Modelling posttraumatic stress disorders in animals

Török, Bibiána; Sipos, Eszter; Pivac, Nela; Zelena, Dóra

doi:10.1016/j.pnpbp.2018.11.013

Cited by 39 publications

(18 citation statements)

References 226 publications

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“…As such, Yehuda and Antelman defined five criteria for the face validity of translational models: (1) the stressor induces PTSD biological and behavioral responses, (2) responses are intensity-dependent, (3) biological alterations persist or progress over time, (4) biobehavioral alterations are bidirectional, and (5) responses have inter-individual variability caused from experience, genetics, or both 8 . PTSD rodent models have been previously reviewed [9][10][11][12][13][14][15] . This review offers a comprehensive assessment of stress model variants against multiple criteria with a focus on behavioral assays used for model validation.…”

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confidence: 99%

Rodent models of post-traumatic stress disorder: behavioral assessment

2020

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Although the etiology and expression of psychiatric disorders are complex, mammals show biologically preserved behavioral and neurobiological responses to valent stimuli which underlie the use of rodent models of post-traumatic stress disorder (PTSD). PTSD is a complex phenotype that is difficult to model in rodents because it is diagnosed by patient interview and influenced by both environmental and genetic factors. However, given that PTSD results from traumatic experiences, rodent models can simulate stress induction and disorder development. By manipulating stress type, intensity, duration, and frequency, preclinical models reflect core PTSD phenotypes, measured through various behavioral assays. Paradigms precipitate the disorder by applying physical, social, and psychological stressors individually or in combination. This review discusses the methods used to trigger and evaluate PTSD-like phenotypes. It highlights studies employing each stress model and evaluates their translational efficacies against DSM-5, validity criteria, and criteria proposed by Yehuda and Antelman's commentary in 1993. This is intended to aid in paradigm selection by informing readers about rodent models, their benefits to the clinical community, challenges associated with the translational models, and opportunities for future work. To inform PTSD model validity and relevance to human psychopathology, we propose that models incorporate behavioral test batteries, individual differences, sex differences, strain and stock differences, early life stress effects, biomarkers, stringent success criteria for drug development, Research Domain Criteria, technological advances, and cross-species comparisons. We conclude that, despite the challenges, animal studies will be pivotal to advances in understanding PTSD and the neurobiology of stress. Introduction Post-traumatic stress disorder (PTSD) is an incapacitating chronic disorder. With a 3.9% lifetime prevalence rate worldwide and a 6.4-7.8% rate in the USA, PTSD's health burden is substantial 1-5. Based on the World Mental Health Surveys, 69.7% worldwide (82.7% in the USA) reported exposure to a traumatic experience. While trauma exposure is a required criterion for PTSD diagnosis, only 5.6% worldwide (8.3% in the USA) of those who experienced trauma developed the disorder 1. This is due to numerous factors, including trauma type, variation in trauma response, social support, and endogenous factors of individuals. For adults, adolescents, and children older than six years, eight diagnostic criteria, defined in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), specify measures concerning the victim's perception of trauma and symptoms. For children six years and younger, Criteria C and D (described below) are combined, making for seven diagnostic criteria 6. Criterion A: Exposure to actual or threatened death, serious injury, or sexual violence; one or more ways (e.g., direct experience, witnessing others, learning of close family member's or friend's trauma...

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confidence: 99%

Rodent models of post-traumatic stress disorder: behavioral assessment

2020

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“…In the present study, we show that acupuncture treatment at HT7 is effective in reducing freezing responses of fear-conditioned mice. Since freezing behavior has been considered to reflect re-experiencing of a traumatic event 21) , acupuncture stimulation at HT7 can be assumed to be effective in reducing the fear memory related to the electric foot-shock in the foot-shock cage. However, fear memory is important in that it helps to escape from dangerous situations and thus plays a critical role in the survival of an individual.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we chose fear-conditioning by electric footshock and a single acupoint, HT7, as the PTSD animal model and as the target of acupuncture treatment, respectively. Electric foot-shock models have been widely used in preclinical studies, since they are easily repeatable and suitable for the analysis of cognitive functions, with freezing responses reflecting re-experiencing of the traumatic event 21) . In addition, accumulating studies have revealed anatomical and physiological neural mechanisms underlying fear memories induced by electric foot-shock 22) .…”

Section: Introductionmentioning

confidence: 99%

Reduction of Freezing Behavior by Acupuncture Stimulation at HT7 in Contextual Fear-Conditioned Mice

Hwang

Koike

Hioki

2019

Juntendo Medical Journal

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Objective: Acupuncture at acupoint Shenmen (HT7) is used for the treatment of neuropsychological disorders, such as anxiety disorders, in oriental medicine. In the present study, to elucidate the influence of HT7-acupuncture on the reduction of fear memory, we examined freezing responses in contextual fear-conditioned mice with or without acupuncture treatment at HT7. Materials and Methods: Adult male C57BL/6J mice were subjected to electric foot-shock, which represents a common animal model of post-traumatic stress disorder (PTSD), in a foot-shock cage. The mice were then immediately returned to their home cages and randomly divided into two groups, an HT7 and a sham groups. In the HT7 group, 30 seconds of bilateral acupuncture at HT7 was applied for 7 consecutive days. We then placed the mice from both groups either in their home cages or in the foot-shock cage and observed their freezing behavior for 2 minutes. Results: In the home cage, HT7 and sham mice displayed almost no freezing responses. In the foot-shock cage, in contrast, the sham group showed freezing responses for 51.3 ± 16.7% in 2 minutes, indicating that in these mice, fear memory was strongly maintained even after 1 week. Surprisingly, the freezing responses of the HT7 group mice in the foot-shock cage were significantly lower, at 25.7 ± 14.9% in 2 minutes. Conclusions: These findings suggest that acupuncture treatment at HT7 might be effective in reducing fear memories in PTSD.

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“…Protracted social isolation stress may offer an alternative to this methodological problem and provide the advantage of administering the chronic stressor continuously and for as long as desired (often weeks; reviewed in Zelikowsky et al, 2018). This phase of neurochemical changes, such as social isolation stress-induced neurosteroid biosynthesis downregulation, may provide the required conditions that precipitate PTSD-like behavior following the administration of acute stressors (i.e., foot shocks that are part of the fear conditioning paradigm; Torok et al, 2018).…”

Section: Animal Models Of Ptsdmentioning

confidence: 99%

“…The recent progress that has been made in understanding PTSD neurobiology has facilitated the development of experimental stress-induced animal models (Torok et al, 2018). However, PTSD remains a neuropathology with no specific pharmacological treatments, no established and reliable biomarkers, and PTSD animal models only reproduce PTSD neurobiology to a limited degree.…”

Section: Introductionmentioning

confidence: 99%

Animal Models of PTSD: The Socially Isolated Mouse and the Biomarker Role of Allopregnanolone

Pinna

2019

Front. Behav. Neurosci.

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Post-traumatic stress disorder (PTSD) is a debilitating undertreated condition that affects 8%–13% of the general population and 20%–30% of military personnel. Currently, there are no specific medications that reduce PTSD symptoms or biomarkers that facilitate diagnosis, inform treatment selection or allow monitoring drug efficacy. PTSD animal models rely on stress-induced behavioral deficits that only partially reproduce PTSD neurobiology. PTSD heterogeneity, including comorbidity and symptoms overlap with other mental disorders, makes this attempt even more complicated. Allopregnanolone, a neurosteroid that positively, potently and allosterically modulates GABA A receptors and, by this mechanism, regulates emotional behaviors, is mainly synthesized in brain corticolimbic glutamatergic neurons. In PTSD patients, allopregnanolone down-regulation correlates with increased PTSD re-experiencing and comorbid depressive symptoms, CAPS-IV scores and Simms dysphoria cluster scores. In PTSD rodent models, including the socially isolated mouse, decrease in corticolimbic allopregnanolone biosynthesis is associated with enhanced contextual fear memory and impaired fear extinction. Allopregnanolone, its analogs or agents that stimulate its synthesis offer treatment approaches for facilitating fear extinction and, in general, for neuropsychopathologies characterized by a neurosteroid biosynthesis downregulation. The socially isolated mouse model reproduces several other deficits previously observed in PTSD patients, including altered GABA A receptor subunit subtypes and lack of benzodiazepines pharmacological efficacy. Transdiagnostic behavioral features, including expression of anxiety-like behavior, increased aggression, a behavioral component to reproduce behavioral traits of suicidal behavior in humans, as well as alcohol consumption are heightened in socially isolated rodents. Potentials for assessing novel biomarkers to predict, diagnose, and treat PTSD more efficiently are discussed in view of developing a precision medicine for improved PTSD pharmacological treatments.

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Modelling posttraumatic stress disorders in animals

Cited by 39 publications

References 226 publications

Rodent models of post-traumatic stress disorder: behavioral assessment

Rodent models of post-traumatic stress disorder: behavioral assessment

Reduction of Freezing Behavior by Acupuncture Stimulation at HT7 in Contextual Fear-Conditioned Mice

Animal Models of PTSD: The Socially Isolated Mouse and the Biomarker Role of Allopregnanolone

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