epilepsy in the Female

Epilepsia. Sep, 2006  |  Pubmed ID: 16981857

It is clear from both clinical observations of women, and research in laboratory animals, that gonadal hormones exert a profound influence on neuronal excitability, seizures, and epilepsy. These studies have led to a focus on two of the primary ovarian steroid hormones, estrogen and progesterone, to clarify how gonadal hormones influence seizures in women with epilepsy. The prevailing view is that estrogen is proconvulsant, whereas progesterone is anticonvulsant. However, estrogen and progesterone may not be the only reproductive hormones to consider in evaluating excitability, seizures, or epilepsy in the female. It seems unlikely that estrogen and progesterone would exert single, uniform actions given our current understanding of their complex pharmacological and physiological relationships. Their modulatory effects are likely to depend on endocrine state, relative concentration, metabolism, and many other factors. Despite the challenges these issues raise to future research, some recent advances have helped clarify past confusion in the literature. In addition, testable hypotheses have developed for complex clinical problems such as "catamenial epilepsy." Clinical and animal research, designed with the relevant endocrinological and neurobiological issues in mind, will help advance this field in the future.

Estrogen and Brain-derived Neurotrophic Factor (BDNF) in Hippocampus: Complexity of Steroid Hormone-growth Factor Interactions in the Adult CNS

Frontiers in Neuroendocrinology. Dec, 2006  |  Pubmed ID: 17055560

In the CNS, there are widespread and diverse interactions between growth factors and estrogen. Here we examine the interactions of estrogen and brain-derived neurotrophic factor (BDNF), two molecules that have historically been studied separately, despite the fact that they seem to share common targets, effects, and mechanisms of action. The demonstration of an estrogen-sensitive response element on the BDNF gene provided an impetus to explore a direct relationship between estrogen and BDNF, and predicted that the effects of estrogen, at least in part, might be due to the induction of BDNF. This hypothesis is discussed with respect to the hippocampus, where substantial evidence has accumulated in favor of it, but alternate hypotheses are also raised. It is suggested that some of the interactions between estrogen and BDNF, as well as the controversies and implications associated with their respective actions, may be best appreciated in light of the ability of BDNF to induce neuropeptide Y (NPY) synthesis in hippocampal neurons. Taken together, this tri-molecular cascade, estrogen-BDNF-NPY, may be important in understanding the hormonal regulation of hippocampal function. It may also be relevant to other regions of the CNS where estrogen is known to exert profound effects, such as amygdala and hypothalamus; and may provide greater insight into neurological disorders and psychiatric illness, including Alzheimer's disease, depression and epilepsy.

Effects of Androgens and Estradiol on Spine Synapse Formation in the Prefrontal Cortex of Normal and Testicular Feminization Mutant Male Rats

Endocrinology. May, 2007  |  Pubmed ID: 17317772

Recent studies suggest that, in female monkeys and rats, estrogens elicit dendritic spine synapse formation in the prefrontal cortex, an area that, similar to the hippocampus, plays a critical role in cognition. However, whether gonadal hormones induce synaptic remodeling in the male prefrontal cortex remains unknown. Here we report that gonadectomy reduced, whereas administration of 5alpha-dihydrotestosterone or estradiol-benzoate to castrated male rats increased, the number of medial prefrontal cortical (mPFC) spine synapses, with estradiol-benzoate being less effective than 5alpha-dihydrotestosterone. To investigate whether the androgen receptor contributes to the mediation of these changes, we compared the response of testicular feminization mutant (Tfm) male rats to that of wild-type animals. The number of mPFC spine synapses in gonadally intact Tfm rats and 5alpha-dihydrotestosterone-treated castrated Tfm males was considerably reduced compared to intact wild-type animals, whereas the synaptogenic effect of estradiol-benzoate was surprisingly enhanced in Tfm rats. These data are consistent with the hypothesis that remodeling of spine synapses in the prefrontal cortex may contribute to the cognitive effect of gonadal steroids. Our findings in Tfm animals indicate that androgen receptors may mediate a large part of the synaptogenic action of androgens in the mPFC of adult males. However, because this effect of 5alpha-dihydrotestosterone is not completely lost in Tfm rats, additional mechanisms may also be involved.

Anti-inflammatory and Chondroprotective Effects of Nutraceuticals from Sasha's Blend in a Cartilage Explant Model of Inflammation

Molecular Nutrition & Food Research. Aug, 2007  |  Pubmed ID: 17639996

New Zealand green lipped mussel (NZGLM), abalone (AB), and shark cartilage (SC) are extensively used for treatment of and/or as preventatives for arthritis, despite a relative paucity of scientific evidence for efficacy. This research integrated a simulated digestion protocol with ultrafiltration and cartilage explants to generate new information on the anti-inflammatory and chondroprotective properties of NZGLM, SC, and AB. Each nutraceutical was artificially digested using simulated gastric and intestinal fluids, and the crude digest was ultrafiltered (50 kDa). Each filtrate was applied individually to cartilage explants before the explants were stimulated with IL-1 to induce an acute inflammatory response. Media were collected daily for 48 h and analyzed for prostaglandin E(2) (PGE(2)), glycosaminoglycan (GAG), and nitric oxide (NO), and cartilage tissue was differentially stained to determine the relative proportion of live and dead cells. SC and NZGLM significantly inhibited IL-1-induced PGE(2) synthesis and IL-1-induced GAG release, and AB was an effective inhibitor of IL-1-induced NO production. The three test nutraceuticals affect at least three major pathways involved in the catabolic cycle of arthritis and may prove important treatments and/or preventatives for the pain and degradation associated with this condition. The methodology and results describe a useful model for evaluating dietary nutraceuticals in vitro.

Changes in Hippocampal Function of Ovariectomized Rats After Sequential Low Doses of Estradiol to Simulate the Preovulatory Estrogen Surge

The European Journal of Neuroscience. Nov, 2007  |  Pubmed ID: 17970745

In adult female rats, robust hippocampal changes occur when estradiol rises on the morning of proestrus. Whether estradiol mediates these changes, however, remains unknown. To address this issue, we used sequential injections of estradiol to simulate two key components of the preovulatory surge: the rapid rise in estradiol on proestrous morning, and the slower rise during the preceding day, diestrus 2. Animals were examined mid-morning of simulated proestrus, and compared to vehicle-treated or intact rats. In both simulated and intact rats, CA1-evoked responses were potentiated in hippocampal slices, and presynaptic mechanisms appeared to contribute. In CA3, multiple population spikes were evoked in response to mossy fiber stimuli, and expression of brain-derived neurotrophic factor was increased. Simulation of proestrous morning also improved performance on object and place recognition tests, in comparison to vehicle treatment. Surprisingly, effects on CA1-evoked responses showed a dependence on estradiol during simulated diestrus 2, as well as a dependence on proestrous morning. Increasing estradiol above the physiological range on proestrous morning paradoxically decreased evoked responses in CA1. However, CA3 pyramidal cell activity increased further, and became synchronized. Together, the results confirm that physiological estradiol levels are sufficient to profoundly affect hippocampal function. In addition: (i) changes on proestrous morning appear to depend on slow increases in estradiol during the preceding day; (ii) effects are extremely sensitive to the peak serum level on proestrous morning; and (iii) there are striking subfield differences within the hippocampus.

Effects of Multiparity on Recognition Memory, Monoaminergic Neurotransmitters, and Brain-derived Neurotrophic Factor (BDNF)

Hormones and Behavior. Jun, 2008  |  Pubmed ID: 17927990

Recognition memory and anxiety were examined in nulliparous (NP: 0 litters) and multiparous (MP: 5-6 litters) middle-aged female rats (12 months old) to assess possible enduring effects of multiparity at least 3 months after the last litter was weaned. MP females performed significantly better than NP females on the non-spatial memory task, object recognition, and the spatial memory task, object placement. Anxiety as measured on the elevated plus maze did not differ between groups. Monoaminergic activity and levels were measured in prefrontal cortex, CA1 hippocampus, CA3 hippocampus, and olfactory bulb (OB). NP and MP females differed in monoamine concentrations in the OB only, with MP females having significantly greater concentrations of dopamine and metabolite DOPAC, norepinephrine and metabolite MHPG, and the serotonin metabolite 5-HIAA, as compared to NP females. These results indicate a long-term change in OB neurochemistry as a result of multiparity. Brain-derived neurotrophic factor (BDNF) was also measured in hippocampus (CA1, CA3, dentate gyrus) and septum. MP females had higher BDNF levels in both CA1 and septum; as these regions are implicated in memory performance, elevated BDNF may underlie the observed memory task differences. Thus, MP females (experiencing multiple bouts of pregnancy, birth, and pup rearing during the first year of life) displayed enhanced memory task performance but equal anxiety responses, as compared to NP females. These results are consistent with previous studies showing long-term changes in behavioral function in MP, as compared to NP, rats and suggest that alterations in monoamines and a neurotrophin, BDNF, may contribute to the observed behavioral changes.

Bisphenol A Prevents the Synaptogenic Response to Testosterone in the Brain of Adult Male Rats

Endocrinology. Mar, 2008  |  Pubmed ID: 18048497

Exposure measurement data from several developed countries indicate that human beings are widely exposed to low levels of the synthetic xenoestrogen, bisphenol A. We reported previously that bisphenol A, even at doses below the reference safe daily limit for human exposure, recommended by the U.S. Environmental Protection Agency, impairs the synaptogenic response to 17beta-estradiol in the hippocampus of ovariectomized rats. Recent experiments revealed that bisphenol A also interferes with androgen receptor-mediated transcriptional activities. Thus, to investigate whether bisphenol A impairs synaptogenesis in the medial prefrontal cortex (mPFC) and hippocampus of adult male rats, castrated and sham-operated animals were treated with different combinations of bisphenol A (300 microg/kg), testosterone propionate (1.5 mg/kg), and sesame oil vehicle. The brains were processed for electron microscopic stereology, and the number of asymmetric spine synapses in the mPFC and CA1 hippocampal area was estimated. In both regions analyzed, bisphenol A reduced the number of spine synapses in sham-operated, gonadally intact animals, which was accompanied by a compensatory increase in astroglia process density. In addition, bisphenol A prevented both the prefrontal and hippocampal synaptogenic response to testosterone supplementation in castrated males. These results demonstrate that bisphenol A interferes with the synaptogenic response to testosterone in the mPFC and hippocampus of adult male rats. Because the hippocampal synaptogenic action of androgens seems to be independent of androgen and estrogen receptors in males, the potential mechanisms that underlie these negative effects of bisphenol A remain the subject of further investigation.

Role of Androgens and the Androgen Receptor in Remodeling of Spine Synapses in Limbic Brain Areas

Hormones and Behavior. May, 2008  |  Pubmed ID: 18262185

Accumulating evidence indicate that structural synaptic plasticity in limbic areas plays a vital role not only in normal brain functions, such as cognition and mood, but also in the development of neurological and mental disorders. We have learned from studies investigating neuronal remodeling that estrogens have an exceptional synaptogenic potential that seems to be specific to limbic areas of the adult female brain. On the other hand, structural synaptic plasticity in the adult male brain and the synaptogenic effect of androgens received relatively little attention. During the last five years, the Leranth laboratory provided conclusive evidence that the hippocampus and prefrontal cortex of adult male rodents and non-human primates retain considerable structural synaptic plasticity similar to the female, and that androgens are capable of inducing spine synapse growth in both the hippocampus and prefrontal cortex similar to estrogens. Our recent work also demonstrates that androgen-induced remodeling of spine synapses in the prefrontal cortex of adult male rats is dependent, at least to some extent, on functional androgen receptors, while being entirely independent of the androgen receptor in the hippocampus. Based on these findings and on their many beneficial effects, we believe that androgens hold a great and undeservingly neglected therapeutic potential that could be employed to reverse synaptic pathology in various neurocognitive and neuropsychiatric disorders.

Estrogen-growth Factor Interactions and Their Contributions to Neurological Disorders

Headache. Jul, 2008  |  Pubmed ID: 18700946

Estrogen has diverse and powerful effects in the brain, including actions on neurons, glia, and the vasculature. It is not surprising, therefore, that there are many changes in the female brain as serum estradiol levels rise and fall during the normal ovarian cycle. At times of life when estradiol levels change dramatically, such as puberty, postpartum, or menopause, there also are dramatic changes in the central nervous system. Changes that occur because of fluctuations in serum estrogen levels are potentially relevant to neurological disorders because symptoms often vary with the time of the ovarian cycle. Moreover, neurological disorders (eg, seizures and migraine) often increase in frequency in women when estradiol levels change. In this review, the contribution of 2 growth factors targeted by estrogen, the neurotrophin brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), will be discussed. Estrogen-sensitive response elements are present on the genes for both BDNF and VEGF, and they are potent modulators of neuronal, glial, and vascular function, making them logical candidates to mediate the multitude of effects of estrogen. In addition, BDNF induces neuropeptide Y, which has diverse actions that are relevant to estrogen action and to the same neurological disorders.

Bisphenol A Prevents the Synaptogenic Response to Estradiol in Hippocampus and Prefrontal Cortex of Ovariectomized Nonhuman Primates

Proceedings of the National Academy of Sciences of the United States of America. Sep, 2008  |  Pubmed ID: 18768812

Exposure measurements from several countries indicate that humans are routinely exposed to low levels of bisphenol A (BPA), a synthetic xenoestrogen widely used in the production of polycarbonate plastics. There is considerable debate about whether this exposure represents an environmental risk, based on reports that BPA interferes with the development of many organs and that it may alter cognitive functions and mood. Consistent with these reports, we have previously demonstrated that BPA antagonizes spine synapse formation induced by estrogens and testosterone in limbic brain areas of gonadectomized female and male rats. An important limitation of these studies, however, is that they were based on rodent animal models, which may not be representative of the effects of human BPA exposure. To address this issue, we examined the influence of continuous BPA administration, at a daily dose equal to the current U.S. Environmental Protection Agency's reference safe daily limit, on estradiol-induced spine synapse formation in the hippocampus and prefrontal cortex of a nonhuman primate model. Our data indicate that even at this relatively low exposure level, BPA completely abolishes the synaptogenic response to estradiol. Because remodeling of spine synapses may play a critical role in cognition and mood, the ability of BPA to interfere with spine synapse formation has profound implications. This study is the first to demonstrate an adverse effect of BPA on the brain in a nonhuman primate model and further amplifies concerns about the widespread use of BPA in medical equipment, and in food preparation and storage.

Seizures and Reproductive Function: Insights from Female Rats with Epilepsy

Annals of Neurology. Dec, 2008  |  Pubmed ID: 19107990

Chronic seizures in women can have adverse effects on reproductive function, such as polycystic ovarian syndrome, but it has been difficult to dissociate the effects of epilepsy from the role of antiepileptic drugs. To distinguish the effects of chronic seizures from medication, we used the laboratory rat, because an epileptic condition can be induced without concomitant anticonvulsant drug treatment.

A Randomized Double-blind Trial of the Effects of Hormone Therapy on Delayed Verbal Recall in Older Women

Psychoneuroendocrinology. Aug, 2009  |  Pubmed ID: 19297102

We examined whether estradiol and norethindrone hormone therapy (HT) prevented decline in delayed verbal recall in older women with normal to mildly impaired memory functioning. This was a 2-year, randomized, double-blind, placebo-controlled trial of 142 women aged 61-87, randomly assigned to receive 1 mg 17-beta estradiol daily and 0.35 mg norethindrone 3 days/week or daily placebo for 2 years. The primary outcome was short-delay verbal recall of the California Verbal Learning Test (CVLT). To look for differences in response to HT by baseline short-delay recall, we examined the primary outcome in participants grouped according to whether their baseline scores were below average for the age group or greater than or equal to this score and according to whether they met criteria for Mild Cognitive Impairment (MCI) or not. 133 women completed 1 year of the trial and 128 completed 2 years. Prespecified covariates in all repeated measures analyses of covariance (RANCOVA) included age, education, APOE epsilon4, and prior HT use. RANCOVA showed no overall significant treatment effects at year 1 or year 2. After testing for an interaction, which was significant (p=0.02), we found that women in the HT group who scored at or above the average showed significantly less decline than the placebo group in short-delay verbal recall after 1 year, p=0.007 and 2 years, p=0.01. No treatment effects were found in women below the average in either year. When grouped according to whether the participant met criteria for MCI, the interaction between treatment group and MCI subgroup was not significant. These results suggest that benefits of estrogen exposure may be limited to those with average to above average scores on the delayed verbal recall. HT dose and formulation may have contributed to these beneficial outcomes. Replication is warranted before recommendations can be made in the clinical setting.

A Rat Model of Epilepsy in Women: a Tool to Study Physiological Interactions Between Endocrine Systems and Seizures

Endocrinology. Sep, 2009  |  Pubmed ID: 19443573

Epilepsy in women is influenced by endocrine status and antiepileptic drugs, but without an animal model, the effects of endocrine variables and antiepileptic drugs cannot be easily dissociated from the influence of epilepsy itself. Animal models have had limited utility because experimentally induced seizures typically result in reproductive failure. This study was conducted to develop an improved animal model. The muscarinic convulsant pilocarpine was used to elicit status epilepticus (SE) in adult female Sprague Dawley rats. The selective estrogen receptor modulator raloxifene was administered 30 min before pilocarpine. An anticonvulsant barbiturate, pentobarbital, was injected 5-10 min after the onset of SE and at least once thereafter to minimize acute convulsions. Mortality, morbidity, estrous cyclicity, and the ultimate success of the procedure (i.e. induction of recurrent, spontaneous seizures) were monitored. The combination of raloxifene and pentobarbital led to significantly improved estrous cyclicity compared with previous methods. Animals treated with raloxifene and pentobarbital became epileptic, as defined by the recurrence of spontaneous convulsions in the weeks after SE. The results of this study provide an improved animal model to examine the interactions between seizures and ovarian hormone secretion. The results also suggest that treatment of SE with raloxifene may benefit women with SE.

Euthanasia in Endocrinology: the Choices Get More Complex

Endocrinology. Jun, 2009  |  Pubmed ID: 19458246

Effects of Estradiol on Learned Helplessness and Associated Remodeling of Hippocampal Spine Synapses in Female Rats

Biological Psychiatry. Jan, 2010  |  Pubmed ID: 19811775

Despite the fact that women are twice as likely to develop depression as men, our understanding of depression neurobiology in female subjects is limited. We have recently reported in male rats that development of helpless behavior is associated with a severe loss of hippocampal spine synapses, which is reversed by treatment with the antidepressant desipramine. Considering that estradiol has a hippocampal synaptogenic effect similar to those of antidepressants, the presence of estradiol during the female reproductive life might influence behavioral and synaptic responses to stress and depression.

Regulated Messenger Ribonucleic Acid Stability: a Key Actor in the Complex Play of Hormonal Control

Endocrinology. Apr, 2010  |  Pubmed ID: 20332202

Rapid Effects of Estrogen Receptor α and β Selective Agonists on Learning and Dendritic Spines in Female Mice

Endocrinology. Apr, 2011  |  Pubmed ID: 21285321

Estrogen receptor (ER) agonists rapidly affect neural plasticity within 1 h, suggesting they play a functional role in learning and memory. However, behavioral learning experiments on such a rapid time scale are lacking. Therefore we investigated whether the ERα agonist propyl pyrazole triol (PPT) and ERβ agonist diarylpropionitrile (DPN) could affect social recognition, object recognition, or object placement learning within 40 min of drug administration. At the same time, we examined their effects on CA1 hippocampal dendritic spines. Ovariectomized female CD1 mice were administered a range of PPT or DPN doses (0, 30, 50, 75, or 150 μg/mouse). PPT at the middle doses improved social recognition, facilitated object recognition and placement at a dose of 75 μg, and increased dendritic spine density in the stratum radiatum and lacunosum-moleculare. In contrast, DPN impaired social recognition at higher doses, did not affect object recognition, but slightly facilitated object placement learning at the 75-μg dose. DPN did not affect spines in the stratum radiatum but decreased spine density and increased spine length in the lacunosum-moleculare. This suggests that rapid estrogen-mediated learning enhancements may predominantly be mediated through ERα, while the effects of DPN are weaker and may depend on the learning paradigm. The role of ERα and ERβ in learning and memory may vary depending on the timing of drug administration, as genomic studies often implicate ERβ in enhancing effects on learning and memory. To our knowledge, this is the first report of estrogens' effects on learning within such a short time frame.

17β-estradiol Increases Astrocytic Vascular Endothelial Growth Factor (VEGF) in Adult Female Rat Hippocampus

Endocrinology. May, 2011  |  Pubmed ID: 21343256

Vascular endothelial growth factor (VEGF) is critical to angiogenesis and vascular permeability. It is also important in the endocrine system, in which VEGF mediates the vascular effects of estrogens in target tissues such as the uterus, a response attributed to an estrogen response element on the VEGF gene. Here we asked whether 17β-estradiol increases VEGF levels in the brain. We focused on the hippocampus, in which 17β-estradiol and VEGF both have important actions, and used immunocytochemistry to evaluate VEGF protein. VEGF immunoreactivity was compared in adult female rats sampled during the estrous cycle when serum levels of 17β-estradiol peak (proestrous morning) as well as when they are low (metestrous morning). In addition, adult rats were ovariectomized and compared after treatment with 17β-estradiol or vehicle. The results demonstrated that VEGF immunoreactivity was increased when serum levels of 17β-estradiol were elevated. Confocal microscopy showed that VEGF immunofluorescence was predominantly nonneuronal, often associated with astrocytes. Glial VEGF labeling was primarily punctate rather than diffuse and labile because glial VEGF immunoreactivity was greatly reduced if tissue sections were left in an aqueous medium overnight. We conclude that VEGF protein in normal female hippocampus is primarily nonneuronal rather than neuronal and suggest that glial VEGF immunoreactivity has been underestimated by past studies with other methods because there is a labile extracellular pool. We suggest that estrogens may exert actions on female hippocampal structure and function by increasing hippocampal VEGF.

Reduced Hippocampal Brain-derived Neurotrophic Factor (BDNF) in Neonatal Rats After Prenatal Exposure to Propylthiouracil (PTU)

Endocrinology. Mar, 2012  |  Pubmed ID: 22253429

Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy.

Low Doses of 17β-estradiol Rapidly Improve Learning and Increase Hippocampal Dendritic Spines

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. Sep, 2012  |  Pubmed ID: 22669167

While a great deal of research has been performed on the long-term genomic actions of estrogens, their rapid effects and implications for learning and memory are less well characterized. The often conflicting results of estrogenic effects on learning and memory may be due to complex and little understood interactions between genomic and rapid effects. Here, we investigated the effects of low, physiologically relevant, doses of 17β-estradiol on three different learning paradigms that assess social and non-social aspects of recognition memory and spatial memory, during a transcription independent period of memory maintenance. Ovariectomized female CD1 mice were subcutaneously administered vehicle, 1.5 μg/kg, 2 μg/kg, or 3 μg/kg of 17β-estradiol 15 minutes before social recognition, object recognition, or object placement learning. These paradigms were designed to allow the testing of learning effects within 40 min of hormone administration. In addition, using a different set of ovariectomized mice, we examined the rapid effects of 1.5 μg/kg, 2 μg/kg, or 3 μg/kg of 17β-estradiol on CA1 hippocampal dendritic spines. All 17β-estradiol doses tested impacted learning, memory, and CA1 hippocampal spines. 17β-Estradiol improved both social and object recognition, and may facilitate object placement learning and memory. In addition, 17β-estradiol increased dendritic spine density in the stratum radiatum subregion of the CA1 hippocampus, but did not affect dendritic spines in the lacunosum-moleculare, within 40 min of administration. These results demonstrate that the rapid actions of 17β-estradiol have important implications for general learning and memory processes that are not specific for a particular type of learning paradigm. These effects may be mediated by the rapid formation of new dendritic spines in the hippocampus.

Lifelong Estrogen Exposure and Memory in Older Postmenopausal Women

Journal of Alzheimer's Disease : JAD. 2013  |  Pubmed ID: 23246919

Menopausal changes in endogenous estrogen have been associated with memory decline. However, because earlier findings regarding the effects of lifelong estrogen exposure on memory have been inconsistent, our purpose was to investigate these effects in older postmenopausal women with a comprehensive battery of memory measures. Participants were 126 nondemented naturally postmenopausal women, not currently using hormone therapy (HT), 60 to 89 years of age, who showed normal to below average verbal memory performance on a screening test. Memory measures included tests of visual, verbal, and working memory. Regression analyses were performed with each memory measure as the outcome and length of reproductive period (time between menarche and menopause) as the predictor, controlling for age, education, parity, duration of breastfeeding, previous HT and oral contraceptive use, as well as body mass index and depression. Longer reproductive period was significantly associated with better delayed visual memory, immediate and delayed verbal memory, and working memory. Previous HT use was also significantly associated with better verbal memory and delayed visual memory. Our findings suggest an enduring protective role of endogenous and exogenous estrogen on memory in older postmenopausal women with normal to below average verbal memory performance on a screening test. They also support our contention that the neuroprotective benefits of a longer reproductive period might only be evident after a longer period of postmenopausal estrogen deprivation, which would help clarify why such an association was not previously found in younger postmenopausal women. Replication is required with a larger sample representing a broader cross-section of the aging female population.

Understanding the Direct Synaptic Effects of Estradiol

Endocrinology. Feb, 2013  |  Pubmed ID: 23338709

Testosterone Depletion in Adult Male Rats Increases Mossy Fiber Transmission, LTP, and Sprouting in Area CA3 of Hippocampus

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Feb, 2013  |  Pubmed ID: 23392664

Androgens have dramatic effects on neuronal structure and function in hippocampus. However, androgen depletion does not always lead to hippocampal impairment. To address this apparent paradox, we evaluated the hippocampus of adult male rats after gonadectomy (Gdx) or sham surgery. Surprisingly, Gdx rats showed increased synaptic transmission and long-term potentiation of the mossy fiber (MF) pathway. Gdx rats also exhibited increased excitability and MF sprouting. We then addressed the possible underlying mechanisms and found that Gdx induced a long-lasting upregulation of MF BDNF immunoreactivity. Antagonism of Trk receptors, which bind neurotrophins, such as BDNF, reversed the increase in MF transmission, excitability, and long-term potentiation in Gdx rats, but there were no effects of Trk antagonism in sham controls. To determine which androgens were responsible, the effects of testosterone metabolites DHT and 5α-androstane-3α,17β-diol were examined. Exposure of slices to 50 nm DHT decreased the effects of Gdx on MF transmission, but 50 nm 5α-androstane-3α,17β-diol had no effect. Remarkably, there was no effect of DHT in control males. The data suggest that a Trk- and androgen receptor-sensitive form of MF transmission and synaptic plasticity emerges after Gdx. We suggest that androgens may normally be important in area CA3 to prevent hyperexcitability and aberrant axon outgrowth but limit MF synaptic transmission and some forms of plasticity. The results also suggest a potential explanation for the maintenance of hippocampal-dependent cognitive function after androgen depletion: a reduction in androgens may lead to compensatory upregulation of MF transmission and plasticity.

Differential Regulation of BDNF, Synaptic Plasticity and Sprouting in the Hippocampal Mossy Fiber Pathway of Male and Female Rats

Neuropharmacology. Jan, 2014  |  Pubmed ID: 23660230

Many studies have described potent effects of BDNF, 17β-estradiol or androgen on hippocampal synapses and their plasticity. Far less information is available about the interactions between 17β-estradiol and BDNF in hippocampus, or interactions between androgen and BDNF in hippocampus. Here we review the regulation of BDNF in the mossy fiber pathway, a critical part of hippocampal circuitry. We discuss the emerging view that 17β-estradiol upregulates mossy fiber BDNF synthesis in the adult female rat, while testosterone exerts a tonic suppression of mossy fiber BDNF levels in the adult male rat. The consequences are interesting to consider: in females, increased excitability associated with high levels of BDNF in mossy fibers could improve normal functions of area CA3, such as the ability to perform pattern completion. However, memory retrieval may lead to anxiety if stressful events are recalled. Therefore, the actions of 17β-estradiol on the mossy fiber pathway in females may provide a potential explanation for the greater incidence of anxiety-related disorders and post-traumatic stress syndrome (PTSD) in women relative to men. In males, suppression of BDNF-dependent plasticity in the mossy fibers may be protective, but at the 'price' of reduced synaptic plasticity in CA3. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

Orchidectomy Does Not Significantly Affect Spine Synapse Density in the CA3 Hippocampal Subfield in St. Kitts Vervet Monkeys (Chlorocebus Aethiops Sabaeus)

Neuroscience Letters. Jan, 2014  |  Pubmed ID: 24269983

Gonadal hormones induce significant changes in cognitive function, associated with alterations in the structure of the hippocampus. We have previously shown that androgens increase the number of spine synapses in the CA1 stratum radiatum of the monkey hippocampus. Recent evidence, however, suggests that loss of testicular hormone production may have variable effects on neuroplasticity in different regions of the hippocampus. To test this hypothesis, we examined the effects of orchidectomy in the dentate gyrus and CA3 subfield of the hippocampus in male St. Kitts vervet monkeys (Chlorocebus aethiops sabaeus). Spine synapse density was significantly reduced (39%) after orchidectomy in the dentate gyrus, consistent with previously published reports in CA1 (40%). However, in CA3 orchidectomy induced a much smaller (22%) reduction in synapse density, which did not reach the limits of statistical significance. These results suggest that orchidectomy exerts heterogeneous effects on hippocampal spine synapse density, the CA3 subfield being relatively spared compared to CA1 and the dentate gyrus. This heterogeneity may contribute to the mixed functional responses observed in males following loss of testicular hormone secretions.

Spike-wave Discharges in Adult Sprague-Dawley Rats and Their Implications for Animal Models of Temporal Lobe Epilepsy

Epilepsy & Behavior : E&B. Mar, 2014  |  Pubmed ID: 24534480

Spike-wave discharges (SWDs) are thalamocortical oscillations that are often considered to be the EEG correlate of absence seizures. Genetic absence epilepsy rats of Strasbourg (GAERS) and Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) exhibit SWDs and are considered to be genetic animal models of absence epilepsy. However, it has been reported that other rat strains have SWDs, suggesting that SWDs may vary in their prevalence, but all rats have a predisposition for them. This is important because many of these rat strains are used to study temporal lobe epilepsy (TLE), where it is assumed that there is no seizure-like activity in controls. In the course of other studies using the Sprague-Dawley rat, a common rat strain for animal models of TLE, we found that approximately 19% of 2- to 3-month-old naive female Sprague-Dawley rats exhibited SWDs spontaneously during periods of behavioral arrest, which continued for months. Males exhibited SWDs only after 3 months of age, consistent with previous reports (Buzsáki et al., 1990). Housing in atypical lighting during early life appeared to facilitate the incidence of SWDs. Spike-wave discharges were often accompanied by behaviors similar to stage 1-2 limbic seizures. Therefore, additional analyses were made to address the similarity. We observed that the frequency of SWDs was similar to that of hippocampal theta rhythm during exploration for a given animal, typically 7-8 Hz. Therefore, activity in the frequency of theta rhythm that occurs during frozen behavior may not reflect seizures necessarily. Hippocampal recordings exhibited high frequency oscillations (>250 Hz) during SWDs, suggesting that neuronal activity in the hippocampus occurs during SWDs, i.e., it is not a passive structure. The data also suggest that high frequency oscillations, if rhythmic, may reflect SWDs. We also confirmed that SWDs were present in a common animal model of TLE, the pilocarpine model, using female Sprague-Dawley rats. Therefore, damage and associated changes to thalamic, hippocampal, and cortical neurons do not prevent SWDs, at least in this animal model. The results suggest that it is possible that SWDs occur in rodent models of TLE and that investigators mistakenly assume that they are stage 1-2 limbic seizures. We discuss the implications of the results and ways to avoid the potential problems associated with SWDs in animal models of TLE.

Sex Differences in the Neurobiology of Epilepsy: a Preclinical Perspective

Neurobiology of Disease. Dec, 2014  |  Pubmed ID: 25058745

When all of the epilepsies are considered, sex differences are not always clear, despite the fact that many sex differences are known in the normal brain. Sex differences in epilepsy in laboratory animals are also unclear, although robust effects of sex on seizures have been reported, and numerous effects of gonadal steroids have been shown throughout the rodent brain. Here we discuss several reasons why sex differences in seizure susceptibility are unclear or are difficult to study. Examples of robust sex differences in laboratory rats, such as the relative resistance of adult female rats to the chemoconvulsant pilocarpine compared to males, are described. We also describe a novel method that has shed light on sex differences in neuropathology, which is a relatively new technique that will potentially contribute to sex differences research in the future. The assay we highlight uses the neuronal nuclear antigen NeuN to probe sex differences in adult male and female rats and mice. In females, weak NeuN expression defines a sex difference that previous neuropathological studies have not described. We also show that in adult rats, social isolation stress can obscure the normal effects of 17β-estradiol to increase excitability in area CA3 of the hippocampus. These data underscore the importance of controlling behavioral stress in studies of seizure susceptibility in rodents and suggest that behavioral stress may be one factor that has led to inconsistencies in outcomes of sex differences research. These and other issues have made it difficult to translate our increasing knowledge about the effects of gonadal hormones on the brain to improved treatment for men and women with epilepsy.

Interictal Spike Frequency Varies with Ovarian Cycle Stage in a Rat Model of Epilepsy

Experimental Neurology. Jul, 2015  |  Pubmed ID: 25864929

In catamenial epilepsy, seizures exhibit a cyclic pattern that parallels the menstrual cycle. Many studies suggest that catamenial seizures are caused by fluctuations in gonadal hormones during the menstrual cycle, but this has been difficult to study in rodent models of epilepsy because the ovarian cycle in rodents, called the estrous cycle, is disrupted by severe seizures. Thus, when epilepsy is severe, estrous cycles become irregular or stop. Therefore, we modified kainic acid (KA)- and pilocarpine-induced status epilepticus (SE) models of epilepsy so that seizures were rare for the first months after SE, and conducted video-EEG during this time. The results showed that interictal spikes (IIS) occurred intermittently. All rats with regular 4-day estrous cycles had IIS that waxed and waned with the estrous cycle. The association between the estrous cycle and IIS was strong: if the estrous cycles became irregular transiently, IIS frequency also became irregular, and when the estrous cycle resumed its 4-day pattern, IIS frequency did also. Furthermore, when rats were ovariectomized, or males were recorded, IIS frequency did not show a 4-day pattern. Systemic administration of an estrogen receptor antagonist stopped the estrous cycle transiently, accompanied by transient irregularity of the IIS pattern. Eventually all animals developed severe, frequent seizures and at that time both the estrous cycle and the IIS became irregular. We conclude that the estrous cycle entrains IIS in the modified KA and pilocarpine SE models of epilepsy. The data suggest that the ovarian cycle influences more aspects of epilepsy than seizure susceptibility.

Rapid Increases in Immature Synapses Parallel Estrogen-induced Hippocampal Learning Enhancements

Proceedings of the National Academy of Sciences of the United States of America. Dec, 2015  |  Pubmed ID: 26655342

Dramatic increases in hippocampal spine synapse density are known to occur within minutes of estrogen exposure. Until now, it has been assumed that enhanced spinogenesis increased excitatory input received by the CA1 pyramidal neurons, but how this facilitated learning and memory was unclear. Delivery of 17β-estradiol or an estrogen receptor (ER)-α (but not ER-β) agonist into the dorsal hippocampus rapidly improved general discrimination learning in female mice. The same treatments increased CA1 dendritic spines in hippocampal sections over a time course consistent with the learning acquisition phase. Surprisingly, estrogen-activated spinogenesis was associated with a decrease in CA1 hippocampal excitatory input, rapidly and transiently reducing CA1 AMPA activity via a mechanism likely reflecting AMPA receptor internalization and creation of silent or immature synapses. We propose that estrogens promote hippocampally mediated learning via a mechanism resembling some of the broad features of normal development, an initial overproduction of functionally immature connections being subsequently "pruned" by experience.

Androgen Modulation of Hippocampal Structure and Function

The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry. Feb, 2016  |  Pubmed ID: 25416742

Androgens have profound effects on hippocampal structure and function, including induction of spines and spine synapses on the dendrites of CA1 pyramidal neurons, as well as alterations in long-term synaptic plasticity (LTP) and hippocampally dependent cognitive behaviors. How these effects occur remains largely unknown. Emerging evidence, however, suggests that one of the key elements in the response mechanism may be modulation of brain-derived neurotrophic factor (BDNF) in the mossy fiber (MF) system. In male rats, orchidectomy increases synaptic transmission and excitability in the MF pathway. Testosterone reverses these effects, suggesting that testosterone exerts tonic suppression on MF BDNF levels. These findings suggest that changes in hippocampal function resulting from declining androgen levels may reflect the outcome of responses mediated through normally balanced, but opposing, mechanisms: loss of androgen effects on the hippocampal circuitry may be compensated, at least in part, by an increase in BDNF-dependent MF plasticity.

In Vitro Autoradiographic Analysis of Regional Changes in Estrogen Receptor Alpha in the Brains of Cycling Female Rats

Neuroendocrinology. 2016  |  Pubmed ID: 26422138

The contributions of the three principal ovarian steroid hormones (estradiol, progesterone and testosterone) to the regulation of estrogen receptor alpha (ERα) levels in the rat brain were examined during the estrous cycle.

Curiouser and Curiouser: The Evolving Story of the Mechanisms Involved in Puberty

Endocrinology. Jan, 2016  |  Pubmed ID: 26717471

5α-Androstane-3α,17β-Diol Inhibits Neurotoxicity in SH-SY5Y Human Neuroblastoma Cells and Mouse Primary Cortical Neurons

Endocrinology. Dec, 2016  |  Pubmed ID: 27754784

Low free T levels in men are associated with age-related cognitive decline and increased risk for neurotoxicity, resulting in disease. The mechanisms underlying these observations remain poorly defined. Although rapid, androgen receptor-dependent activation of ERK has been postulated as a neurotrophic and neuroprotective mechanism, actions of T metabolites such as 5α-androstane-3α,17β-diol (3α-diol) may also be involved. We investigated the influence of 3α-diol on the induction of ERK phosphorylation in SH-SY5Y human female neuroblastoma cells and primary cortical neurons from male and female mice. In SH-SY5Y cells, ERK phosphorylation was induced by 10 nM DHT, epidermal growth factor, hydrogen peroxide (H2O2), and acetylcholine. The addition of 10 nM 3α-diol, which did not itself activate ERK, significantly inhibited ERK phosphorylation induced by DHT, epidermal growth factor, or H2O2, but not acetylcholine. In both SH-SY5Y cells and primary cortical neurons, prolonged ERK phosphorylation and caspase-3 cleavage resulting from amyloid β-peptide 1-42 (Aβ42) exposure were inhibited by cotreatment with 3α-diol. 3α-diol also reduced the loss in cellular viability induced by Aβ42 or H2O2 in SH-SY5Y cells. These data suggest that T-mediated neuroprotection may occur via two distinct but complementary mechanisms: an initial rapid activation of ERK phosphorylation, followed by modulation via 3α-diol of the potentially adverse consequences of prolonged ERK activation.

Expansion of Mossy Fibers and CA3 Apical Dendritic Length Accompanies the Fall in Dendritic Spine Density After Gonadectomy in Male, but Not Female, Rats

Brain Structure & Function. Jan, 2017  |  Pubmed ID: 27283589

Androgen loss is an important clinical concern because of its cognitive and behavioral effects. Changes in androgen levels are also suspected to contribute to neurological disease. However, the available data on the effects of androgen deprivation in areas of the brain that are central to cognition, like the hippocampus, are mixed. In this study, morphological analysis of pyramidal cells was used to investigate if structural changes could potentially contribute to the mixed cognitive effects that have been observed after androgen loss in males. Male Sprague-Dawley rats were orchidectomized or sham-operated. Two months later, their brains were Golgi-impregnated for morphological analysis. Morphological endpoints were studied in areas CA3 and CA1, with comparisons to females either intact or 2 months after ovariectomy. CA3 pyramidal neurons of orchidectomized rats exhibited marked increases in apical dendritic arborization. There were increases in mossy fiber afferent density in area CA3, as well as robust enhancements to dendritic structure in area CA3 of orchidectomized males, but not in CA1. Remarkably, apical dendritic length of CA3 pyramidal cells increased, while spine density declined. By contrast, in females overall dendritic structure was minimally affected by ovariectomy, while dendritic spine density was greatly reduced. Sex differences and subfield-specific effects of gonadal hormone deprivation on the hippocampal circuitry may help explain the different behavioral effects reported in males and females after gonadectomy, or other conditions associated with declining gonadal hormone secretion.

Sex Differences in Hippocampal Area CA3 Pyramidal Cells

Journal of Neuroscience Research. Jan, 2017  |  Pubmed ID: 27870399

Numerous studies have demonstrated differences between males and females in hippocampal structure, function, and plasticity. There also are many studies about the different predisposition of a males and females for disorders where the hippocampus plays an important role. Many of these reports focus on area CA1, but other subfields are also very important, and unlikely to be the same as area CA1 based on what is known. Here we review basic studies of male and female structure, function, and plasticity of area CA3 pyramidal cells of adult rats. The data suggest that the CA3 pyramidal cells of males and females are distinct in structure, function, and plasticity. These sex differences cannot be simply explained by the effects of circulating gonadal hormones. This view agrees with previous studies showing that there are substantial sex differences in the brain that cannot be normalized by removing the gonads and depleting peripheral gonadal hormones. Implications of these comparisons for understanding sex differences in hippocampal function and dysfunction are discussed. © 2016 Wiley Periodicals, Inc.

Stress Induces Equivalent Remodeling of Hippocampal Spine Synapses in a Simulated Postpartum Environment and in a Female Rat Model of Major Depression

Neuroscience. Feb, 2017  |  Pubmed ID: 28012870

Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague-Dawley rats (n=76). The number of hippocampal spine synapses and the depressive behavior of rats in an active escape task were investigated in untreated control, hormone-withdrawn 'postpartum', simulated proestrus, and hormone-treated 'postpartum' animals. After 'postpartum' withdrawal of gonadal steroids, inescapable stress caused a loss of hippocampal spine synapses, which was related to poor escape performance in hormone-withdrawn 'postpartum' females. These responses were equivalent with the changes observed in untreated controls that is an established animal model of major depression. Maintaining proestrus levels of ovarian hormones during 'postpartum' stress exposure did not affect synaptic and behavioral responses to inescapable stress in simulated proestrus animals. By contrast, maintaining pregnancy levels of estradiol and progesterone during 'postpartum' stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated 'postpartum' females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging 'synaptogenic hypothesis' of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness.

Low Dietary Soy Isoflavonoids Increase Hippocampal Spine Synapse Density in Ovariectomized Rats

Brain Research. Feb, 2017  |  Pubmed ID: 28063855

High dietary intake of plant estrogens (phytoestrogens) can affect brain structure and function. The effects of phytoestrogen intake within the range of normal animal and human dietary consumption, however, remain uncertain. The aim of the present study was to determine the effects of the isoflavonoids present in a standard low phytoestrogen laboratory rat chow on spine synapse density in the stratum radiatum of area CA1 of the hippocampus. Weanling rats (22days old) were fed either standard chow (Teklad 2018), a nutritionally comparable diet without soy (Teklad 2016) or a custom diet containing Teklad 2016 supplemented with the principal soy isoflavonoids, daidzein and genistein, for 40days. Rats were ovariectomized at 54days of age. Eight days later, spine synapse density on the apical dendrites of hippocampal pyramidal neurons in the stratum radiatum of area CA1 was measured by electron microscopic stereological analysis. Animals maintained on Teklad 2016 exhibited an approximately 60% lower CA1 spine synapse density than animals consuming Teklad 2018. Replacing genistein and daidzein in Teklad 2016 returned synapse density to levels indistinguishable from those in animals on Teklad 2018. These results indicate that the isoflavonoids in a standard laboratory rat diet exert significant effects on spine synapse density in the CA1 region of the hippocampus. Since changes in spine synapse density in this region of the hippocampus have been linked to cognitive performance and mood state, these data suggest that even relatively low daily consumption of soy phytoestrogens may be sufficient to influence hippocampal function.

Studies To Examine Potential Tolerability Differences Between the 5-HT2C Receptor Selective Agonists Lorcaserin and CP-809101

ACS Chemical Neuroscience. Mar, 2017  |  Pubmed ID: 28338324

Lorcaserin (LOR) is a selective 5-HT2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference. In a conditioned gaping model, a rodent test of nausea, LOR produced significantly higher gapes compared to CP consistent with it having higher emetogenic properties. Subsequent studies were designed to identify features of each drug that may account for such differences. In rats trained to discriminate CP-809101 from saline, both CP and LOR produced full generalization suggesting a similar interoceptive cue. In vitro tests of functional selectivity designed to examine signaling pathways activated by both drugs in CHO (Chinese hamster ovary) cells expressing h5-HT2C receptors failed to identify evidence for biased signaling differences between LOR and CP. Thus, both drugs showed similar profiles across PLC, PLA2, and ERK signaling pathways. In studies designed to examine pharmacokinetic differences between LOR and CP, while drug plasma levels correlated with increasing dose, CSF levels did not. CSF levels of LOR increased proportionally with dose; however CSF levels of CP plateaued from 6 to 12 mg/kg. Thus, the apparently improved tolerability of CP likely reflects a limit to CNS levels attained at relatively high doses.

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