RESUMEN

A growing body of literature suggests that testosterone (T) rapidly modulates behavior in a context-specific manner. However, the timescales in which T can rapidly mediate distinct types of behavior, such as pro- vs. anti- social responses, has not been studied. Thus, here we examined acute T influences on social behavior in male and female Mongolian gerbils in nonreproductive contexts. Females and males received an injection of either saline or T and were first tested in a social interaction test with a same-sex, familiar peer. 5 min after the peer interaction, subjects then underwent a resident-intruder test with a novel, same-sex conspecific. After another 5 min, gerbils were tested in a novel object task to test context-specificity (i.e., social vs. nonsocial) of T effects on behavior. Within 1 h, males and females injected with T exhibited more huddling with a peer but more active avoidance of and less time spent in proximity of an intruder than did animals injected with saline. T effects on behavior were specific to social contexts, such that T did not influence investigation of the novel object. Together these findings show that T rapidly promotes pro-social responses to a familiar peer and anti-social responses to an intruder in the same individuals within 5 min of experiencing these disparate social contexts. This demonstrates that T rapidly facilitates behavior in a context-appropriate manner outside the context of reproduction and reveals that rapid effects of T on behavior are not restricted to males.

Asunto(s)

RESUMEN

Mary Dallman has left a legacy in neuroendocrinology, not only as the scientist who elaborated on new concepts such as rapid corticosteroid feedback pathways, but also as a role model, particularly for women who followed in her footsteps. In this contribution, I compare (i) the remarkable journey she made toward her position as the first female faculty member ever at the physiology department at USCF with that of generations after her; (ii) the contribution of our labs on rapid corticosteroid actions; and, (iii) finally, our experiences with unexpected findings for which one should always keep an open mind, a standpoint that was fervently advocated by Mary Dallman.

Asunto(s)

RESUMEN

Cerebrovascular diseases, such as ischemic cerebral vascular accident (CVA), are responsible for causing high rates of morbidity, mortality, and disability in the population. The neurovascular unit (NVU) during and after ischemic CVA plays crucial roles in cell regulation and preservation, the immune and inflammatory response, and cell and/or tissue survival and repair. Cellular responses to 17ß-estradiol (E2) can be triggered by two mechanisms: one called classical or genomic, which is due to the activation of the "classical" nuclear estrogen receptors α (ERα) and ß (ERß), and the non-genomic or rapid mechanism, which is due to the activation of the G protein-coupled estrogen receptor 1 (GPER) that is located in the plasma membrane and some in intracellular membranes, such as in the Golgi apparatus and endoplasmic reticulum. Nuclear receptors can regulate gene expression and cellular functions. On the contrary, activating the GPER by E2 and/or its G-1 agonist triggers several rapid cell signaling pathways. Therefore, E2 or its G-1 agonist, by mediating GPER activation and/or expression, can influence several NVU cell types. Most studies argue that the activation of the GPER may be used as a potential therapeutic target in various pathologies, such as CVA. Thus, with this review, we aimed to summarize the existing literature on the role of GPER mediated by E2 and/or its agonist G-1 in the physiology and pathophysiology of NVU.

Asunto(s)

RESUMEN

Menopause transition can be interpreted as a vulnerable state characterized by estrogen deficiency with detrimental systemic effects as the low-grade chronic inflammation that appears with aging and partly explains age-related disorders as cancer, diabetes mellitus and increased risk of cognitive impairment. Over the course of a lifetime, estrogen produces several beneficial effects in healthy neurological tissues as well as cardioprotective effects, and anti-inflammatory effects. However, clinical evidence on the efficacy of hormone treatment in menopausal women has failed to confirm the benefit reported in observational studies. Unambiguously, enhanced verbal memory is the most robust finding from longitudinal and cross-sectional studies, what merits consideration for future studies aiming to determine estrogen neuroprotective efficacy. Estrogen related brain activity and functional connectivity remain, however, unexplored. In this context, the resting state paradigm may provide valuable information about reproductive aging and hormonal treatment effects, and their relationship with brain imaging of functional connectivity may be key to understand and anticipate estrogen cognitive protective effects. To go in-depth into the molecular and cellular mechanisms underlying rapid-to-long lasting protective effects of estrogen, we will provide a comprehensive review of cognitive tasks used in animal studies to evaluate the effect of hormone treatment on cognitive performance and discuss about the tasks best suited to the demonstration of clinically significant differences in cognitive performance to be applied in human studies. Eventually, we will focus on studies evaluating the DMN activity and responsiveness to pharmacological stimulation in humans.

RESUMEN

Context: The pharmacokinetics of liothyronine causes concerns for cardiovascular toxicity. While the effects of sustained increase in serum T3 concentrations are well described, little is known on the effects of acute changes in T3 concentrations due to rapid action of thyroid hormone. Objective: To assess the clinical relevance of transient increase of T3 levels on cardiovascular system and energy metabolism. Setting: Double-blind, three arms, placebo controlled, cross-over study (ClinicalTrials.gov Identifier: NCT03098433). Study Participants: Twelve volunteers (3 females, 9 males), age 27.7 ± 5.1 years. Intervention: Oral administration of liothyronine 0.7 mcg/kg, equimolar dose of levothyroxine (0.86 mcg/kg), or placebo in three identical study visits. Blood samples for total T3, free T4 were collected at times 0', 60' 120' 180' 240'. Continuous recording of heart rate, blood pressure, and hemodynamic data was performed using the volume clamp method. Resting energy expenditure was measured by indirect calorimetry. An echocardiogram was performed on each study visit at baseline and after the last blood sampling. Main Outcome Measures: Changes in cardiovascular function and energy expenditure. Results: Following the administration of liothyronine, serum T3 reached a Cmax of 421 ± 57 ng/dL with an estimated Tmax of 120 ± 26 minutes. No differences between study arms were observed in heart rate, blood pressure, hemodynamics parameters, energy expenditure, and in echocardiogram parameters. Conclusions: The absence of measurable rapid effects on the cardiovascular system following a high dose of liothyronine supports the rationale to perform long-term studies to assess its safety and effectiveness in patients affected by hypothyroidism.

Asunto(s)

RESUMEN

Estrogen produces several beneficial effects in healthy neurological tissues and exhibits cardioprotective effects. Hormone therapy has been widely used to treat menopausal estrogen deficiency for more than 80 years. Despite high initial expectations of cardioprotective effects, there has been substantial distrust following important randomized clinical trials, such as the Women's Health Initiative. Subsequently, the timing of treatment in relation to the onset of menopause came under consideration and led to the proposal of the timing hypothesis, that early initial treatment is important, and benefits are lost as the timing since menopause becomes prolonged. Subsequent analyses of the Women's Health Initiative data, together with more recent data from randomized and observational trials, consistently show reductions in coronary heart disease and mortality in younger menopausal women. Regarding cognitive function, the timing hypothesis is consistent with observations from basic and animal studies. There is some clinical evidence to support the benefits of hormonal therapy in this context, though skepticism remains due to the paucity of clinical trials of substantial length in younger menopausal women. It is likely that the effects of estrogens on cognitive performance are due to rapid mechanisms, including mechanisms that influence Ca2+ homeostasis dynamics, provide protection in a hostile environment and reduce inflammatory signals from neural tissues. In the future, inflammatory profiles accounting for early signs of pathological inflammation might help identify the 'window of opportunity' to use estrogen therapy for successful cognitive protection.

RESUMEN

Activation of mineralocorticoid receptor antagonists (MRAs) is cardioprotective; however, this property is lost upon blockade or inactivation of adenosine (ADO) receptor A2b. In this study, we investigated whether the effects of MRAs are mediated by an interaction between cardioprotective ADO receptors A1 and A3. Spironolactone (SPI) or eplerenone (EPL) increased ADO levels in the plasma of treated animals compared to control animals. SPI or EPL increased the protein and activity levels of ecto-5'-nucleotidase (NT5E), an enzyme that synthesizes ADO, compared to control. The levels of ADO deaminase (ADA), which degrades ADO, were not affected by SPI or EPL; however, the activity of ADA was reduced in SPI-treated rats compared to control. Using an isolated cardiomyocyte model, we found inotropic and chronotropic effects, and increased calcium transient [Ca2+]i in cells treated with ADO receptor A1 or A3 antagonists compared to control groups. Upon co-treatment with MRAs, EPL and SPI fully and partially reverted the effects of receptor A1 or A3 antagonism, respectively. Collectively, MRAs in vivo lead to increased ADO bioavailability. In vitro, the rapid effects of SPI and EPL are mediated by an interaction between ADO receptors A1 and A3.

Asunto(s)

RESUMEN

Our review focuses on findings from mammals as part of a Special Issue "30th Anniversary of the Challenge Hypothesis". Here we put forth an integration of the mechanisms through which testosterone controls territorial behavior and consider how reproductive experience may alter these mechanisms. The emphasis is placed on the function of socially induced increases in testosterone (T) pulses, which occur in response to social interactions, as elegantly developed by Wingfield and colleagues. We focus on findings from the monogamous California mouse, as data from this species shows that reproductive status is a key factor influencing social interactions, site fidelity, and vigilance for offspring defense. Specifically, we examine differences in T pulses in sexually naïve versus sexually experienced pair bonded males. Testosterone pulses influence processes such as social decision making, the winner-challenge effect, and location preferences through rewarding effects of T. We also consider how social and predatory vigilance contribute to T pulses and how these interactions contribute to a territory centered around maximizing reproduction. Possible underlying mechanisms for these effects include the nucleus accumbens (rewarding effects of testosterone), hippocampus (spatial memories for territories), and the bed nucleus of the stria terminalis (social vigilance). The development of the challenge effect has provided an ideal framework for understanding the complex network of behavioral, environmental, physiological and neural mechanisms that ultimately relates to competition and territoriality across taxa. The opportunity to merge research on the challenge effect using both laboratory and field research to understand social behavior is unparalleled.

Asunto(s)

RESUMEN

Since the beginning of this century, research methods in neuroendocrinology enjoyed extensive refinements and innovation. These advances allowed collection of huge amounts of new data and the development of new ideas but have not led to this point, with a few exceptions, to the development of new conceptual advances. Conceptual advances that took place largely resulted from the ingenious insights of several investigators. I summarize here some of these new ideas as they relate to the sexual differentiation and activation by sex steroids of reproductive behaviors and I discuss how our research contributed to the general picture. This selective review clearly demonstrates the importance of conceptual changes that have taken place in this field since beginning of the 21st century. The recent technological advances suggest that our understanding of hormones, brain and behavior relationships will continue to improve in a very fundamental manner over the coming years.

Asunto(s)

RESUMEN

Contribution to Special Issue on Fast effects of steroids. Estrogens affect learning and memory through rapid and delayed mechanisms. Here we review studies on rapid effects on short-term memory. Estradiol rapidly improves social and object recognition memory, spatial memory, and social learning when administered systemically. The dorsal hippocampus mediates estrogen rapid facilitation of object, social and spatial short-term memory. The medial amygdala mediates rapid facilitation of social recognition. The three estrogen receptors, α (ERα), ß (ERß) and the G-protein coupled estrogen receptor (GPER) appear to play different roles depending on the task and brain region. Both ERα and GPER agonists rapidly facilitate short-term social and object recognition and spatial memory when administered systemically or into the dorsal hippocampus and facilitate social recognition in the medial amygdala. Conversely, only GPER can facilitate social learning after systemic treatment and an ERß agonist only rapidly improved short-term spatial memory when given systemically or into the hippocampus, but also facilitates social recognition in the medial amygdala. Investigations into the mechanisms behind estrogens' rapid effects on short term memory showed an involvement of the extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K) kinase pathways. Recent evidence also showed that estrogens interact with the neuropeptide oxytocin in rapidly facilitating social recognition. Estrogens can increase the production and/or release of oxytocin and other neurotransmitters, such as dopamine and acetylcholine. Therefore, it is possible that estrogens' rapid effects on short-term memory may occur through the regulation of various neurotransmitters, although more research is need on these interactions as well as the mechanisms of estrogens' actions on short-term memory.

Asunto(s)

RESUMEN

Many of estradiol's behavioral effects are mediated, at least partially, via extra-nuclear estradiol signaling. Here, we investigated whether two estrogen receptor (ER) agonists, targeting ERα and G protein-coupled ER-1 (GPER-1), can promote rapid anorexigenic effects. Food intake was measured in ovariectomized (OVX) rats at 1, 2, 4, and 22 h following subcutaneous (s.c.) injection of an ERα agonist (PPT; 0-200 µg/kg), a GPER-1 agonist (G-1; 0-1600 µg/kg), and a GPER-1 antagonist (G-36; 0-80 µg/kg). To investigate possible cross-talk between ERα and GPER-1, we examined whether GPER-1 blockade affects the anorexigenic effect of PPT. Feeding was monitored in OVX rats that received s.c. injections of vehicle or 40 µg/kg G-36 followed 30 min later by s.c. injections of vehicle or 200 µg/kg PPT. Selective activation of ERα and GPER-1 alone decreased food intake within 1 h of drug treatment, and feeding remained suppressed for 22 h following PPT treatment and 4 h following G-1 treatment. Acute administration of G-36 alone did not suppress feeding at any time point. Blockade of GPER-1 attenuated PPT's rapid (within 1 h) anorexigenic effect, but did not modulate PPT's ability to suppress food intake at 2, 4 and 22 h. These findings demonstrate that selective activation of ERα produces a rapid (within 1 h) decrease in food intake that is best explained by a non-genomic signaling pathway and thus implicates the involvement of extra-nuclear ERα. Our findings also provide evidence that activation of GPER-1 is both sufficient to suppress feeding and necessary for PPT's rapid anorexigenic effect.

Asunto(s)

RESUMEN

Aldosterone acts on its target tissue through a classical mechanism or through the rapid pathway through a putative membrane-bound receptor. Our goal here was to better understand the molecular and biochemical rapid mechanisms responsible for aldosterone-induced cardiomyocyte hypertrophy. We have evaluated the hypertrophic process through the levels of ANP, which was confirmed by the analysis of the superficial area of cardiomyocytes. Aldosterone increased the levels of ANP and the cellular area of the cardiomyocytes; spironolactone reduced the aldosterone-increased ANP level and cellular area of cardiomyocytes. Aldosterone or spironolactone alone did not increase the level of cyclic 3',5'-adenosine monophosphate (cAMP), but aldosterone plus spironolactone led to increased cAMP level; the treatment with aldosterone + spironolactone + BAPTA-AM reduced the levels of cAMP. These data suggest that aldosterone-induced cAMP increase is independent of mineralocorticoid receptor (MR) and dependent on Ca(2+). Next, we have evaluated the role of A-kinase anchor proteins (AKAP) in the aldosterone-induced hypertrophic response. We have found that St-Ht31 (AKAP inhibitor) reduced the increased level of ANP which was induced by aldosterone; in addition, we have found an increase on protein kinase C (PKC) and extracellular signal-regulated kinase 5 (ERK5) activity when cells were treated with aldosterone alone, spironolactone alone and with a combination of both. Our data suggest that PKC could be responsible for ERK5 aldosterone-induced phosphorylation. Our study suggests that the aldosterone through its rapid effects promotes a hypertrophic response in cardiomyocytes that is controlled by an AKAP, being dependent on ERK5 and PKC, but not on cAMP/cAMP-dependent protein kinase signaling pathways. Lastly, we provide evidence that the targeting of AKAPs could be relevant in patients with aldosterone-induced cardiac hypertrophy and heart failure.

Asunto(s)

RESUMEN

Administration of Kampo formulas frequently bring about rapid effects for such acute symptoms as coughs, nasal discharge, nasal congestion, nausea, chills headaches, and gastric pain.<br>In order to confirm the Kampo diagnosis (Sho) and evaluate the efficacy of the Kampo formula selected for patients with acute symptoms, the author performs a “confirmatory administration.” This is done by administering Kampo to out-patients, then evaluating the effects in 30 minutes.<br>A study was carried out on the rapid effects of Kampo formulas (Tsumura) in 339 cases receiving “confirmatory administration”<br>Among the Kampo formulas used most frequently were Makyokanseki-to (Ma-xing-gan-shi-tang). Goreisan (Wu-ling-san) Ninjin-to (Ren-shen-tang), Hangekoboku-to (Ban-xia-hou-po-tang), Shinbu-to (Shen-wu-tang), Hangeshashin-to (Ban-xia-xic-xin-tang), Orengedoku-to (Huang-lian-jie-du-tang), and Senkyuchacho-san (Chuang-xiong-cha-tiao-san). The following major formulas indicated an efficacy rate of over 70%: Ryokankyomishingenin-to (Ling-gan-jiang-wei-xia-ren-tang), Senkyuchacho-san (Chian-xiong-tiao-san), Anchu-san (An-zhong-san), Hangeshashin-to (Ban-xia-xie-xin-tang). Shoseiryu-to (Xiao-qing-long-tang), Makyokanseki-to (Ma-xing-gan-shi-tang), Bakumondo-to (Mai-men-dong-tang), Shinbuto (Shen-wu-tang).<br>“Confirmatory administration” demonstrated the rapid effects of the Kampo formulas and was useful in determining the Sho and appropriate formula.