An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials

Bowers, Mallory E.; Ressler, Kerry J.

doi:10.1016/j.biopsych.2015.06.008

Cited by 126 publications

(108 citation statements)

References 240 publications

(214 reference statements)

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“…Associated behavior has been shown to be analogous to the extinction resistance and memory persistence that PTSD patients experience (46). We modified this paradigm for use in male (Figure 1A) and female (Figure 2) mice.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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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“…Once this association is formed, the neutral stimulus becomes a conditioned stimulus (CS) and elicits a fear response when presented alone (e.g., increased freezing behavior or a heightened startle response; Bowers and Ressler, 2015; Maren et al, 2013). Subjects can also be exposed repeatedly to the CS in the absence of the UCS to extinguish the associated between these stimuli (Milad and Quirk, 2012).…”

Section: Fear Learningmentioning

confidence: 99%

Adolescent Social Isolation as a Model of Heightened Vulnerability to Comorbid Alcoholism and Anxiety Disorders

Butler

Karkhanis

Jones

et al. 2016

Alcoholism Clin & Exp Res

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Individuals diagnosed with anxiety-related illnesses are at increased risk of developing alcoholism, exhibit a telescoped progression of this disease and fare worse in recovery, relative to alcoholics that do not suffer from a comorbid anxiety disorder. Similarly, preclinical evidence supports the notion that stress and anxiety represent major risk factors for the development of alcohol use disorder (AUD). Despite the importance of understanding the link between anxiety and alcoholism, much remains unknown about the neurobiological substrates underlying this relationship. One stumbling block has been the lack of animal models that reliably reproduce the spectrum of behaviors associated with increased vulnerability to these diseases. Here, we review the literature that has examined the behavioral and neurobiological outcomes of a simple rodent adolescent social isolation procedure and discuss its validity as a model of vulnerability to comorbid anxiety disorders and alcoholism. Recent studies have provided strong evidence that adolescent social isolation of male rats leads to the expression of a variety of behaviors linked with increased vulnerability to anxiety and/or AUD, including deficits in sensory gating and fear extinction, and increases in anxiety measures and ethanol drinking. Neurobiological studies are beginning to identify mesolimbic adaptations that may contribute to the behavioral phenotype engendered by this model. Some of these changes include increased excitability of ventral tegmental area dopamine neurons and pyramidal cells in the basolateral amygdala and significant alterations in baseline and stimulated catecholamine signaling. A growing body of evidence suggests that adolescent social isolation may represent a reliable rodent model of heightened vulnerability to anxiety disorders and alcoholism in male rats. These studies provide initial support for the face, construct, and predictive validity of this model and highlight its utility in identifying neurobiological adaptations associated with increased risk of developing these disorders.

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“…In this regard, animal studies of inhibitory avoidance, and Pavlovian fear conditioning studies in both animals and humans have provided insight into the neurobiological underpinnings of aversive learning and memory that contribute to the development and expression of PTSD (Bowers & Ressler, 2015; Fanselow & Poulos, 2005; LeDoux, 2000; Maren, 2001; Maren, Phan, & Liberzon, 2013; Myers & Davis, 2007; Roozendaal, McEwen, & Chattarji, 2009). Here we primarily focus on reviewing Pavlovian fear conditioning studies because the interpretation of drug studies using an inhibitory avoidance design may be less clear, since the accuracy and specificity of learning are difficult to parse.…”

Section: Introductionmentioning

confidence: 99%

Revisiting propranolol and PTSD: Memory erasure or extinction enhancement?

Giustino

Fitzgerald

Maren

2016

Neurobiology of Learning and Memory

132

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Posttraumatic stress disorder (PTSD) has been described as the only neuropsychiatric disorder with a known cause, yet effective behavioral and pharmacotherapies remain elusive for many afflicted individuals. PTSD is characterized by heightened noradrenergic signaling, as well as a resistance to extinction learning. Research aimed at promoting more effective treatment of PTSD has focused on memory erasure (disrupting reconsolidation) and/or enhancing extinction retention through pharmacological manipulations. Propranolol, a β-adrenoceptor antagonist, has received considerable attention for its therapeutic potential in PTSD, although its impact on patients is not always effective. In this review, we briefly examine the consequences of β-noradrenergic manipulations on both reconsolidation and extinction learning in rodents and in humans. We suggest that propranolol is effective as a fear-reducing agent when paired with behavioral therapy soon after trauma when psychological stress is high, possibly preventing or dampening the later development of PTSD. In individuals who have already suffered from PTSD for a significant period of time, propranolol may be less effective at disrupting reconsolidation of strong fear memories. Also, when PTSD has already developed, chronic treatment with propranolol may be more effective than acute intervention, given that individuals with PTSD tend to experience long-term, elevated noradrenergic hyperarousal.

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An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials

Cited by 126 publications

References 240 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

Adolescent Social Isolation as a Model of Heightened Vulnerability to Comorbid Alcoholism and Anxiety Disorders

Revisiting propranolol and PTSD: Memory erasure or extinction enhancement?

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