The reciprocal regulation of stress hormones and GABAA receptors

Stress-derived steroid hormones regulate the expression and function of GABAA receptors (GABAARs). Changes in GABAAR subunit expression have been demonstrated under conditions of altered steroid hormone levels, such as stress, as well as following exogenous steroid hormone administration. In addition to the effects of stress-derived steroid hormones on GABAAR subunit expression, stress hormones can also be metabolized to neuroactive derivatives which can alter the function of GABAARs. Neurosteroids allosterically modulate GABAARs at concentrations comparable to those during stress. In addition to the actions of stress-derived steroid hormones on GABAARs, GABAARs reciprocally regulate the production of stress hormones. The stress response is mediated by the hypothalamic-pituitary-adrenal (HPA) axis, the activity of which is governed by corticotropin releasing hormone (CRH) neurons. The activity of CRH neurons is largely controlled by robust GABAergic inhibition. Recently, it has been demonstrated that CRH neurons are regulated by neurosteroid-sensitive, GABAAR δ subunit-containing receptors representing a novel feedback mechanism onto the HPA axis. Further, it has been demonstrated that neurosteroidogenesis and neurosteroid actions on GABAAR δ subunit-containing receptors on CRH neurons are necessary to mount the physiological response to stress. Here we review the literature describing the effects of steroid hormones on GABAARs as well as the importance of GABAARs in regulating the production of steroid hormones. This review incorporates what we currently know about changes in GABAARs following stress and the role in HPA axis regulation

Enshrining Vietnamese-Irish Lives

Abstract included in tex

Enshrining Vietnamese-Irish Lives

Abstract included in tex

Promoting student engagement with academic literacy feedback: an institute wide initiative

The transition to higher education, while often exciting, is demanding for many students. Successful transition necessitates learning the conventions of scholarly conversation, including how to read and create work in an academic context. Knowledge of academic literacy practices is an important part of this process but these discourses and practices are often unfamiliar to students and this has implications for the development of academic identities. In this article, we report on an institution-wide initiative between librarians, lecturers and learning developers, designed to raise awareness of the role of feedback in developing academic literacies. While the rate of participation was low this initiative offered a space outside the formal curriculum and assessment processes to engage with students about feedback. The associated publicity raised the profile of feedback internally and offered valuable opportunities to open conversations about feedback with students and staff. The evolution of the initiative is discussed

Hippocampal corticotropin-releasing hormone neurons support recognition memory and modulate hippocampal excitability

Corticotropin-releasing hormone (CRH) signaling in the hippocampus has been established to be important for mediating the effects of stress on learning and memory. Given our laboratory’s recent characterization of a subset of hippocampal CRH neurons as a novel class of GABAergic interneurons, we hypothesized that these local GABAergic hippocampal CRH neurons may influence hippocampal function. Here we applied an array of molecular tools to selectively label and manipulate hippocampal CRH neurons in mice, in order to assess this interneuron population’s impact on hippocampus-dependent behaviors and hippocampal network excitability. Genetically-targeted ablation of hippocampal CRH neurons in vivo impaired object recognition memory and substantially enhanced the severity of kainic acid-induced seizures. Conversely, selective activation of CRH neurons in vitro suppressed the excitability of the mossy fiber-CA3 pathway. Additional experiments are needed to reconcile the functions of GABA and CRH signaling of hippocampal CRH neurons on hippocampal function. However, our results indicate that this interneuron population plays an important role in maintaining adaptive network excitability, and provide a specific circuit-level mechanism for this role

A Novel, Synthetic, Neuroactive Steroid Is Effective at Decreasing Depression-Like Behaviors and Improving Maternal Care in Preclinical Models of Postpartum Depression

Preclinical testing of treatments for postpartum depression (PPD) has been limited due to the lack of available animal models of such a complex disorder. To address this limitation, our laboratory has generated unique preclinical mouse models that exhibit abnormal postpartum behaviors. Mice with a loss or reduction in the expression of the GABAA receptor (GABAAR) δ subunit (Gabrd−/− or Gabrd+/−, respectively) and mice that lack the K+/Cl− co-transporter, KCC2, specifically in corticotropin-releasing hormone (CRH) neurons (KCC2/Crh mice) exhibit depression-like behaviors restricted to the postpartum period and deficits in maternal care, which serve as useful tools for testing novel therapeutic compounds. Utilizing these preclinical models, we tested the ability of a novel, synthetic, neuroactive steroid developed by SAGE Therapeutics, SGE-516, to improve abnormal postpartum behaviors. Gabrd−/−, Gabrd+/−, and KCC2/Crh dams treated with SGE-516 (450 mg/kg chow) during late pregnancy exhibit a decrease in depression-like behaviors and improvements in maternal care at 48 h postpartum. Interestingly, acute treatment with SGE-516 also exhibits robust therapeutic effects in these preclinical PPD models. We previously discovered abnormal stress reactivity associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation associated with depression-like behaviors in the preclinical PPD models, evident from an increase in stress-induced corticosterone levels and dephosphorylation and downregulation of KCC2 in the paraventricular nucleus of the hypothalamus (PVN) during the peripartum period. Here we demonstrated that SGE-516 treatment is sufficient to prevent the stress-induced increase in corticosterone and dephosphorylation and downregulation of KCC2 in the PVN. In contrast, and consistent with the distinct pharmacology of SGE-516 compared to benzodiazepines, treatment with clobazam (250 mg/kg chow) did not alter the depression-like phenotype or deficits in maternal care observed in these preclinical models of PPD. These findings are consistent with the positive double-blind, randomized, placebo-controlled trial findings of a similar compound, brexanolone, in the treatment of patients with postpartum depression. Further, these findings validate the use of these preclinical models of PPD for screening novel compounds for the treatment of postpartum depression

A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development: IUPHAR Review 29.

In this review, we identify opportunities for drug discovery in the treatment of COVID-19 and, in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic. We assess the scope for targeting key host and viral targets in the mid-term, by first screening these targets against drugs already licensed, an agenda for drug repurposing, which should allow rapid translation to clinical trials. A simultaneous, multi-pronged approach using conventional drug discovery methods aimed at discovering novel chemical and biological means of targeting a short list of host and viral entities which should extend the arsenal of anti-SARS-CoV-2 agents. This longer term strategy would provide a deeper pool of drug choices for future-proofing against acquired drug resistance. Second, there will be further viral threats, which will inevitably evade existing vaccines. This will require a coherent therapeutic strategy which pharmacology and pharmacologists are best placed to provide. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.Welcome Trust 107715/Z/15/

Pengaruh Harga Terhadap Peningkatan Penjualan Produk Semen Tiga Roda Pada PT. Robcaga Beo Kabupaten Kepulauan Talaud

The development in business world these days is market by the competition between the business company is getting fierce. Especially in managing the company business unit. It is shown by the appearance of a company that offer a good quality product with a compete price on the market. To handle the fierce competition on the market then one from so many effort that the company do is by apply the strategic price. Which on the way of applying that strategi the company try to set a price that can be compete in the market so the increase sale of the product become maximum. With right price and controlled will result the domino effect to a company to build long term relationship with costumer so it can increase the sales volume. This research is a descriptive quantitative research by using the correlation approach and simple regression. To see relation between variable and to measure the impact to the variable itself. So the purpose of this research is to know how far the price effect and to the increase of PT. ROBCAGA in Talaud. According to the sesult of the research, can be shown as following: price has a correlation and significant determination effort to the increase sale of PT. ROBCAGA Talaud. According to the data analysis, coefficient value moment r = 0,685. That show there is a positive relation, and can be categorize as high and strong, also price coefficient determination to the increase sale is by 46,5% and 53,5% by the rest of it depends on the unknown factors that not been analyze in this research

Mental health of adults in Ireland during the first year of the COVID-19 pandemic: Results from a nationally representative, longitudinal study

No abstract available