Estradiol and luteinizing hormone regulate recognition memory following subchronic phencyclidine: Evidence for hippocampal GABA action.

The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could mitigate short-term episodic memory loss in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP. To modulate E and LH, animals received estradiol capsules or Antide injections. Short-term episodic memory was assessed using the novel object recognition task (NORT). Brain expression of GAD67 was analyzed via western blot, and parvalbumin-containing cells were counted using immunohistochemistry. Some rats received hippocampal infusions of a GABAA agonist, GABAA antagonist, or GAD inhibitor before behavioral testing. We found that PCP reduced hippocampal GAD67 and abolished recognition memory. Antide restored hippocampal GAD67 and rescued recognition memory in PCP-treated animals. Estradiol prevented PCP's amnesic effect in NORT but failed to restore hippocampal GAD67. PCP did not cause significant differences in number of parvalbumin-expressing cells or cortical expression of GAD67. Hippocampal infusions of a GABAA agonist restored recognition memory in PCP-treated rats. Blocking hippocampal GAD or GABAA receptors in ovx animals reproduced recognition memory loss similar to PCP and inhibited estradiol's protection of recognition memory in PCP-treated animals. In summary, decreasing LH or increasing E can lessen short-term episodic memory loss, as measured by novel object recognition, in a PCP model of schizophrenia. Alterations in hippocampal GABA may contribute to both PCP's effects on recognition memory and the hormones' ability to prevent or reverse them.

ERIN: A Portal to Resources for Higher Education in Neuroscience.

ERIN, Educational Resources in Neuroscience, is the Society for Neuroscience's web portal to selected, high-quality materials for higher education. A Board of Editors approves resources after describing them and classifying them by topic, subtopic, media type, author, and appropriate educational level. Some resources are also accompanied by reviews and ratings from faculty who have used the resource. These features make a search of ERIN far more useful than a typical Google search. ERIN's development was funded by the National Science Foundation with a three-year grant to SfN. Along the way, various unexpected problems arose and solutions were found, many of which are described in this overview of ERIN's history and the various decisions that were made in its design and development.

Luteinizing hormone as a key player in the cognitive decline of Alzheimer's disease.

This article is part of a Special Issue "SBN 2014". Alzheimer's disease is one of the most prevalent and costly neurological diseases in the world. Although decades of research have focused on understanding Alzheimer's disease pathology and progression, there is still a great lack of clinical treatments for those who suffer from it. One of the factors most commonly associated with the onset of Alzheimer's disease is a decrease in levels of gonadal hormones, such as estrogens and androgens. Despite the correlational and experimental data which support the role of these hormones in the etiology of Alzheimer's disease, clinical trials involving their reintroduction through hormone therapy have had varied results and these gonadal hormones often have accompanying health risks. More recently, investigation has turned toward other hormones in the hypothalamic-pituitary-gonadal axis that are disrupted by age-related decreases in gonadal hormones. Specifically, luteinizing hormone, which is increased with age in both men and women (in response to removal of negative feedback), has surfaced as a potentially powerful player in the risk and onset of Alzheimer's disease. Mounting evidence in basic research and epidemiological studies supports the role of elevated luteinizing hormone in exacerbating age-related cognitive decline in both males and females. This review summarizes the recent developments involving luteinizing hormone in increasing the cognitive deficits and molecular pathology characteristic of Alzheimer's disease.

Estradiol attenuates the cognitive deficits in the novel object recognition task induced by sub-chronic phencyclidine in ovariectomized rats.

Clinical studies have suggested that estrogens may affect the symptoms of schizophrenia. The novel object recognition task (NORT) in female rats treated with sub-chronic phencyclidine (PCP) was used as an animal model of the cognitive deficits in schizophrenia. The current studies investigated whether chronic estradiol (E) could alleviate sub-chronic PCP-induced cognitive deficits in the NORT. Adult Sprague-Dawley rats were ovariectomized (ovx) and treated with either sub-chronic PCP (2 mg/kg bidaily i.p. for seven days), or with 0.9% saline and their object recognition memory was tested with the NORT using an acquisition trial, 1 min inter-trial interval, and retention trial. Sub-chronic PCP administration did not reliably affect behavior in the acquisition trial but significantly impaired object recognition in the retention trial for 1-2 and 27-29 weeks. Ovx females spent significantly (p<0.05) more time exploring the novel compared to the familiar object, whereas PCP-treated ovx females did not. This effect of PCP was attenuated by long-lasting E capsules implanted prior to PCP treatment. PCP-treated females implanted with E again spent significantly more time exploring the novel compared to the familiar object (p<0.01). When ovx rats were treated with sub-chronic PCP and a long-lasting E capsule was implanted either before or after PCP treatment, estradiol alleviated the PCP-induced deficits when administered in either regimen (p=0.01 and p=0.047 respectively). These data suggest that further exploration of estradiol as a possible therapeutic compound to treat the cognitive deficits of schizophrenia is warranted.

The role of testicular hormones and luteinizing hormone in spatial memory in adult male rats.

Attempts to determine the influence of testicular hormones on learning and memory in males have yielded contradictory results. The present studies examined whether testicular hormones are important for maximal levels of spatial memory in young adult male rats. To minimize any effect of stress, we used the Object Location Task which is a spatial working memory task that does not involve food or water deprivation or aversive stimuli for motivation. In Experiment 1 sham gonadectomized male rats demonstrated robust spatial memory, but gonadectomized males showed diminished spatial memory. In Experiment 2 subcutaneous testosterone (T) capsules restored spatial memory performance in gonadectomized male rats, while rats with blank capsules demonstrated compromised spatial memory. In Experiment 3, gonadectomized male rats implanted with blank capsules again showed compromised spatial memory, while those with T, dihydrotestosterone (DHT), or estradiol (E) capsules demonstrated robust spatial memory, indicating that T's effects may be mediated by its conversion to E or to DHT. Gonadectomized male rats injected with Antide, a gonadotropin-releasing hormone receptor antagonist which lowers luteinizing hormone levels, also demonstrated spatial memory, comparable to that shown by T-, E-, or DHT-treated males. These data indicate that testicular androgens are important for maximal levels of spatial working memory in male rats, that testosterone may be converted to E and/or DHT to exert its effects, and that some of the effects of these steroid hormones may occur via negative feedback effects on LH.

Identifying and using 'core competencies' to help design and assess undergraduate neuroscience curricula.

There has been a growing emphasis on the use of core competencies to design and inform curricula. Based on our Faculty for Undergraduate Neuroscience workshop at Pomona we developed a set of neuroscience core competencies. Following the workshop, faculty members were asked to complete an online survey to determine which core competencies are considered most essential and the results are presented. Backward Design principles are then described and we discuss how core competencies, through a backward design process, can be used to design and assess an undergraduate neuroscience curriculum. Oberlin College is used as a case study to describe the use of core competencies to help develop learning objectives, activities, and assessment measures for an undergraduate neuroscience major.

Low luteinizing hormone enhances spatial memory and has protective effects on memory loss in rats.

Though several studies have suggested that estradiol improves hippocampal-dependent spatial memory, the effects of other hormones in the hypothalamic-pituitary-gonadal axis on memory have largely been ignored. Estradiol and luteinizing hormone (LH) are generally inversely related and LH may significantly affect spatial memory. Ovariectomized (ovx) rats treated with Antide (a gonadotropin releasing hormone receptor antagonist) had low LH levels and showed enhanced spatial memory, comparable to treatment with estradiol. Antide-treated ovx females retained spatial memory longer than estradiol-treated ovx females. Deficits in spatial memory are a primary symptom of neurodegenerative disorders including Alzheimer's disease (AD). Treatment with Antide prevented spatial memory deficits in a neurotoxin-induced model typical of early AD. These data suggest that memory impairments seen in female rats after ovariectomy or women after menopause may be due to high LH levels and that a reduction in LH enhances memory. These results also implicate an LH lowering agent as a potential preventative therapy for AD.

Dihydrotestosterone increases hippocampal N-methyl-D-aspartate binding but does not affect choline acetyltransferase cell number in the forebrain or choline transporter levels in the CA1 region of adult male rats.

Testosterone, acting through its androgenic metabolite 5alpha-dihydrotestosterone (DHT), can increase dendritic spine density in the CA1 region of the male rat hippocampus. The mechanisms mediating this increase in spines are presently unknown. In female rats, estrogen (E) has been shown to increase spine density, which is in part mediated by increases in N-methyl-d-aspartate (NMDA) receptors in the CA1 region and cholinergic forebrain inputs to the hippocampus. Whether similar mechanisms are responsible for the DHT-induced increase in spines in the male remains to be determined. In the first experiment, we used [(3)H]glutamate NMDA receptor binding autoradiography to assess whether DHT-treated males had higher NMDA receptor levels in the CA1 region of the hippocampus, compared with oil-treated males. In the second set of experiments, we used choline acetyltransferase (ChAT) in situ hybridization and immunohistochemistry to assess whether DHT could affect ChAT cell number in the forebrain. We also investigated the effect of DHT on hemicholinium-3-sensitive choline transporter levels in the CA1 region of the male hippocampus. We found that DHT significantly increased NMDA receptor binding in the CA1 region of males but had no effect on ChAT cell number in the forebrain or hemicholinium-3-sensitive choline transporter protein levels in the CA1 region. These data indicate that, similar to E-induced spinogenesis in females, DHT-induced increases in spine formation in males may require increases in NMDA receptors. However, unlike E-treated females, these data suggest that DHT does not influence cholinergic inputs to the hippocampus.