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2 Corticosteroid receptors. The glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) are located primarily in the cytoplasm and are associated with several other proteins, including heat shock proteins. They are both members of the nuclear receptor family and, upon binding, translocate to the nucleus and regulate gene transcription. Membrane-associated corticosteroid receptors may be GR, MR or a separate, possibly G protein-coupled, receptor, which is located in the membrane and which signals by activation of second messenger cascades.
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The central nervous system responds to stressful events by activating a generalized neuroendocrine stress response, which is followed by the feedback orchestration of diffuse brain processes that coordinate a strategy for coping with the stress. Ascending brainstem and/or descending limbic circuits converge in the hypothalamus to provide the excita...
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... The goal of this approach was to administer 'stress' in a precisely controlled manner while reducing the inter-animal variability often found in chronic stress paradigms. Therefore, our studies used a chemogenetic approach designed to validate expected outcomes aligned findings from decades of stress research [12,23,25,32,37,[56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74]. ...
... These data suggest that the effects of chronic stress may be encoded upstream of CRF neurons. Indeed, chronic stress decreases PVN CRF neuron inhibition through both reduced GABAergic signaling and decreases endocannabinoidmediated negative feedback, and increases glutamatergic and noradrenergic excitation [69,73,[123][124][125][126]. ...
Trauma and chronic stress exposure are the strongest predictors of lifetime neuropsychiatric disease presentation. These disorders often have significant sex biases, with females having higher incidences of affective disorders such as major depression, anxiety, and PTSD. Understanding the mechanisms by which stress exposure heightens disease vulnerability is essential for developing novel interventions. Current rodent stress models consist of a battery of sensory, homeostatic, and psychological stressors that are ultimately integrated by corticotropin-releasing factor (CRF) neurons to trigger corticosteroid release. These stress paradigms, however, often differ between research groups in the type, timing, and duration of stressors utilized. These inconsistencies, along with the variability of individual animals’ perception and response to each stressor, present challenges for reproducibility and translational relevance. Here, we hypothesized that a more direct approach using chemogenetic activation of CRF neurons would recapitulate the effects of traditional stress paradigms and provide a high-throughput method for examining stress-relevant phenotypes. Using a transgenic approach to express the Gq-coupled Designer Receptor Exclusively Activated by Designer Drugs (DREADD) receptor hM3Dq in CRF-neurons, we found that the DREADD ligand clozapine-N-oxide (CNO) produced an acute and robust activation of the hypothalamic-pituitary-adrenal (HPA) axis, as predicted. Interestingly, chronic treatment with this method of direct CRF activation uncovered a novel sex-specific dissociation of glucocorticoid levels with stress-related outcomes. Despite hM3Dq-expressing females producing greater corticosterone levels in response to CNO than males, hM3Dq-expressing males showed significant typical physiological stress sensitivity with reductions in body and thymus weights. hM3Dq-expressing females while resistant to the physiological effects of chronic CRF activation, showed significant increases in baseline and fear-conditioned freezing behaviors. These data establish a novel mouse model for interrogating stress-relevant phenotypes and highlight sex-specific stress circuitry distinct for physiological and limbic control that may underlie disease risk.
... In these animals, we have measured neurogenic changes, analysing cell proliferation and immature neurons, inflammatory changes, hypothalamic microglial response and the relationship between both processes in three hypothalamic nuclei key in emotional regulation and stress response. Specifically, we investigated the paraventricular nucleus (PVN) which is directly involved in regulating the hypothalamic-pituitary-adrenal axis (HPA) (Herman et al., 2016), the ventromedial nucleus (VMN), because of its relation to food intake and metabolism (Eghbal-Ahmadi et al., 1997;Tasker and Joëls, 2015), the arcuate nucleus (ARC), which is crucial for the maintenance of energy homeostasis (Yi et al., 2006), and the periventricular region (PE) which is consider a proliferative area of the adult hypothalamus (Lee and Ahima, 2012). To better characterize the response to stress, we studied proteomic changes 1 h and 24 h after stress. ...
In recent years, the hypothalamus has emerged as a new neurogenic area, capable of generating new neurons after development. Neurogenesis-dependent neuroplasticity seems to be critical to continuously adapt to internal and environmental changes. Stress is a potent environmental factor that can produce potent and enduring effects on brain structure and function. Acute and chronic stress is known to cause alterations in neurogenesis and microglia in classical adult neurogenic regions such as the hippocampus. The hypothalamus is one of the major brain regions implicated in homeostatic stress and emotional stress systems, but little is known about the effect of stress on the hypothalamus. Here, we studied the impact of acute and intense stress (water immersion and restrain stress, WIRS), which may be considered as an inducer of an animal model of posttraumatic stress disorder, on neurogenesis and neuroinflammation in the hypothalamus of adult male mice, focusing on three nuclei: PVN, VMN and ARC, and also in the periventricular area. Our data revealed that a unique stressor was sufficient to provoke a significant impact on hypothalamic neurogenesis by inducing a reduction in the proliferation and number of immature neurons identified as DCX+ cells. These differences were accompanied by marked microglial activation in the VMN and ARC, together with a concomitant increase in IL-6 levels, indicating that WIRS induced an inflammatory response. To investigate the possible molecular mechanisms responsible for neuroplastic and inflammatory changes, we tried to identify proteomic changes. The data revealed that WIRS induced changes in the hypothalamic proteome, modifying the abundance of three and four proteins after 1 h or 24 h of stress application, respectively. These changes were also accompanied by slight changes in the weight and food intake of the animals. These results are the first to show that even a short-term environmental stimulus such as acute and intense stress can have neuroplastic, inflammatory, functional and metabolic consequences on the adult hypothalamus.
... Aún más, los efectos de la nicotina parecen tener una relación estrecha con sistemas cerebrales de estrés (Chen et al., 2008;Koob & Schulkin, 2019); sin embargo, estas relaciones también permanecen sin aclarar. Dado el importante papel del estrés en la modulación del aprendizaje y la memoria (McEwen et al., 2016;Tasker & Joëls, 2015), así como su hipotética contribución a los desórdenes mentales (de Kloet et al., 2005); el estudio de las relaciones entre el estrés, las drogas y su influencia sobre el aprendizaje y la memoria podría contribuir a describir consecuencias a largo plazo del uso de esta droga que han sido inadvertidas. ...
... Acciones moduladoras de la respuesta de estrés en el cerebro, el aprendizaje y la memoria La respuesta de estrés consiste en un conjunto de reacciones fisiológicas coordinadas que ocurren frente a amenazas a la integridad del organismo, ya sean reales o potenciales; esta respuesta está integrada principalmente por los componentes autónomo y neuroendocrino (Lupien et al., 2009;Tasker & Joëls, 2015). El componente autónomo implica la activación de la médula de la glándula adrenal que resulta en la liberación de adrenalina en el torrente sanguíneo (Kvetnansky et al., 2009). ...
... Por su parte, el componente neuroendocrino implica la activación del eje HPA y resulta en la liberación de corticosteroides en el torrente sanguíneo; la respuesta de este componente inicia con la estimulación de células neurosecretoras en el núcleo paraventricular del hipotálamo (PVN) que producen el factor liberador de corticotropina (CRF por sus siglas en inglés); a su vez el CRF liberado estimula células en el lóbulo anterior de la glándula pituitaria que liberan la hormona adrenocorticótropa (ACTH) la cual alcanza la corteza de las glándulas adrenales y estimula la liberación de hormonas corticosteroides en el torrente sanguíneo (Spencer & Deak, 2017). Estas hormonas ejercen efectos en múltiples sistemas a través de la modulación de funciones orgánicas esenciales (Chrousos, 1992;Tasker & Joëls, 2015). ...
Multiple learning and memory systems interact to produce adapted responses to environmental demands. However, these interactions can result in abnormal response patterns when events that control brain organization favor one system over the others. In this sense, the potential of drugs of abuse to generate long-term behavioral adaptations could lie in their ability to promote neural reorganization processes that alter fundamental brain functions (e.g. reinforcement and stress response) and, consequently, individual sensitivity to different stimuli and learning situations. The present study examined the long-term adaptation of brain emotional systems and their modulation of learning processes and spatial memory, during a period of protracted withdrawal after chronic exposure to nicotine. Two experiments were performed. For the first experiment 22 male Wistar rats were treated with nicotine (0.14 mg/kg free base) or vehicle (0.9% saline solution), administered by one subcutaneous (s.c.) injection per day for a period of 21 days. Following this, the treatment was suspended for a period of 30 days and then the animals were trained and evaluated on a spatial task using the Barnes maze (LCB). For the second experiment 22 Wistar rats received the same treatment described above and were trained under the same conditions; unlike the first experiment, the animals of the second experiment were challenged with an acute stress event using movement restriction before the recovery test in the LCB. Immediately after the recovery test, brain tissue samples were collected and the induction of the c-Fos protein in response to acute stress was determined by means of an immunohistochemical assay. The results showed that: 1) for the short term, chronic nicotine induced sensitization of locomotor activity; 2) for the long term, chronic nicotine did not affect acquisition in the LCB, but improved performance during the recovery test under standard conditions; 3) in contrast, for the long term, chronic nicotine impaired recovery performance in the LCB under the effects of stress, and 4) selectively increased the induction of the c-Fos protein in response to acute stress in regions of brain emotional systems. Together, these results may suggest that nicotine exerts modulatory actions on learning and memory processes thanks to the remodeling of regions involved in emotional processing, taking advantage of molecular mechanisms recruited during chronic exposure to the drug.
... El estrés evolucionó como una respuesta adaptativa que permite a un organismo prepararse y responder a eventos inesperados que ponen en potencial peligro su supervivencia o alteran la homeostasis del sistema (Tasker & Joëls, 2015). Está activación está caracterizada por respuestas hormonales, autónomas y comportamentales que dependen del tipo y naturaleza del estresor. ...
... La actividad del eje HPA inicia con la activación de las neuronas parvocelulares del núcleo paraventricular del hipotálamo (PVN), neuronas que secretan la hormona liberadora de corticotropina (CRH) en la hipófisis anterior donde se estimula la producción de la hormona adrenocorticotropina (ACTH). Al ser liberada al torrente sanguíneo, esta hormona | 10 Marco Teórico estimula la producción de cortisol (corticosterona en roedores) en la corteza adrenal, el cual, una vez liberado, ejerce acción de regulación negativa sobre la activación del eje (Tasker & Joëls, 2015). Gracias a su naturaleza lipofílica, los glucocorticoides cruzan fácilmente la barrera hematoencefálica y en el sistema nervioso central se unen a dos tipos de receptores específicos: el receptor tipo I, para mineralocorticoides (MRs), al que los glucocorticoides se unen con gran afinidad y el de tipo II, para glucocorticoides (GRs), al que se unen con menor afinidad. ...
El estudio de la relación entre estrés y nicotina se ha enfocado en la forma que los eventos estresantes pueden constituir un factor de riesgo para el establecimiento de una adicción. Sin embargo, poco se ha explorado sobre la relación inversa, es decir, la forma en la cual la exposición a una sustancia de abuso puede modificar la respuesta de un organismo ante situaciones emocionalmente demandantes. El presente estudio tuvo como objeto establecer los efectos del estrés agudo en el recobro de la memoria espacial en animales adultos expuestos crónicamente a la nicotina durante la adolescencia. Para esto, 44 ratas Wistar macho recibieron 21 inyecciones de nicotina (0.14 mg/kg s.c.) o vehículo (solución salina 0,9% s.c.) durante la adolescencia y 30 días después fueron entrenadas en el Laberinto Circular de Barnes. Antes de la prueba de recobro realizada 24 horas después del entrenamiento, los animales fueron sometidos a estrés agudo por restricción motora. Finalizada la prueba de memoria se tomarón muestras de plasma sanguíneo para la cuantificación de corticosterona. Los animales tratados con nicotina durante el desafío crónico recorrieron mayor distancia que el grupo de animales tratados con vehículo. Se observó que el tratamiento realizado durante la adolescencia con nicotina no afectó la adquisición de la tarea, pero facilitó su recobro. La nicotina mejoró la precisión de los animales en el recobro de la memoria espacial. Por otro lado, el estrés disminuyó el tiempo para comenzar a explorar en el laberinto, y no tuvo efecto con significancia estadística sobre el desempeño de los animales en el recobro de la tarea; no obstante, los efectos del estrés sobre la recuperación de la información son discutidos. El análisis de corticosterona en plasma sanguíneo reveló que la nicotina disminuyo levemente la liberación de corticosterona ante el estrés agudo, lo que sugiere que la exposición temprana a la nicotina puede modificar los mecanismos a través de los cuales los animales responden ante situaciones emocionalmente demandantes asociadas al recobro de una tarea de memoria espacial. Adicionalmente, a partir de una comparación realizada con experimentos realizados previamente en el laboratorio de neurociencias se encontró que (1) el estrés aumentó el alertamiento del organismo durante el recobro facilitando la recuperación de la información espacial, (2) la manipulación prolongada disminuyó la activación emocional ante la demanda ambiental alterando la formación y expresión de la memoria declarativa, resultando en un efecto deletéreo sobre la recuperación de la memoria. Teniendo en cuenta se propone que la manipulación prolongada de los animales subyacente al tratamiento disminuyó el alertamiento generado por el Laberinto Circular de Barnes y que está modificación alteró el efecto de la nicotina y el estrés sobre el recobro de la tarea. Finalmente, se propone una extensión del modelo de alertamiento al recobro de memoria.
... The stress response is widely conserved across the vertebrate species, to maintain survival. 61 Nevertheless, due to our sedentary lives, this mechanism may lead to health problems. 14 In his later research, Hans Selye found that not all stress responses are bad for our health. ...
Anxiety is a widespread psychiatric disorder. The search for a cure is still continuing since many of the synthetic drugs were inefficient in completely treating anxiety, yet caused some dangerous side effects until many of the drugs were withdrawn from the market. One promising source of new anxiolytics could be herbal medicines. The challenge is to screen plant extracts. Rodent models can be used for this purpose but are expensive. Moreover, rodent tests are costly and consume relatively large quantities of sample. For this reason, alternative animal models may be useful. Zebrafish larvae have many advantages for screening natural products. The main advantage is that they can be produced cheaply and in large numbers. Several studies have shown that the zebrafish is a good model for studying drugs that affect anxiety. This review focuses on the use of animal models, including zebrafish larvae, for studying anxiety and screening for herbal medicines that modulate anxiety. Finally, future prospects of the zebrafish larva as an alternative model in this field are also discussed.
... Blocking GRs and enhancing eCBs were found to prevent the effects of stress on a variety of memory tasks (de Kloet, de Kock, Schild, & Veldhuis, 1988;Ganon-Elazar & Akirav, 2013;Maroun & Akirav, 2008;Oomen, Mayer, de Kloet, Joels, & Lucassen, 2007;Roozendaal, Brunson, Holloway, McGaugh, & Baram, 2002;Segev, Ramot, & Akirav, 2012;Segev, Rubin, Abush, Richter-Levin, & Akirav, 2014;Wulsin, Herman, & Solomon, 2010). Moreover, studies indicate a bidirectional relationship between glucocorticoids and the eCB system (for review see: Akirav, 2013;Di, Malcher-Lopes, Halmos, & Tasker, 2003;Tasker & Joë ls, 2015;Di et al., 2016;Hillard, Beatka, & Sarvaideo, 2016;Morena, Patel, Bains, & Hill, 2016). ECBs play a key role in regulation of the HPA axis under basal and stressful conditions (Patel et al., 2004;Steiner & Wotjak, 2008;Ganon-Elazar & Akirav, 2009;Hill et al., 2010a;Ganon-Elazar & Akirav, 2012;Ganon-Elazar & Akirav, 2013;Gray et al., 2015;Hill & Tasker, 2012). ...
... The CORT facilitation of glutamate release was also nonreversible, but unlike the suppression of GABA release, the sustained facilitation of glutamate release was transcriptiondependent, suggesting a genomic mechanism (Karst et al., 2010). The mineralocorticoid receptor dependence of the rapid corticosteroid facilitation of glutamate release in the BLA and hippocampus (Karst et al., 2005(Karst et al., , 2010 suggests that multiple membrane-associated corticosteroid receptors mediate the rapid corticosteroid effects at different synapses in the brain Tasker and Joëls, 2015). ...
Unlabelled:
Stress and glucocorticoids stimulate the rapid mobilization of endocannabinoids in the basolateral amygdala (BLA). Cannabinoid receptors in the BLA contribute to anxiogenesis and fear-memory formation. We tested for rapid glucocorticoid-induced endocannabinoid regulation of synaptic inhibition in the rat BLA. Glucocorticoid application to amygdala slices elicited a rapid, nonreversible suppression of spontaneous, but not evoked, GABAergic synaptic currents in BLA principal neurons; the effect was also seen with a membrane-impermeant glucocorticoid, but not with intracellular glucocorticoid application, implicating a membrane-associated glucocorticoid receptor. The glucocorticoid suppression of GABA currents was not blocked by antagonists of nuclear corticosteroid receptors, or by inhibitors of gene transcription or protein synthesis, but was blocked by inhibiting postsynaptic G-protein activity, suggesting a postsynaptic nongenomic steroid signaling mechanism that stimulates the release of a retrograde messenger. The rapid glucocorticoid-induced suppression of inhibition was prevented by blocking CB1 receptors and 2-arachidonoylglycerol (2-AG) synthesis, and it was mimicked and occluded by CB1 receptor agonists, indicating it was mediated by the retrograde release of the endocannabinoid 2-AG. The rapid glucocorticoid effect in BLA neurons in vitro was occluded by prior in vivo acute stress-induced, or prior in vitro glucocorticoid-induced, release of endocannabinoid. Acute stress also caused an increase in anxiety-like behavior that was attenuated by blocking CB1 receptor activation and inhibiting 2-AG synthesis in the BLA. Together, these findings suggest that acute stress causes a long-lasting suppression of synaptic inhibition in BLA neurons via a membrane glucocorticoid receptor-induced release of 2-AG at GABA synapses, which contributes to stress-induced anxiogenesis.
Significance statement:
We provide a cellular mechanism in the basolateral amygdala (BLA) for the rapid stress regulation of anxiogenesis in rats. We demonstrate a nongenomic glucocorticoid induction of long-lasting suppression of synaptic inhibition that is mediated by retrograde endocannabinoid release at GABA synapses. The rapid glucocorticoid-induced endocannabinoid suppression of synaptic inhibition is initiated by a membrane-associated glucocorticoid receptor in BLA principal neurons. We show that acute stress increases anxiety-like behavior via an endocannabinoid-dependent mechanism centered in the BLA. The stress-induced endocannabinoid modulation of synaptic transmission in the BLA contributes, therefore, to the stress regulation of anxiety, and may play a role in anxiety disorders of the amygdala.
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.
The ginsenoside Rh2 (Rh2) is a saponin of medicinal ginseng, and it has attracted much attention for its pharmacological activities. In this study, we investigated the interaction of Rh2 with biological membranes using model membranes. We examined the effects of various lipids on the membrane-disrupting activity of Rh2 and found that cholesterol and sphingomyelin (SM) had no significant effect. Furthermore, the effects of Rh2 on acyl chain packing (DPH anisotropy) and water molecule permeability (GP340 values) did not differ significantly between bilayers containing SM and saturated phosphatidylcholine. These results suggest that the formation of the liquid-ordered (Lo) phase affects the behavior of Rh2 in the membrane rather than a specific interaction of Rh2 with a particular lipid. We investigated the effects of Rh2 on the Lo and liquid-disordered (Ld) phases using surface tension measurements and fluorescence experiments. In the surface tension-area isotherms, we compared the monolayers of the Ld and Lo lipid compositions and found that Rh2 is abundantly bound to both monolayers, with the amount being greater in the Ld phase than in the Lo phase. In addition, the hydration state of the bilayers, mainly consisting of the Lo or Ld phase, showed that Rh2 tends to bind to the surface of the bilayer in both phases. At higher concentrations, Rh2 tends to bind more abundantly to the relatively shallow interior of the Ld phase than the Lo phase. The phase-dependent membrane behavior of Rh2 is probably due to the phase-selective affinity and binding mode of Rh2.
The hypothalamic-pituitary-adrenal (HPA) axis mediates the physiological response to stressors and also synchronizes different physiological systems to environmental cues. Changes in day length (i.e., photoperiod) as well as chronic exposure to stressors are known to impact the HPA axis activity regulating the levels of glucocorticoid hormones. Over-exposure to inappropriate levels of glucocorticoids has been implicated in increased disease risk. In the present study, we examined the impact of chronic stress, using a chronic variable stress (CVS) paradigm, in combination with changes in photoperiod on physiological and behavioral measures, as well as on the reactivity and regulation of the HPA axis, in male and female mice. Six weeks of CVS, regardless of the photoperiod condition, decreased the body weight and attenuated the HPA axis reactivity to an acute stressor in both sexes. The attenuated HPA axis reactivity observed in stressed animals was related to reduce POMC mRNA levels in the pituitary of females. The gene expression analyses of key regulators of the HPA axis also indicated a sex-dependent effect with opposite patterns in the pituitary and adrenal glands. CVS effects on behavior were limited and related to an anxiety-like phenotype in both sexes, regardless of photoperiod condition. Our findings highlight sex-specific differences in the HPA axis and also sex-dependent effects of CVS on physiological parameters.
