The effect of chronic phenytoin administration on single prolonged stress induced extinction retention deficits and glucocorticoid upregulation in the rat medial prefrontal cortex

George, Sophie; Rodriguez-Santiago, Mariana; Riley, John; Rodriguez, Elizabeth; Liberzon, Israel

doi:10.1007/s00213-014-3635-x

Cited by 40 publications

(35 citation statements)

References 37 publications

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“…Upregulation of dHipp GRs in SPS/male rats was not observed, which is inconsistent with previous studies [10–12]. Potential reasons to explain this discrepancy include enhanced levels of handling and older age of rats at SPS exposure in the current study.…”

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confidence: 99%

“…Enhanced GR levels have been implicated in PTSD symptomatology [7], and changes in GR function have been suggested to contribute to trauma susceptibility in females [9]. Fear extinction retention deficits and enhanced hippocampal GR expression are also observed in the SPS model [10, 11], and these two effects may be linked [12]. Thus, examining sex differences in the SPS model with regard to fear extinction retention and GR expression could lead to a better understanding of how GR function contributes to susceptibility to trauma in female humans.…”

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confidence: 99%

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Sex differences in the single prolonged stress model

Keller

Schreiber

Staib

et al. 2015

Behavioural Brain Research

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Post traumatic stress disorder (PTSD) is a debilitating anxiety disorder resulting from traumatic stress exposure. Females are more likely to develop PTSD than males, but neurobiological mechanisms underlying female susceptibility are lacking. This can be addressed by using nonhuman animal models. Single prolonged stress (SPS), a nonhuman animal model of PTSD, results in cued fear extinction retention deficits and hippocampal glucocorticoid receptor (GR) upregulation in male rats. These effects appear linked in the SPS model, as well as in PTSD. However, the effects of SPS on cued fear extinction retention and hippocampal GRs in female rats remain unknown. Thus, we examined sex differences in SPS-induced cued fear extinction retention deficits and hippocampal GR upregulation. SPS induced cued fear extinction retention deficits in male rats but not female rats. SPS enhanced GR levels in the dorsal hippocampus of female rats, but not male rats. SPS had no effects on ventral hippocampal GR levels, but ventral hippocampal GR levels were attenuated in female rats relative to males. These results suggest that female rats are more resilient to the effects of SPS. The results also suggest that GR upregulation and cued fear extinction retention deficits can be dissociated in the SPS model. Keywords: sex differences, stress, post traumatic stress disorder, extinction recall, fear, glucocorticoids

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confidence: 99%

Sex differences in the single prolonged stress model

Keller

Schreiber

Staib

et al. 2015

Behavioural Brain Research

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“…Diminished mPFC function has also been consistently reported in PTSD (Shin and Liberzon, 2010) and confirmed by meta-analyses (Etkin and Wager, 2007). In our PTSD animal model (SPS), which successfully replicates the enhanced HPA negative feedback seen in patients (Yamamoto et al, 2009), abnormalities in fear renewal are also seen (Figure 5, top panel), and upregulation of glucocorticoid receptors in mPFC has been shown to be critical for expression of the PTSD-like phenotype (George et al, 2015). Similarly, glucocorticoid signaling in Hpc plays a critical role in pattern separation and can induce PTSD-like memory abnormalities in a mouse model (Kaouane et al, 2012); and in our SPS rat model, upregulation of GR in Hpc also appears critical to emergence of the PTSD-like phenotype (Knox et al, 2012).…”

Section: A New Model: Deficient Context Processingmentioning

confidence: 65%

Context Processing and the Neurobiology of Post-Traumatic Stress Disorder

Liberzon

Abelson

2016

Neuron

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361

335

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Summary Progress in clinical and affective neuroscience is redefining psychiatric illness as symptomatic expression of cellular/molecular dysfunctions in specific brain circuits. Post-traumatic stress disorder (PTSD) has been an exemplar of this progress, with improved understanding of neurobiological systems subserving fear learning, salience detection, and emotion regulation explaining much of its phenomenology and neurobiology. However, many features remain unexplained and a parsimonious model that more fully accounts for symptoms and the core neurobiology remains elusive. Contextual processing is a key modulatory function of hippocampal-prefrontal-thalamic circuitry, allowing organisms to disambiguate cues and derive situation-specific meaning from the world. We propose that dysregulation within this context-processing circuit is at the core of PTSD pathophysiology, accounting for much of its phenomenology and most of its biological findings. Understanding core mechanisms like this, and their underlying neural circuits, will sharpen diagnostic precision and understanding of risk factors, enhancing our ability to develop preventive and “personalized” interventions.

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“…This notion concurs with the observation that mouse strains One interpretation of these seemingly contradictory findings is that extinction may be sensitive to the deviations from normal GR signaling, with either increases or decreases being sufficient to disrupt behavior. Indeed, while some of the aforementioned studies (e.g., George et al, 2015) suggest that preventing corticohippocampal GR upregulation may be able to prevent stress from impairing extinction, the formation of extinction memories is also known to require glucocorticoids. In a variety of experimental designs, acute administration of exogenous corticosterone or the synthetic glucocorticoid, dexamethasone, facilitates extinction in rats and certain mouse strains (Abrari et al, 2008;Brinks et al, 2009;Cai et al, 2006;Ninomiya et al, 2010;Yang et al, 2006;Yang et al, 2007).…”

Section: Stress Glucocorticoids and Extinctionmentioning

confidence: 99%

Stress and Fear Extinction

Maren

Holmes

2015

Neuropsychopharmacol

340

264

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Stress has a critical role in the development and expression of many psychiatric disorders, and is a defining feature of posttraumatic stress disorder (PTSD). Stress also limits the efficacy of behavioral therapies aimed at limiting pathological fear, such as exposure therapy. Here we examine emerging evidence that stress impairs recovery from trauma by impairing fear extinction, a form of learning thought to underlie the suppression of trauma-related fear memories. We describe the major structural and functional abnormalities in brain regions that are particularly vulnerable to stress, including the amygdala, prefrontal cortex, and hippocampus, which may underlie stress-induced impairments in extinction. We also discuss some of the stress-induced neurochemical and molecular alterations in these brain regions that are associated with extinction deficits, and the potential for targeting these changes to prevent or reverse impaired extinction. A better understanding of the neurobiological basis of stress effects on extinction promises to yield novel approaches to improving therapeutic outcomes for PTSD and other anxiety and trauma-related disorders.

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The effect of chronic phenytoin administration on single prolonged stress induced extinction retention deficits and glucocorticoid upregulation in the rat medial prefrontal cortex

Cited by 40 publications

References 37 publications

Sex differences in the single prolonged stress model

Sex differences in the single prolonged stress model

Context Processing and the Neurobiology of Post-Traumatic Stress Disorder

Stress and Fear Extinction

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