Capturing Individual Differences: Challenges in Animal Models of Posttraumatic Stress Disorder and Drug Abuse

Holly, Elizabeth N.; Miczek, Klaus A.

doi:10.1016/j.biopsych.2015.09.015

Cited by 14 publications

(12 citation statements)

References 9 publications

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“…Many recent reviews have called for improved PTSD models (17, 18), suggesting that therapeutic discovery cannot progress without improving validity. Several features have been highlighted in recent reviews as key elements needed in a PTSD-like model (17, 18).…”

Section: Introductionmentioning

confidence: 99%

“…Several features have been highlighted in recent reviews as key elements needed in a PTSD-like model (17, 18). These include a brief, rather than chronic stressor, to differentiate from major depressive disorder (MDD); persistent manifestation of the response; hyperarousal; interindividual variability where resilient and susceptible subgroups result from the same protocol (10, 17–19), and assessment in both sexes, as the risk of PTSD may be higher among females (see 9, but also (20, 21)).…”

Section: Introductionmentioning

confidence: 99%

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Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

Sillivan

Joseph

Jamieson

et al. 2017

Biological Psychiatry

100

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Background The limited neurobiological understanding of PTSD has been partially attributed to the need for improved animal models. Stress-enhanced fear learning (SEFL) in rodents recapitulates many PTSD-associated behaviors, including stress-susceptible (SS) and –resilient (SR) subgroups in outbred rats. Identification of subgroups requires additional behavioral phenotyping, a confound to mechanistic studies. Methods We employed a SEFL paradigm in inbred male and female C57BL/6 that combines acute stress with fear conditioning to precipitate “traumatic” memories. Extinction and long-term retention of extinction were examined after SEFL. Further characterization of SEFL effects on male mice was performed with additional behavioral tests, determination of regional activation by Fos immunofluorescence and RNA-sequencing of the basolateral amygdala (BLA). Results Stressed animals displayed persistently elevated freezing during extinction. While more uniform in females, SEFL produced male subgroups with differential susceptibility that were identified without post-training phenotyping. Additional phenotyping of males revealed PTSD-associated behaviors, including extinction-resistant fear memory, hyperarousal, generalization and dysregulated corticosterone in SS males. Altered Fos activation was also seen in the infralimbic cortex and BLA of SS males after remote memory retrieval. Key behavioral outcomes, including susceptibility, were replicated by two independent laboratories. RNA-sequencing of the BLA revealed transcriptional divergence between the male subgroups, including genes with reported polymorphic association to PTSD patients. Conclusions This SEFL model provides a tool for development of PTSD therapeutics that is compatible with the growing number of mouse-specific resources. Furthermore, use of an inbred strain allows for investigation into epigenetic mechanisms that are expected to critically regulate susceptibility and resilience.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

Sillivan

Joseph

Jamieson

et al. 2017

Biological Psychiatry

100

View full text Add to dashboard Cite

show abstract

“…While these studies have generally examined stressed subjects as a homogenous population, it has recently become evident that, like in humans, stress exposure often produces a heterogeneous population in rodents (Cao et al, 2010; Cohen et al, 2012; Edwards et al, 2013; Friedman et al, 2014; Koresh et al, 2016; Krishnan et al, 2007; Levkovitz et al, 2015). This heterogeneity in response to stress may mask some of the behavioral and physiological factors that predispose individuals to developing cocaine self-administration behaviors when stressed populations are viewed as a homogenous group (Holly and Miczek, 2015). To date, the relationship between the variable expression of behavioral aberrations following traumatic stress and cocaine self-administration has not been directly tested (Holly and Miczek, 2015).…”

Section: 0 Introductionmentioning

confidence: 99%

“…This heterogeneity in response to stress may mask some of the behavioral and physiological factors that predispose individuals to developing cocaine self-administration behaviors when stressed populations are viewed as a homogenous group (Holly and Miczek, 2015). To date, the relationship between the variable expression of behavioral aberrations following traumatic stress and cocaine self-administration has not been directly tested (Holly and Miczek, 2015). …”

Section: 0 Introductionmentioning

confidence: 99%

Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine

et al. 2017

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Patients with post-traumatic stress disorder have a heightened vulnerability to developing substance use disorders; however, the biological underpinnings of this vulnerability remain unresolved. We used the predator odor stress model of post-traumatic stress disorder with segregation of subjects as susceptible or resilient based on elevated plus maze behavior and context avoidance. We then determined behavioral and neurochemical differences across susceptible, resilient, and control populations using a panel of behavioral and neurochemical assays. Susceptible subjects showed a significant increase in the motoric and dopaminergic effects of cocaine, and this corresponded with heightened motivation to self-administer cocaine. Resilient subjects did not show differences in the motoric effects of cocaine, in dopamine signaling vivo, or in any measure of cocaine self-administration. Nonetheless, we found that these animals displayed elevations in both the dopamine release-promoting effects of cocaine and dopamine autoreceptor sensitivity ex vivo. Our results suggest that the experience of traumatic stress may produce alterations in dopamine systems that drive elevations in cocaine self-administration behavior in susceptible subjects, but may also produce both active and passive forms of resilience that function to prevent gross changes in cocaine’s reinforcing efficacy in resilient subjects.

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“…Although considerable effort has been directed at understanding the genetic and behavioral risk factors (Bomyea et al, 2012;Lommen et al, 2013;Orr et al, 2012), we cannot accurately predict which individuals will develop PTSD. Establishing a reliable prediction method has the potential to advance research on therapeutics for PTSD, and developing better animal models may facilitate this effort (Holly and Miczek, 2015).…”

Section: Introductionmentioning

confidence: 99%

Selectively Bred Rats Provide a Unique Model of Vulnerability to PTSD-Like Behavior and Respond Differentially to FGF2 Augmentation Early in Life

Prater

Aurbach

Larcinese

et al. 2017

Neuropsychopharmacol

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Individuals respond differently to traumatic experiences, including their propensity to develop posttraumatic stress disorder (PTSD). Understanding individual differences in PTSD vulnerability will allow the development of improved prevention and treatment options. Here we characterized fear conditioning and extinction in rats selectively bred for differences in their locomotor response to a novel environment. Selectively bred high-responder (bHR) and low-responder (bLR) male rats are known to differ in their emotional reactivity on a range of measures of spontaneous anxiety- and depressive-like behaviors. We demonstrate that bHRs have facilitated extinction learning and retention compared with outbred Sprague Dawley rats, whereas bLRs show reduced extinction learning and retention. This indicates that bLRs are more vulnerable to PTSD-like behavior. Fibroblast growth factor 2 (FGF2) has previously been implicated in the development of these behavioral phenotypes and facilitates extinction learning in outbred animals, therefore we examined the effects of early-life FGF2 on bHR and bLR behavior. FGF2 administered on the day after birth facilitated extinction learning and retention in bHRs, but not in bLRs or control rats, during adulthood. This indicates that, under the current fear conditioning paradigm, early-life FGF2 has protective effects only in resilient animals. This stands in contrast to FGF2's ability to protect vulnerable animals in milder tests of anxiety. These results provide a unique animal model of individual differences in PTSD-like behavior, allowing the study of genetic, developmental, and environmental factors in its expression.

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Capturing Individual Differences: Challenges in Animal Models of Posttraumatic Stress Disorder and Drug Abuse

Cited by 14 publications

References 9 publications

Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

Susceptibility and Resilience to Posttraumatic Stress Disorder–like Behaviors in Inbred Mice

Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine

Selectively Bred Rats Provide a Unique Model of Vulnerability to PTSD-Like Behavior and Respond Differentially to FGF2 Augmentation Early in Life

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