Steroid Hormone Interaction with Dendritic Spines: Implications for Neuropsychiatric Disease.

Dendritic spines, key sites for neural plasticity, are influenced by gonadal steroids. In this chapter, we review the effects of gonadal steroids on dendritic spine density in areas important to cognitive function, the hippocampus, and prefrontal cortex. Most of these animal model studies investigated the effects of estrogen in females, but we also include more recent data on androgen effects in both males and females.

Sex differences in cognition following variations in endocrine status.

Spatial memory, mediated primarily by the hippocampus, is responsible for orientation in space and retrieval of information regarding location of objects and places in an animal's environment. Since the hippocampus is dense with steroid hormone receptors and is capable of robust neuroplasticity, it is not surprising that changes in spatial memory performance occur following a variety of endocrine alterations. Here, we review cognitive changes in both spatial and nonspatial memory tasks following manipulations of the hypothalamic-pituitary-adrenal and gonadal axes and after exposure to endocrine disruptors in rodents.

Androgens Enhance Recognition Memory and Dendritic Spine Density in the Hippocampus and Prefrontal Cortex of Ovariectomized Female Rats.

Estrogen replacement has been repeatedly shown to enhance memory and increase dendritic spine density in the hippocampus and prefrontal cortex of ovariectomized (OVX) female rats. Given the potential deleterious effects of chronic estrogen administration, the present study assessed cognitive function using recognition memory tasks and measured dendritic spine density in the CA1 region of the hippocampus and medial prefrontal cortex after subchronic androgen replacement to adult OVX female rats. All androgens enhanced recognition memory in OVX rats, but object placement (OP) and object recognition (OR) results differed.

Metformin-mediated mitochondrial protection post-cardiac arrest improves EEG activity and confers neuroprotection and survival benefit.

Cardiac arrest (CA) produces global ischemia/reperfusion injury resulting in substantial multiorgan damage. There are limited efficacious therapies to save lives despite CA being such a lethal disease process. The small population of surviving patients suffer extensive brain damage that results in substantial morbidity.

Rapid Golgi Stain for Dendritic Spine Visualization in Hippocampus and Prefrontal Cortex.

Golgi impregnation, using the Golgi staining kit with minor adaptations, is used to impregnate dendritic spines in the rat hippocampus and medial prefrontal cortex. This technique is a marked improvement over previous methods of Golgi impregnation because the premixed chemicals are safer to use, neurons are consistently well impregnated, there is far less background debris, and for a given region, there are extremely small deviations in spine density between experiments. Moreover, brains can be accumulated after a certain point and kept frozen until further processing.

A potential role for dendritic spines in bisphenol-A induced memory impairments during adolescence and adulthood.

Developmental exposure to Bisphenol A (BPA), an endocrine disrupting chemical, alters many behaviors and neural parameters in rodents and non-human-primates. The effects of BPA are mediated via gonadal hormone, primarily, estrogen receptors, and are not limited to the perinatal period since recent studies show impairments further into development. The studies described in this chapter address the effects of BPA administration during early adolescence on memory and dendritic spine density in intact male and female rats as well as ovariectomized (OVX) rats in late adolescence and show that some of these adolescent induced changes endure into adulthood.

Estrogenic regulation of memory: The first 50 years.

This review highlights fifty years of progress in research on estradiol's role in regulating behavior(s). It was initially thought that estradiol was only involved in regulating estrus/menstrual cycles and concomitant sexual behavior, but it is now clear that estradiol also influences the higher order neural function of cognition. We provide a brief overview of estradiol's regulation of memory and some mechanisms which underlie its effects.

Reducing luteinizing hormone levels after ovariectomy improves spatial memory: Possible role of brain-derived neurotrophic factor.

Alzheimer's disease and other forms of cognitive decline are significantly more prevalent in post-menopausal women. Decreased estrogen levels, due to menopause or ovariectomy, may contribute to memory impairments and neurodegeneration. Another result of decreased estrogen levels is elevated luteinizing hormone (LH).

Effects of adolescent Bisphenol-A exposure on memory and spine density in ovariectomized female rats: Adolescence vs adulthood.

The endocrine disruptor, Bisphenol-A (BPA), alters many behavioral and neural parameters in rodents. BPA administration to gonadally intact adolescent rats increases anxiety, impairs spatial memory, and decreases dendritic spine density when measured in adulthood. Since BPA's action seems to be mediated through gonadal steroid receptors, the current experiments were done in ovariectomized (OVX) female rats to examine the effects on behavior and spine density of adolescent BPA exposure under controlled hormone conditions.

Molecular profiling of reticular gigantocellularis neurons indicates that eNOS modulates environmentally dependent levels of arousal.

Neurons of the medullary reticular nucleus gigantocellularis (NGC) and their targets have recently been a focus of research on mechanisms supporting generalized CNS arousal (GA) required for proper cognitive functions. Using the retro-TRAP method, we characterized transcripts enriched in NGC neurons which have projections to the thalamus. The unique expression and activation of the endothelial nitric oxide (eNOS) signaling pathway in these cells and their intimate connections with blood vessels indicate that these neurons exert direct neurovascular coupling.

Rapid effects on memory consolidation and spine morphology by estradiol in female and male rodents.

Contribution to Special Issue on Fast effects of steroids. Rapid, neurosteroid-like effects of estrogens on memory consolidation during recognition memory tasks in both male and female rodents are described. We discuss how these mnemonic changes are related to rapid estrogenic effects on dendritic spine density, the distribution of spine types and the expression of PSD95 and GluA2 within spines in the hippocampus and medial prefrontal cortex, two areas critical for learning and memory.

Preclinical models of overwhelming sepsis implicate the neural system that encodes contextual fear memory.

Long-term sepsis survivors sustain cryptic brain injury that leads to cognitive impairment, emotional imbalance, and increased disability burden. Suitable animal models of sepsis, such as cecal ligation and puncture (CLP), have permitted the analysis of abnormal brain circuits that underlie post-septic behavioral phenotypes. For instance, we have previously shown that CLP-exposed mice exhibit impaired spatial memory together with depleted dendritic arbors and decreased spines in the apical dendrites of pyramidal neurons in the CA1 region of the hippocampus.

Gonadal Hormones Rapidly Enhance Spatial Memory and Increase Hippocampal Spine Density in Male Rats.

17β-estradiol (E2) rapidly, within minutes, activates behaviors and cognition by binding to membrane estrogen receptors, activating cell signaling cascades and increasing dendritic spines. In female rodents, E2 enhances spatial memory within 2-4 hours, and spine density is increased in the CA1 area of the hippocampus within 30-60 minutes. Although chronic gonadal hormone treatments in male rats alter cognition and spines/spine synapses and acute hormone effects occur in hippocampal slices, effects of acute, in vivo hormone administration in males are unknown.

Estradiol-Mediated Spine Changes in the Dorsal Hippocampus and Medial Prefrontal Cortex of Ovariectomized Female Mice Depend on ERK and mTOR Activation in the Dorsal Hippocampus.

Unlabelled: Dendritic spine plasticity underlies the formation and maintenance of memories. Both natural fluctuations and systemic administration of 17β-estradiol (E2) alter spine density in the dorsal hippocampus (DH) of rodents. DH E2 infusion enhances hippocampal-dependent memory by rapidly activating extracellular signal-regulated kinase (ERK)-dependent signaling of mammalian target of rapamycin (mTOR), a key protein synthesis pathway involved in spine remodeling.

The brain at risk: the sepsis syndrome and lessons from preclinical experiments.

There is a growing awareness of the chronic brain injury that results from the sepsis syndrome. We review experiments in several animal models of sepsis and show in one model, cecal ligation and puncture (CLP), that permanent structural pathology matures after the initial event. Specifically, we observed after exposure to CLP significant decreased spine density on the apical tree, but not the basal tree, of dendrites in the CA1 region of the dorsal hippocampus that was accompanied by a significantly diminished arbor of the apical dendrites, by 8 weeks, but not after 2 weeks.

The evolving role of dendritic spines and memory: Interaction(s) with estradiol.

This article is part of a Special Issue "Estradiol and Cognition". Memory processing is presumed to depend on synaptic plasticity, which appears to have a role in mediating the acquisition, consolidation, and retention of memory. We have studied the relationship between estrogen, recognition memory, and dendritic spine density in the hippocampus and medial prefrontal cortex, areas critical for memory, across the lifespan in female rodents.

Bisphenol-A exposure during adolescence leads to enduring alterations in cognition and dendritic spine density in adult male and female rats.

We have previously demonstrated that adolescent exposure of rats to bisphenol-A (BPA), an environmental endocrine disrupter, increases anxiety, impairs spatial memory, and decreases dendritic spine density in the CA1 region of the hippocampus (CA1) and medial prefrontal cortex (mPFC) when measured in adolescents in both sexes. The present study examined whether the behavioral and morphological alterations following BPA exposure during adolescent development are maintained into adulthood. Male and female, adolescent rats received BPA, 40μg/kg/bodyweight, or control treatments for one week.

Adolescent bisphenol-A exposure decreases dendritic spine density: role of sex and age.

Bisphenol-A (BPA), a common environmental endocrine disruptor, modulates estrogenic, androgenic, and antiandrogenic effects throughout the lifespan. We recently showed that low dose BPA exposure during adolescence increases anxiety and impairs spatial memory independent of sex. In this study, six week old Sprague Dawley rats (n=24 males, n=24 females) received daily subcutaneous injections (40 µg/kg bodyweight) of BPA or vehicle for one week.

Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function.

Expression of A53T mutant human alpha-synuclein under the mouse prion promoter is among the most successful transgenic models of Parkinson's disease. Accumulation of A53T alpha-synuclein causes adult mice to develop severe motor impairment resulting in early death at 8-12 months of age. In younger, pre-symptomatic animals, altered motor activity and anxiety-like behaviors have also been reported.

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

Several lines of evidence have converged to indicate that memory formation involves plasticity of dendritic spines in the medial prefrontal cortex (PFC) and the hippocampus. Memory varies with estrogen levels throughout the lifespan of the female. Generally, increased levels of estrogen are related to greater dendritic spine density on pyramidal cells in the PFC and the hippocampus and to improved memory function.

Estrogens facilitate memory processing through membrane mediated mechanisms and alterations in spine density.

Estrogens exert sustained, genomically mediated effects on memory throughout the female life cycle, but here we review new studies documenting rapid effects of estradiol on memory, which are exerted through membrane-mediated mechanisms. Use of recognition memory tasks in rats shows that estrogens enhance memory consolidation within 1h. 17α-Estradiol is more potent than 17β-estradiol, and the dose response relationship between estrogens and memory is an inverted U shape.

Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A.

PTI-125 is a novel compound demonstrating a promising new approach to treating Alzheimer's disease (AD), characterized by neurodegeneration and amyloid plaque and neurofibrillary pathologies. We show that the toxic signaling of amyloid-β(42) (Aβ(42)) by the α7-nicotinic acetylcholine receptor (α7nAChR), which results in tau phosphorylation and formation of neurofibrillary tangles, requires the recruitment of the scaffolding protein filamin A (FLNA). By binding FLNA with high affinity, PTI-125 prevents Aβ(42)'s toxic cascade, decreasing phospho-tau and Aβ aggregates and reducing the dysfunction of α7nAChRs, NMDARs, and insulin receptors.

HMGB1 mediates cognitive impairment in sepsis survivors.

Severe sepsis, a syndrome that complicates infection and injury, affects 750,000 annually in the United States. The acute mortality rate is approximately 30%, but, strikingly, sepsis survivors have a significant disability burden: up to 25% of survivors are cognitively and physically impaired. To investigate the mechanisms underlying persistent cognitive impairment in sepsis survivors, here we developed a murine model of severe sepsis survivors following cecal ligation and puncture (CLP) to study cognitive impairments.

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

Acute effects of bisphenol (BPA), an environmental chemical, on estradiol (17α or β-E2)-dependent recognition memory and dendritic spines in the medial prefrontal cortex and hippocampus were investigated in adult female rats. Ovariectomized rats received BPA 30 min before or immediately after a sample trial (viewing objects), and retention trials were performed 4 h later. Retention trials tested discrimination between old and new objects (visual memory) or locations (place memory).