The Lysine Acetyltransferase PCAF Functionally Interacts with Estrogen Receptor Alpha in the Hippocampus of Gonadally Intact Male-But Not Female-Rats to Enhance Short-Term Memory.

Acetylation of histone proteins by histone acetyltransferases (HATs), and the resultant change in gene expression, is a well-established mechanism necessary for long-term memory (LTM) consolidation, which is not required for short-term memory (STM). However, we previously demonstrated that the HAT p300/CBP-associated factor (PCAF) also influences hippocampus (HPC)-dependent STM in male rats. In addition to their epigenetic activity, HATs acetylate nonhistone proteins involved in nongenomic cellular processes, such as estrogen receptors (ERs).

Membrane receptors mediate the rapid facilitation of short-term memory by estradiol in the dorsal hippocampus of female mice.

Estrogens play a key role in learning and memory via delayed genomic and early-onset rapid mechanisms. Systemic treatment with 17β-estradiol (E2) rapidly facilitates object recognition, social recognition and object placement short-term memory in ovariectomized female mice within a timescale of only 40 min following administration. The dorsal hippocampus is one critical site of rapid estrogenic effects.

Androgen Effects on Neural Plasticity.

Androgens are synthesized in the brain, gonads, and adrenal glands, in both sexes, exerting physiologically important effects on the structure and function of the central nervous system. These effects may contribute to the incidence and progression of neurological disorders such as autism spectrum disorder, schizophrenia, and Alzheimer's disease, which occur at different rates in males and females. This review briefly summarizes the current state of knowledge with respect to the neuroplastic effects of androgens, with particular emphasis on the hippocampus, which has been the focus of much of the research in this field.

Endocrine Insights into the Pathophysiology of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders that affects males more frequently than females. Numerous genetic and environmental risk factors have been suggested to contribute to the development of ASD. However, no one factor can adequately explain either the frequency of the disorder or the male bias in its prevalence.

Synaptic effects of estrogen.

The concept that estradiol may act as a local neuromodulator in the brain, rapidly affecting connectivity and synaptic function, has been firmly established by research over the last 30 years. De novo synthesis of estradiol within the brain as well as signaling mechanisms mediating responses to the hormone have been demonstrated, along with morphological evidence indicating rapid changes in synaptic input following increases in local estradiol levels. These rapid synaptic effects may play important roles in both physiological and pathophysiological responses to changes in circulating hormone levels, as well as in neurodegenerative disease.

Inhibition of 5α Reductase Impairs Cognitive Performance, Alters Dendritic Morphology and Increases Tau Phosphorylation in the Hippocampus of Male 3xTg-AD Mice.

Recent work has suggested that 5α-reduced metabolites of testosterone may contribute to the neuroprotection conferred by their parent androgen, as well as to sex differences in the incidence and progression of Alzheimer's disease (AD). This study investigated the effects of inhibiting 5α-reductase on object recognition memory (ORM), hippocampal dendritic morphology and proteins involved in AD pathology, in male 3xTg-AD mice. Male 6-month old wild-type or 3xTg-AD mice received daily injections of finasteride (50 mg/kg i.

Low dose prenatal testosterone exposure decreases the corticosterone response to stress in adult male, but not female, mice.

Gonadal steroid hormones affect the organization of the brain during sensitive periods of development, resulting in sex differences in the neuroendocrine function and behaviour of the offspring. Although alterations in developmental testosterone exposure have been hypothesized to play a role in male-biased neurodevelopmental disorders, the underlying mechanisms remain unknown. The present study investigated the hypothesis that early prenatal exposure to low concentrations of testosterone might affect the control of stress responses in later life.

Dissociable involvement of estrogen receptors in perirhinal cortex-mediated object-place memory in male rats.

Estrogens and the estrogen receptors (ER) - ERα, ERβ, and the G-protein coupled estrogen receptor (GPER) - are implicated in various forms of hippocampus (HPC)-dependent memory. However, the involvement of ER-related mechanisms in perirhinal cortex (PRh), which is necessary for object memory, remains much less clear. Moreover, there is a paucity of data assessing ER contributions to cognition in males,despite documented sex differences at the cellular level.

Dissociable cognitive impairments in two strains of transgenic Alzheimer's disease mice revealed by a battery of object-based tests.

Object recognition tasks detect cognitive deficits in transgenic Alzheimer's disease (AD) mouse models. Object recognition, however, is not a unitary process, and there are many uncharacterized facets of object processing with relevance to AD. We therefore systematically evaluated object processing in 5xFAD and 3xTG AD mice to clarify the nature of object recognition-related deficits.

The testosterone metabolite 3α-androstanediol inhibits oxidative stress-induced ERK phosphorylation and neurotoxicity in SH-SY5Y cells through an MKP3/DUSP6-dependent mechanism.

Testosterone exerts neuroprotective effects on the brain, but the mechanisms by which these effects are exerted appear to be different in males and females. While in females they involve local conversion to estradiol, in males they may be androgen receptor-dependent, or mediated through metabolism to neurosteroids such as 5α-androstane-3α,17β-diol (3α-diol), which acts through different mechanisms than testosterone itself. Recently, we demonstrated that 3α-diol can protect neurons and neuronal-like cells against oxidative stress-induced neurotoxicity associated with prolonged phosphorylation of the extracellular signal-regulated kinase (ERK).

Neurosteroid Metabolites of Gonadal Steroid Hormones in Neuroprotection: Implications for Sex Differences in Neurodegenerative Disease.

Gonadal steroid hormones are neurotrophic and neuroprotective. These effects are modulated by local metabolism of the hormones within the brain. Such control is necessary to maintain normal function, as several signaling pathways that are activated by gonadal steroid hormones in the brain can also become dysregulated in disease.

LUMAN/CREB3 Plays a Dual Role in Stress Responses as a Cofactor of the Glucocorticoid Receptor and a Regulator of Secretion.

LUMAN/CREB3, originally identified through its interaction with a cell cycle regulator HCFC1, is a transcription factor involved in the unfolded protein response during endoplasmic reticulum stress. Previously using gene knockout mouse models, we have shown that LUMAN modulates the glucocorticoid (GC) response leading to enhanced glucocorticoid receptor (GR) activity and lower circulating GC levels. Consequently, the stress response is dysregulated, leading to a blunted stress response in the -deficient mice.

Neurosteroid metabolites of testosterone and progesterone differentially inhibit ERK phosphorylation induced by amyloid β in SH-SY5Y cells and primary cortical neurons.

Gonadal steroid hormones exert neurotrophic and neuroprotective effects on the brain. Recent work suggests potential neuroprotective roles for the 3α-hydroxy, 5α-reduced metabolites of these hormones. Two such metabolites are 5α-androstane-3α,17β-diol (3α-diol) and 5α-pregnan-3α-ol-20-one (allopregnanolone; Allo), which may contribute to the overall protection conferred by their precursors (testosterone and progesterone, respectively) through mechanisms including potentiation of gamma-aminobutyric acid (GABA) receptor (GABAR) activity.

Imaging Neurons within Thick Brain Sections Using the Golgi-Cox Method.

The Golgi-Cox method of neuron staining has been employed for more than two hundred years to advance our understanding of neuron morphology within histological brain samples. While it is preferable from a practical perspective to prepare brain sections at the greatest thickness possible, in order to increase the probability of identifying stained neurons that are fully contained within single sections, this approach is limited from a technical perspective by the working distance of high-magnification microscope objectives. We report here a protocol to stain neurons using the Golgi-Cox method in mouse brain sections that are cut at 500 μm thickness, and to visualize neurons throughout the depth of these sections using an upright microscope fitted with a high-resolution 30X 1.

Studies To Examine Potential Tolerability Differences between the 5-HT Receptor Selective Agonists Lorcaserin and CP-809101.

Lorcaserin (LOR) is a selective 5-HT 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-HT agonist CP-809101 (CP) produced fewer equivalent signs.

Low dietary soy isoflavonoids increase hippocampal spine synapse density in ovariectomized rats.

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.

Stress induces equivalent remodeling of hippocampal spine synapses in a simulated postpartum environment and in a female rat model of major depression.

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).

Sex differences in hippocampal area CA3 pyramidal cells.

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.

LUMAN/CREB3 is a key regulator of glucocorticoid-mediated stress responses.

Altered glucocorticoid sensitivity is believed to contribute to a number of human diseases, including inflammatory and autoimmune conditions as well as disorders characterized by abnormal hypothalamic-pituitary-adrenal axis (HPA) function. LUMAN (or CREB3), originally identified through its interaction with a cell cycle regulator HCFC1, is an endoplasmic reticulum membrane-bound transcription factor that is involved in the unfolded protein response. Here we demonstrate that LUMAN changes the glucocorticoid response by modulating the expression of the glucocorticoid receptor leading to an overall increase in GR activity.

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

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.

Expansion of mossy fibers and CA3 apical dendritic length accompanies the fall in dendritic spine density after gonadectomy in male, but not female, rats.

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.

BPA exposure during in vitro oocyte maturation results in dose-dependent alterations to embryo development rates, apoptosis rate, sex ratio and gene expression.

Alterations in the oocyte's environment can negatively affect embryo development. Oocyte quality, which can determine embryonic viability, is easily perturbed, thus factors affecting normal oocyte maturation are a concern. Bisphenol A (BPA) is an endocrine disrupting chemical that elicits a variety of reproductive effects.

Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements.

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.

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

Background/aims: 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.

Methods: Receptor concentrations were measured using an in vitro autoradiographic technique designed to separately quantify free, unoccupied receptors and receptors 'occupied' by (bound to) endogenous hormone.

Results: ERα occupation increased at proestrus and declined at estrus, reflecting changes in circulating estradiol and testosterone levels.