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

Abstract

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.

Establishment of a murine, lipopolysaccharide-induced sepsis model for testing anaerobic exercise thresholds and early mobilization

“…(44) On the other hand, animal studies allow for precise control of variables that remove bias in results (45,46). There has been a recent push for animal studies that reveal not only physical and cognitive changes in sepsis, but also psychological function, represented as post-traumatic stress disorder, using mice models (47)(48)(49)(50)(51). Our establishment of a mouse model that allowed for exploration into the appropriateness of early mobilization and could easily be adapted for translational studies in sepsis that explore clinically relevant biomarkers (such as lactate) or exercise-related parameters.…”

Neurobiological Trajectories Involving Social Isolation in PTSD: A Systematic Review

“…Last but not least, SI is considered a valid animal model of PTSD in the sense that socially isolated animals present symptoms that resemble the human form (face validity) of the disorder like anxiety behavior, contextual fear responses, impaired fear extinction, cognitive alterations, aggressiveness, and neuroendocrine changes [33]. These disturbances are attributed to the corticolimbic downregulation of allopregnanolone (Allo), which normally exerts fast allosteric modulation of the action of GABA at the GABA A receptors, as mentioned before [21].…”

“…Allo is a positive allosteric modulator of GABA action at GABA A receptors and regulates emotional behavior by exerting anxiolytic, antidepressant, sedative effects. It is produced from progesterone in glutamatergic neurons of the cortex, hippocampus and basolateral amygdala through the double enzymatic action of 5α reductase type I (5 α-RI) and 3 α-hydroxysteroid dehydrogenase(3α-HSD) [18,21]. The decrease of Allo in the cerebrospinal fluid of PTSD patients correlates to the severity of reexperiencing and depressive symptoms of both men and women.…”

“…Interestingly enough, the block in the biosynthesis of Allo is sex-specific relating to 5 α-RI deficiency in men and to 3 α-HSD deficiency in premenopausal women [22,23]. In animal models of PTSD, including the isolated mouse, corticolimbic downregulation of Allo levels correlates to enhanced contextual fear and impaired fear extinction, implying that this neurosteroid may serve as a useful biomarker and treatment option for PTSD across humans and animals [21].Different models have tried to explain the psychoneurobiological etiology of stress-related mental disorders and their shaping interaction with trauma(s): The three-hit concept of vulnerability and resilience [24] developed by Daskalakis et al focuses on the interplay between genetic predisposition, early-life adverse events and later-life environment on the occurrence of psychopathology: According to this testable hypothesis, early mild to moderate stress in animals may contribute to stress inoculation and hypothalamic-pituitary-adrenal (HPA) axis adaptability to later adverse events, whereas more severe early stress may affect, beyond HPA-axis functioning, amygdala activation and processing, fear retention, as well as vulnerability to later-life stressors and stress-related disorders (like PTSD) in adulthood. This model does not follow the linearity of the "classic" cumulative stress model…”

“…Interestingly enough, the block in the biosynthesis of Allo is sex-specific relating to 5 α-RI deficiency in men and to 3 α-HSD deficiency in premenopausal women [22,23]. In animal models of PTSD, including the isolated mouse, corticolimbic downregulation of Allo levels correlates to enhanced contextual fear and impaired fear extinction, implying that this neurosteroid may serve as a useful biomarker and treatment option for PTSD across humans and animals [21].…”