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16 pages, 4912 KiB

Open AccessArticle

Offensive Behavior, Striatal Glutamate Metabolites, and Limbic–Hypothalamic–Pituitary–Adrenal Responses to Stress in Chronic Anxiety

by Enrico Ullmann, George Chrousos, Seth W. Perry, Ma-Li Wong, Julio Licinio, Stefan R. Bornstein, Olga Tseilikman, Maria Komelkova, Maxim S. Lapshin, Maryia Vasilyeva, Evgenii Zavjalov, Oleg Shevelev, Nikita Khotskin, Galina Koncevaya, Anna S. Khotskina, Mikhail Moshkin, Olga Cherkasova, Alexey Sarapultsev, Roman Ibragimov, Igor Kritsky, Jörg M. Fegert, Vadim Tseilikman and Rachel Yehuda Show full author list Hide full author list

Int. J. Mol. Sci. 2020, 21(20), 7440; https://doi.org/10.3390/ijms21207440 - 09 Oct 2020

Cited by 11 | Viewed by 3105

Abstract

Variations in anxiety-related behavior are associated with individual allostatic set-points in chronically stressed rats. Actively offensive rats with the externalizing indicators of sniffling and climbing the stimulus and material tearing during 10 days of predator scent stress had reduced plasma corticosterone, increased striatal [...] Read more.

Variations in anxiety-related behavior are associated with individual allostatic set-points in chronically stressed rats. Actively offensive rats with the externalizing indicators of sniffling and climbing the stimulus and material tearing during 10 days of predator scent stress had reduced plasma corticosterone, increased striatal glutamate metabolites, and increased adrenal 11-dehydrocorticosterone content compared to passively defensive rats with the internalizing indicators of freezing and grooming, as well as to controls without any behavioral changes. These findings suggest that rats that display active offensive activity in response to stress develop anxiety associated with decreased allostatic set-points and increased resistance to stress. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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23 pages, 3320 KiB

Open AccessArticle

A Translational Paradigm to Study the Effects of Uncontrollable Stress in Humans

by Laura E. Meine, Katja Schüler, Gal Richter-Levin, Vanessa Scholz and Michele Wessa

Int. J. Mol. Sci. 2020, 21(17), 6010; https://doi.org/10.3390/ijms21176010 - 20 Aug 2020

Cited by 3 | Viewed by 3288

Abstract

Theories on the aetiology of depression in humans are intimately linked to animal research on stressor controllability effects. However, explicit translations of established animal designs are lacking. In two consecutive studies, we developed a translational paradigm to study stressor controllability effects in humans. [...] Read more.

Theories on the aetiology of depression in humans are intimately linked to animal research on stressor controllability effects. However, explicit translations of established animal designs are lacking. In two consecutive studies, we developed a translational paradigm to study stressor controllability effects in humans. In the first study, we compared three groups of participants, one exposed to escapable stress, one yoked inescapable stress group, and a control group not exposed to stress. Although group differences indicated successful stress induction, the manipulation failed to differentiate groups according to controllability. In the second study, we employed an improved paradigm and contrasted only an escapable stress group to a yoked inescapable stress group. The final design successfully induced differential effects on self-reported perceived control, exhaustion, helplessness, and behavioural indices of adaptation to stress. The latter were examined in a new escape behaviour test which was modelled after the classic shuttle box animal paradigm. Contrary to the learned helplessness literature, exposure to uncontrollable stress led to more activity and exploration; however, these behaviours were ultimately not adaptive. We discuss the results and possible applications in light of the findings on learning and agency beliefs, inter-individual differences, and interventions aimed at improving resilience to stress-induced mental dysfunction. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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10 pages, 1379 KiB

Open AccessCommunication

Hexobarbital Sleep Test for Predicting the Susceptibility or Resistance to Experimental Posttraumatic Stress Disorder

by Maria Komelkova, Eugenia Manukhina, H. Fred Downey, Alexey Sarapultsev, Olga Cherkasova, Viacheslav Kotomtsev, Pavel Platkovskiy, Stanislav Fedorov, Petr Sarapultsev, Olga Tseilikman, David Tseilikman and Vadim Tseilikman

Int. J. Mol. Sci. 2020, 21(16), 5900; https://doi.org/10.3390/ijms21165900 - 17 Aug 2020

Cited by 5 | Viewed by 2471

Abstract

Hexobarbital sleep test (HST) was performed in male Wistar rats (hexobarbital 60 mg/kg, i.p.) 30 days prior to stress exposure. Based on the duration of hexobarbital-induced sleep, rats were divided into two groups, animals with high intensity (fast metabolizers (FM), sleep duration <15 [...] Read more.

Hexobarbital sleep test (HST) was performed in male Wistar rats (hexobarbital 60 mg/kg, i.p.) 30 days prior to stress exposure. Based on the duration of hexobarbital-induced sleep, rats were divided into two groups, animals with high intensity (fast metabolizers (FM), sleep duration <15 min) or low intensity of hexobarbital metabolism (slow metabolizers (SM), sleep duration ≥15 min). The SM and FM groups were then divided into two subgroups: unstressed and stressed groups. The stressed subgroups were exposed to predator scent stress for 10 days followed by 15 days of rest. SM and FM rats from the unstressed group exhibited different behavioral and endocrinological patterns. SM showed greater anxiety and higher corticosterone levels. In stressed animals, anxiety-like posttraumatic stress disorder (PTSD) behavior was aggravated only in SM. Corticosterone levels in the stressed FM, PTSD-resistant rats, were lower than in unstressed SM. Thus, HST was able to predict the susceptibility or resistance to experimental PTSD, which was consistent with the changes in glucocorticoid metabolism. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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17 pages, 2755 KiB

Open AccessArticle

Network Neuromodulation of Opioid and GABAergic Receptors Following a Combination of “Juvenile” and “Adult Stress” in Rats

by Omer Horovitz, Ziv Ardi, Shiri Karni Ashkenazi, Gilad Ritov, Rachel Anunu and Gal Richter-Levin

Int. J. Mol. Sci. 2020, 21(15), 5422; https://doi.org/10.3390/ijms21155422 - 30 Jul 2020

Cited by 4 | Viewed by 1991

Abstract

Early life stress is suggested to alter behavioral responses during stressful challenges in adulthood and to exacerbate pathological symptoms that reminisce posttraumatic stress disorder (PTSD). These effects are often associated with changes in γ-Aminobutyric acid type A (GABAA) and κ opioid receptor expression [...] Read more.

Early life stress is suggested to alter behavioral responses during stressful challenges in adulthood and to exacerbate pathological symptoms that reminisce posttraumatic stress disorder (PTSD). These effects are often associated with changes in γ-Aminobutyric acid type A (GABAA) and κ opioid receptor expression and neuromodulation of the limbic system. Anxiety-like and stress coping behaviors were assessed in rats exposed to stress in adulthood on the background of previous exposure to stress in juvenility. Two weeks following behavioral assessment in adulthood, GABAAR α1 and α2 subunits and κ opioid receptor expression levels were measured in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, and periaqueductal gray (PAG). To illustrate changes at the network level, an integrated expression profile was constructed. We found that exposure to juvenile stress affected rats’ behavior during adult stress. The combination of juvenile and adult stress significantly affected rats’ long term anxious-like behavior. Probabilities predicting model integrating the expression of GABAA α1-α2 and κ opioid receptors in different brain regions yielded highly successful classification rates. This study emphasizes the ability of exposure to stress in juvenility to exacerbate the impact of coping with stress in adulthood. Moreover, the use of integrated receptor expression network profiling was found to effectively characterize the discussed affective styles and their behavioral manifestations. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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11 pages, 594 KiB

Open AccessArticle

Free Your Mind: Emotional Expressive Flexibility Moderates the Effect of Stress on Post-Traumatic Stress Disorder Symptoms

by Einat Levy-Gigi, Reut Donner and George A. Bonanno

Int. J. Mol. Sci. 2020, 21(15), 5355; https://doi.org/10.3390/ijms21155355 - 28 Jul 2020

Cited by 11 | Viewed by 2380

Abstract

Servicemen are exposed to high levels of stress as part of their daily routine, however, studies which tested the relationship between stress and clinical symptoms reached inconsistent results. The present study examines the role of expressive flexibility, which was determined according to the [...] Read more.

Servicemen are exposed to high levels of stress as part of their daily routine, however, studies which tested the relationship between stress and clinical symptoms reached inconsistent results. The present study examines the role of expressive flexibility, which was determined according to the ability to enhance or suppress either negative or positive emotional expression in conflictual situations, as a possible moderator between stress and Post-Traumatic Stress Disorder (PTSD) symptoms. A total of 82 active-duty firefighters (all men, age range = 25–66, M = 33.59, SD = 9.56, range of years in duty service = 2–41, M = 14.37, SD = 11.79), with different duty-related repeated traumatic exposure, participated in the study. We predicted and found that firefighters with low, but not high, expressive flexibility showed a significant positive correlation between duty-related traumatic exposure and PTSD symptomology (t(81) = 3.85, p < 0.001). Hence, the greater the exposure the higher level of symptoms they exhibited. In addition, we found a difference between the moderating roles of suppressing positive and negative emotional expression, as high but not low, ability to suppress the expression of negative emotions (t(81) = 1.76, p > 0.05), as low but not high, ability to suppress the expression of positive emotions (t(81) = 1.6, p > 0.05), served as a protective factor in buffering the deleterious effect of repeated traumatic exposure. The results provide a pivotal support for the growing body of evidence that a flexible emotional profile is an adaptive one, in dealing with negative life events. However, while there is a need to update behavior, the direction of the adaptive update may differ as a function of valance. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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15 pages, 3765 KiB

Open AccessArticle

Development and Characterization of an Allergic Asthma Rat Model for Interventional Studies

by Marta Périz, Francisco J. Pérez-Cano, Maria J. Rodríguez-Lagunas, Trinitat Cambras, Santiago Pastor-Soplin, Iván Best, Margarida Castell and Malén Massot-Cladera

Int. J. Mol. Sci. 2020, 21(11), 3841; https://doi.org/10.3390/ijms21113841 - 28 May 2020

Cited by 12 | Viewed by 3335

Abstract

Allergic asthma is one of the most common chronic diseases of the airways, however it still remains underdiagnosed and hence undertreated. Therefore, an allergic asthma rat model would be useful to be applied in future therapeutic strategy studies. The aim of the present [...] Read more.

Allergic asthma is one of the most common chronic diseases of the airways, however it still remains underdiagnosed and hence undertreated. Therefore, an allergic asthma rat model would be useful to be applied in future therapeutic strategy studies. The aim of the present study was to develop an objective model of allergic asthma in atopic rats that allows the induction and quantification of anaphylactic shock with quantitative variables. Female Brown Norway rats were intraperitoneally sensitized with ovalbumin (OVA), alum and Bordetella pertussis toxin and boosted a week later with OVA in alum. At day 28, all rats received an intranasal challenge with OVA. Anaphylactic response was accurately assessed by changes in motor activity and body temperature. Leukotriene concentration was determined in the bronchoalveolar lavage fluid (BALF), and total and IgE anti-OVA antibodies were quantified in blood and BALF samples. The asthmatic animals’ motility and body temperature were reduced after the shock for at least 20 h. The asthmatic animals developed anti-OVA IgE antibodies both in BALF and in serum. These results show an effective and relatively rapid model of allergic asthma in female Brown Norway rats that allows the quantification of the anaphylactic response. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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16 pages, 2774 KiB

Open AccessArticle

GABAergic Transmission in the Basolateral Amygdala Differentially Modulates Plasticity in the Dentate Gyrus and the CA1 Areas

by Rose-Marie Vouimba, Rachel Anunu and Gal Richter-Levin

Int. J. Mol. Sci. 2020, 21(11), 3786; https://doi.org/10.3390/ijms21113786 - 27 May 2020

Cited by 5 | Viewed by 2538

Abstract

The term “metaplasticity” is used to describe changes in synaptic plasticity sensitivity following an electrical, biochemical, or behavioral priming stimulus. For example, priming the basolateral amygdala (BLA) enhances long-term potentiation (LTP) in the dentate gyrus (DG) but decreases LTP in the CA1. However, [...] Read more.

The term “metaplasticity” is used to describe changes in synaptic plasticity sensitivity following an electrical, biochemical, or behavioral priming stimulus. For example, priming the basolateral amygdala (BLA) enhances long-term potentiation (LTP) in the dentate gyrus (DG) but decreases LTP in the CA1. However, the mechanisms underlying these metaplastic effects are only partly understood. Here, we examined whether the mechanism underlying these effects of BLA priming involves intra-BLA GABAergic neurotransmission. Low doses of muscimol, a GABA_A receptor (GABA_AR) agonist, were microinfused into the rat BLA before or after BLA priming. Our findings show that BLA GABA_AR activation via muscimol mimicked the previously reported effects of electrical BLA priming on LTP in the perforant path and the ventral hippocampal commissure-CA1 pathways, decreasing CA1 LTP and increasing DG LTP. Furthermore, muscimol application before or after tetanic stimulation of the ventral hippocampal commissure-CA1 pathways attenuated the BLA priming-induced decrease in CA1 LTP. In contrast, muscimol application after tetanic stimulation of the perforant path attenuated the BLA priming-induced increase in DG LTP. The data indicate that GABA_AR activation mediates metaplastic effects of the BLA on plasticity in the CA1 and the DG, but that the same GABA_AR activation induces an intra-BLA form of metaplasticity, which alters the way BLA priming may modulate plasticity in other brain regions. These results emphasize the need for developing a dynamic model of BLA modulation of plasticity, a model that may better capture processes underlying memory alterations associated with emotional arousing or stressful events. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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13 pages, 3371 KiB

Open AccessArticle

All-trans Retinoic Acid-induced Abnormal Hippocampal Expression of Synaptic Genes SynDIG1 and DLG2 is Correlated with Anxiety or Depression-Like Behavior in Mice

by Xin-Ya Qin, Hui Fang, Qing-Hong Shan, Cong-Cong Qi and Jiang-Ning Zhou

Int. J. Mol. Sci. 2020, 21(8), 2677; https://doi.org/10.3390/ijms21082677 - 11 Apr 2020

Cited by 5 | Viewed by 2968

Abstract

Clinical reports suggest a potential link between excess retinoids and development of depression. Although it has been shown that all-trans retinoic acid (ATRA) administration induces behavioral changes, further insight into how ATRA is involved is lacking. The hippocampus seems to be a major [...] Read more.

Clinical reports suggest a potential link between excess retinoids and development of depression. Although it has been shown that all-trans retinoic acid (ATRA) administration induces behavioral changes, further insight into how ATRA is involved is lacking. The hippocampus seems to be a major target of retinoids, and abnormal synaptic plasticity of the hippocampus is involved in depression. We examined two genes associated with synaptic function, discs large homolog 2 (DLG2), and synapse differentiation-inducing gene protein 1 (SynDIG1) in terms of hippocampal expression and correlation with behavior. Three different doses of ATRA were injected into young mice and 10 mg/kg ATRA was found to induce depression-like behavior. In the hippocampus, DLG2 mRNA was significantly decreased by ATRA. mRNA levels were positively correlated with central area duration and distance in the open-field test. Increased SynDIG1 mRNA levels were observed. There was a negative correlation between SynDIG1 mRNA levels and mobility time in the forced swimming test. Retinoic acid receptor γ mRNA was significantly positively correlated with DLG2 and negatively correlated with SynDIG1. To summarize, ATRA administration induced anxiety- and depression-like behavior accompanied by a decreased expression of DLG2 and an increased expression of SynDIG1. Moreover, DLG2 was correlated with anxiety-like behavior and SynDIG1 was correlated with depression-like behavior. These results might constitute a novel target underlying ATRA-induced anxiety- and depression-like behavior. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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Review

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22 pages, 1860 KiB

Open AccessReview

Rationale, Relevance, and Limits of Stress-Induced Psychopathology in Rodents as Models for Psychiatry Research: An Introductory Overview

by Maria Italia, Chiara Forastieri, Alessandra Longaretti, Elena Battaglioli and Francesco Rusconi

Int. J. Mol. Sci. 2020, 21(20), 7455; https://doi.org/10.3390/ijms21207455 - 09 Oct 2020

Cited by 10 | Viewed by 2510

Abstract

Emotional and cognitive information processing represent higher-order brain functions. They require coordinated interaction of specialized brain areas via a complex spatial and temporal equilibrium among neuronal cell-autonomous, circuitry, and network mechanisms. The delicate balance can be corrupted by stressful experiences, increasing the risk [...] Read more.

Emotional and cognitive information processing represent higher-order brain functions. They require coordinated interaction of specialized brain areas via a complex spatial and temporal equilibrium among neuronal cell-autonomous, circuitry, and network mechanisms. The delicate balance can be corrupted by stressful experiences, increasing the risk of developing psychopathologies in vulnerable individuals. Neuropsychiatric disorders affect twenty percent of the western world population, but therapies are still not effective for some patients. Elusive knowledge of molecular pathomechanisms and scarcity of objective biomarkers in humans present complex challenges, while the adoption of rodent models helps to improve our understanding of disease correlate and aids the search for novel pharmacological targets. Stress administration represents a strategy to induce, trace, and modify molecular and behavioral endophenotypes of mood disorders in animals. However, a mouse or rat model will only display one or a few endophenotypes of a specific human psychopathology, which cannot be in any case recapitulated as a whole. To override this issue, shared criteria have been adopted to deconstruct neuropsychiatric disorders, i.e., depression, into specific behavioral aspects, and inherent neurobiological substrates, also recognizable in lower mammals. In this work, we provide a rationale for rodent models of stress administration. In particular, comparing each rodent model with a real-life human traumatic experience, we intend to suggest an introductive guide to better comprehend and interpret these paradigms. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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27 pages, 1538 KiB

Open AccessReview

Cellular Stress in the Pathogenesis of Muscular Disorders—From Cause to Consequence

by Alexander Mensch and Stephan Zierz

Int. J. Mol. Sci. 2020, 21(16), 5830; https://doi.org/10.3390/ijms21165830 - 13 Aug 2020

Cited by 9 | Viewed by 3802

Abstract

Cellular stress has been considered a relevant pathogenetic factor in a variety of human diseases. Due to its primary functions by means of contractility, metabolism, and protein synthesis, the muscle cell is faced with continuous changes of cellular homeostasis that require rapid and [...] Read more.

Cellular stress has been considered a relevant pathogenetic factor in a variety of human diseases. Due to its primary functions by means of contractility, metabolism, and protein synthesis, the muscle cell is faced with continuous changes of cellular homeostasis that require rapid and coordinated adaptive mechanisms. Hence, a prone susceptibility to cellular stress in muscle is immanent. However, studies focusing on the cellular stress response in muscular disorders are limited. While in recent years there have been emerging indications regarding a relevant role of cellular stress in the pathophysiology of several muscular disorders, the underlying mechanisms are to a great extent incompletely understood. This review aimed to summarize the available evidence regarding a deregulation of the cellular stress response in individual muscle diseases. Potential mechanisms, as well as involved pathways are critically discussed, and respective disease models are addressed. Furthermore, relevant therapeutic approaches that aim to abrogate defects of cellular stress response in muscular disorders are outlined. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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23 pages, 1233 KiB

Open AccessReview

Becoming Stressed: Does the Age Matter? Reviewing the Neurobiological and Socio-Affective Effects of Stress throughout the Lifespan

by Aroa Mañas-Ojeda, Francisco Ros-Bernal, Francisco E. Olucha-Bordonau and Esther Castillo-Gómez

Int. J. Mol. Sci. 2020, 21(16), 5819; https://doi.org/10.3390/ijms21165819 - 13 Aug 2020

Cited by 10 | Viewed by 5589

Abstract

Social and affective relations occur at every stage of our lives. Impairments in the quality of this “social world” can be exceptionally detrimental and lead to psychopathology or pathological behavior, including schizophrenia, autism spectrum disorder, affective disorders, social phobia or violence, among other [...] Read more.

Social and affective relations occur at every stage of our lives. Impairments in the quality of this “social world” can be exceptionally detrimental and lead to psychopathology or pathological behavior, including schizophrenia, autism spectrum disorder, affective disorders, social phobia or violence, among other things. Exposure to highly stressful or traumatic events, depending on the stage of life in which stress exposure occurs, could severely affect limbic structures, including the amygdala, and lead to alterations in social and affective behaviors. This review summarizes recent findings from stress research and provides an overview of its age-dependent effects on the structure and function of the amygdala, which includes molecular and cellular changes, and how they can trigger deviant social and affective behaviors. It is important to highlight that discoveries in this field may represent a breakthrough both for medical science and for society, as they may help in the development of new therapeutic approaches and prevention strategies in neuropsychiatric disorders and pathological behaviors. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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19 pages, 886 KiB

Open AccessReview

Long-Term Impact of Early-Life Stress on Hippocampal Plasticity: Spotlight on Astrocytes

by Gürsel Çalışkan, Anke Müller and Anne Albrecht

Int. J. Mol. Sci. 2020, 21(14), 4999; https://doi.org/10.3390/ijms21144999 - 15 Jul 2020

Cited by 15 | Viewed by 5703

Abstract

Adverse experiences during childhood are among the most prominent risk factors for developing mood and anxiety disorders later in life. Early-life stress interventions have been established as suitable models to study the neurobiological basis of childhood adversity in rodents. Different models such as [...] Read more.

Adverse experiences during childhood are among the most prominent risk factors for developing mood and anxiety disorders later in life. Early-life stress interventions have been established as suitable models to study the neurobiological basis of childhood adversity in rodents. Different models such as maternal separation, impaired maternal care and juvenile stress during the postweaning/prepubertal life phase are utilized. Especially within the limbic system, they induce lasting alterations in neuronal circuits, neurotransmitter systems, neuronal architecture and plasticity that are further associated with emotional and cognitive information processing. Recent studies found that astrocytes, a special group of glial cells, have altered functions following early-life stress as well. As part of the tripartite synapse, astrocytes interact with neurons in multiple ways by affecting neurotransmitter uptake and metabolism, by providing gliotransmitters and by providing energy to neurons within local circuits. Thus, astrocytes comprise powerful modulators of neuronal plasticity and are well suited to mediate the long-term effects of early-life stress on neuronal circuits. In this review, we will summarize current findings on altered astrocyte function and hippocampal plasticity following early-life stress. Highlighting studies for astrocyte-related plasticity modulation as well as open questions, we will elucidate the potential of astrocytes as new targets for interventions against stress-induced neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Diverse Models of Stress: From Animal Model to Human and Back)

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