50 research outputs found
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Does GPER1 play a role in sexual dimorphism?
Estrogens are critical in driving sex-typical social behaviours that are ethologically relevant
in mammals. This is due to both production of local estrogens and signaling by these
ligands, particularly in an interconnected set of nuclei called the social behavioural network
(SBN). The SBN is a sexually dimorphic network studied predominantly in rodents that is
thought to underlie the display of social behaviour in mammals. Signalling by the
predominant endogenous estrogen, 17b-estradiol, can be either via the classical
genomic or non-classical rapid pathway. In the classical genomic pathway, 17bestradiol
binds the intracellular estrogen receptors (ER) a and b which act as liganddependent
transcription factors to regulate transcription. In the non-genomic pathway,
17b-estradiol binds a putative plasma membrane ER (mER) such as GPR30/GPER1 to
rapidly signal via kinases or calcium flux. Though GPER1’s role in sexual dimorphism has
been explored to a greater extent in cardiovascular physiology, less is known about its role
in the brain. In the last decade, activation of GPER1 has been shown to be important for
lordosis and social cognition in females. In this review we will focus on several
mechanisms that may contribute to sexually dimorphic behaviors including the
colocalization of these estrogen receptors in the SBN, interplay between the signaling
pathways activated by these different estrogen receptors, and the role of these receptors
in development and the maintenance of the SBN, all of which remain underexplored
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Detection of the phosphorylation of the estrogen receptor alpha as an outcome of GPR30 activation
Phosphorylation of the serine residues in estrogen receptor (ER) α is important in transcriptional activation.
Hence, methods to detect such posttranslational modifi cation events are valuable. We describe, in
detail, the analysis of the phosphorylated ERα by electrophoretic separation of proteins and subsequent
immuno-blotting techniques. In particular, phosphorylation of the ERα is one possible outcome of activation
of the putative membrane estrogen receptor (mER), GPR30. Hence, phosphorylation represents a
cross talk event between GPR30 and ERα and may be important in estrogen-regulated physiology
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GPR30 activation decreases anxiety in the open field test but not in the elevated plus maze test in female mice
The GPR30 is a novel estrogen receptor (ER) that is a candidate membrane ER based on its binding to 17beta estradiol and its rapid signaling properties such as activation of the extracellular-regulated kinase (ERK) pathway. Its distribution in the mouse limbic system predicts a role for this receptor in the estrogenic modulation of anxiety behaviors in the mouse. A previous study showed that chronic administration of a selective agonist to the GPR30 receptor, G-1, in the female rat can improve spatial memory, suggesting that GPR30 plays a role in hippocampal-dependent cognition. In this study, we investigated the effect of a similar chronic administration of G-1 on behaviors that denote anxiety in adult ovariectomized female mice, using the elevated plus maze (EPM) and the open field test as well as the activation of the ERK pathway in the hippocampus. Although estradiol benzoate had no effect on behaviors in the EPM or the open field, G-1 had an anxiolytic effect solely in the open field that was independent of ERK signaling in either the ventral or dorsal hippocampus. Such an anxiolytic effect may underlie the ability of G-1 to increase spatial memory, by acting on the hippocampus
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mTOR-dependent spine dynamics in autism
Autism Spectrum Conditions (ASC) are a group of neurodevelopmental disorders characterized by deficits in social communication and interaction as well as repetitive behaviors and restricted range of interests. ASC are complex genetic disorders with moderate to high heritability, and associated with atypical patterns of neural connectivity. Many of the genes implicated in ASC are involved in dendritic spine pruning and spine development, both of which can be mediated by the mammalian target of rapamycin (mTOR) signaling pathway. Consistent with this idea, human postmortem studies have shown increased spine density in ASC compared to controls suggesting that the balance between autophagy and spinogenesis is altered in ASC. However, murine models of ASC have shown inconsistent results for spine morphology, which may underlie functional connectivity. This review seeks to establish the relevance of changes in dendritic spines in ASC using data gathered from rodent models. Using a literature survey, we identify 20 genes that are linked to dendritic spine pruning or development in rodents that are also strongly implicated in ASC in humans. Furthermore, we show that all 20 genes are linked to the mTOR pathway and propose that the mTOR pathway regulating spine dynamics is a potential mechanism underlying the ASC signaling pathway in ASC. We show here that the direction of change in spine density was mostly correlated to the upstream positive or negative regulation of the mTOR pathway and most rodent models of mutant mTOR regulators show increases in immature spines, based on morphological analyses. We further explore the idea that these mutations in these genes result in aberrant social behavior in rodent models that is due to these altered spine dynamics. This review should therefore pave the way for further research on the specific genes outlined, their effect on spine morphology or density with an emphasis on understanding the functional role of these changes in ASC
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Estrogenic regulation of social behavior and sexually dimorphic brain formation
It has long been known that the estrogen, 17β-estradiol (17β-E), plays a central role for female reproductive physiology and behavior. Numerous studies have established the neurochemical and molecular basis of estrogenic induction of female sexual behavior, i.e., lordosis, in animal models. In addition, 17β-E also regulates male-type sexual and aggressive behavior. In males, testosterone secreted from the testes is irreversibly aromatized to 17β-E in the brain. We discuss the contribution of two nuclear receptor isoforms, estrogen receptor (ER)α and ERβ to the estrogenic regulation of sexually dimorphic brain formation and sex-typical expression of these social behaviors. Furthermore, 17β-E is a key player for social behaviors such as social investigation, preference, recognition and memory as well as anxiety-related behaviors in social contexts. Recent studies also demonstrated that not only nuclear receptor-mediated genomic signaling but also membrane receptor-mediated non-genomic actions of 17β-E may underlie the regulation of these behaviors. Finally, we will discuss how rapidly developing research tools and ideas allow us to investigate estrogenic action by emphasizing behavioral neural networks
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Localisation of oestrogen receptors in stem cells and in stem cell derived neurons of the mouse
Oestrogen receptors (ER) transduce the effects of the endogenous ligand, 17b-estradiol in
cells to regulate a number of important processes such as reproduction, neuroprotection,
learning and memory and anxiety. The ERa or ERb are classical intracellular nuclear hormone
receptors while some of their variants or novel proteins such as the GPCR, GPER1/GPR30
are reported to localise in intracellular as well as plasma membrane locations. Though the
brain is an important target for oestrogen with oestrogen receptors expressed differentially in
various nuclei, subcellular organisation and crossttalk between these receptors is underexplored.
Using an adapted protocol that is rapid, we first generated neurons from mouse
embryonic stem cells. Our immunocytochemistry approach shows that the full length
ERa (ERa-66) and for the first time, that an ERa variant, ERa-36, as well as GPER1 is present
in embryonic stem cells. In addition, these receptors typically decrease their nuclear
localisation as neuronal maturation proceeds. Finally, though these ERs are present in many
subcellular compartments such as the nucleus and plasma membrane, we show that they are
specifically not colocalised with each other, suggesting that they initiate distinct signalling
pathways
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Membrane-initiated nuclear trafficking of the glucocorticoid receptor in hypothalamic neurons
Glucocorticoid binding to the intracellular glucocorticoid receptor (GR) stimulates the translocation of the GR from the cytosol to the nucleus, which leads to the transactivation or transrepression of gene transcription. However, multiple lines of evidence suggest that glucocorticoid signaling can also be initiated from the plasma membrane. Here, we provide evidence for membrane-initiated glucocorticoid signaling by a membrane-impermeant dexamethasone-bovine serum albumin (Dex-BSA) conjugate, which induced GR nuclear trafficking in hypothalamic neurons in vitro and in vivo. The GR nuclear translocation induced by a membrane-impermeant glucocorticoid suggests trafficking of an unliganded GR. The membrane-initiated GR trafficking was not blocked by inhibiting ERK MAPK, p38 MAPK, PKA, Akt, Src kinase, or calcium signaling, but was inhibited by Akt activation. Short-term exposure of hypothalamic neurons to dexamethasone (Dex) activated the glucocorticoid response element (GRE), suggesting transcriptional transactivation, whereas exposure to the Dex-BSA conjugate failed to activate the GRE, suggesting differential transcriptional activity of the liganded compared to the unliganded GR. Microarray analysis revealed divergent transcriptional regulation by Dex-BSA compared to Dex. Together, our data suggest that signaling from a putative membrane glucocorticoid receptor induces the trafficking of unliganded GR to the nucleus, which elicits a pattern of gene transcription that differs from that of the liganded receptor. The differential transcriptional signaling by liganded and unliganded receptors may contribute to the broad range of genetic regulation by glucocorticoids, and may help explain some of the different off-target actions of glucocorticoid drugs
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Microplastics and their impact on reproduction—can we learn from the C. elegans model?
Biologically active environmental pollutants have significant impact on ecosystems, wildlife, and human health. Microplastic (MP) and nanoplastic (NP) particles are pollutants that are present in the terrestrial and aquatic ecosystems at virtually every level of the food chain. Moreover, recently, airborne microplastic particles have been shown to reach and potentially damage respiratory systems. Microplastics and nanoplastics have been shown to cause increased oxidative stress, inflammation, altered metabolism leading to cellular damage, which ultimately affects tissue and organismal homeostasis in numerous animal species and human cells. However, the full impact of these plastic particles on living organisms is not completely understood. The ability of MPs/NPs to carry contaminants, toxic chemicals, pesticides, and bioactive compounds, such as endocrine disrupting chemicals, present an additional risk to animal and human health. This review will discusses the current knowledge on pathways by which microplastic and nanoplastic particles impact reproduction and reproductive behaviors from the level of the whole organism down to plastics-induced cellular defects, while also identifying gaps in current knowledge regarding mechanisms of action. Furthermore, we suggest that the nematode Caenorhabditis elegans provides an advantageous high-throughput model system for determining the effect of plastic particles on animal reproduction, using reproductive behavioral end points and cellular readouts
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Delayed mechanical response to chemical kinetics in self- oscillating hydrogels driven by the Belousov−Zhabotinsky reaction
We show experimentally that chemical and mechanical self-oscillations in
Belousov−Zhabotinsky hydrogels are inherently asynchronous, that is, there is a detectable
delay in swelling−deswelling response after a change in the chemical redox state. This
phenomenon is observable in many previous experimental studies and potentially has farreaching
implications for the functionality and response time of the material in future
applications; however, so far, it has not been quantified or reported systematically. Here,
we provide a comprehensive qualitative and quantitative description of the chemical-tomechanical
delay, and we propose to explain it as a consequence of the slow nonequilibrium swelling−deswelling dynamics of the
polymer material. Specifically, standard hydrogel pieces are large enough that transport processes, for example, counterion migration
and water diffusion, cannot occur instantaneously throughout the entire gel piece, as opposed to previous theoretical considerations.
As a result, the volume response of the polymer to a chemical change may be governed by a characteristic response time, which leads
to the emergence of delay in mechanical oscillation. This is supported by our theoretical calculations
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Estrogen and testosterone secretion from the mouse brain
Estrogen and testosterone are typically thought of as gonadal or adrenal derived steroids that cross the blood brain barrier to signal via both rapid nongenomic and slower genomic signalling pathways. Estrogen and testosterone signalling has been shown to drive interlinked behaviours such as social behaviours and cognition by binding to their cognate receptors in hypothalamic and forebrain nuclei. So far, acute brain slices have been used to study short-term actions of 17β-estradiol, typically using electrophysiological measures. For example, these techniques have been used to investigate, nongenomic signalling by estrogen such as the estrogen modulation of long-term potentiation (LTP) in the hippocampus. Using a modified method that preserves the slice architecture, we show, for the first time, that acute coronal slices from the prefrontal cortex and from the hypothalamus maintained in aCSF over longer periods i.e. 24 h can be steroidogenic, increasing their secretion of testosterone and estrogen. We also show that the hypothalamic nuclei produce more estrogen and testosterone than the prefrontal cortex. Therefore, this extended acute slice system can be used to study the regulation of steroid production and secretion by discrete nuclei in the brain