Estrogen and Extinction of Fear Memories:Implications for Posttraumatic Stress Disorder Treatment

Glover, Ebony M.; Jovanović, Tanja; Norrholm, Seth D.

doi:10.1016/j.biopsych.2015.02.007

Cited by 100 publications

(55 citation statements)

References 95 publications

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“…Our data support the growing literature indicating that given the relationship between naturally fluctuating endogenous estradiol and fear extinction memory, the success of psychiatric treatment (efficacy, duration, efficiency) may depend on gonadal hormone status (Wegerer et al, 2014; Glover et al, 2015; Pineles et al, 2016). Based on these data, estradiol may strengthen the consolidation of extinction memory via modulation of the amygdalar nuclei by the IL.…”

Section: Discussionsupporting

confidence: 86%

Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats

Maeng

Cover

Taha

et al. 2016

J of Neuroscience Research

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There is growing evidence that estradiol enhances fear extinction memory consolidation. However, it is unclear how estradiol influences the nodes of the fear extinction network to enhance extinction memory. This study begins to delineate the neural circuits underlying the influence of estradiol on fear extinction acquisition and consolidation in female rats. After fear conditioning (day 1), naturally cycling female rats underwent extinction learning (day 2) in a low estradiol state, receiving a systemic administration of either estradiol (E2) or vehicle prior to extinction training. Extinction memory recall was then tested 24h later (day 3). We measured immediate early gene c-fos expression within the extinction network during fear extinction learning and extinction recall. During extinction learning, E2 treatment increased centrolateral amygdala (CeL) c-fos activity and reduced lateral amygdala (LA) activity relative to vehicle. During extinction recall, E2-treated rats exhibited reduced c-fos expression in the centromedial amygdala (CeM). There were no group differences in c-fos expression within the medial prefrontal cortex and dorsal hippocampus. Examining c-fos ratios with the infralimbic cortex (IL) revealed that despite the lack of group differences within the IL, E2 treatment induced greater IL activity relative to both the prelimbic cortex (PL) and central amygdala (CeA) activity during extinction memory recall. Only the relationship between IL and CeA activity positively correlated with extinction retention. In conclusion, estradiol appears to modify interactions between the IL and CeA in females, shifting from stronger amygdalar modulation of fear during extinction learning to stronger IL control during extinction recall.

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Section: Discussionsupporting

confidence: 86%

Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats

Maeng

Cover

Taha

et al. 2016

J of Neuroscience Research

View full text Add to dashboard Cite

show abstract

“…Together, these data demonstrate that estrogen is a potent neuromodulator of fear extinction learning and memory mechanisms. The molecular mechanisms underlying estrogen’s effect on extinction processes have been discussed in a recently published review (Cover et al, 2014; Glover, Jovanovic, & Norrholm, In press). …”

Section: Gonadal Hormones Stress and Fear Extinctionmentioning

confidence: 99%

Sex differences in anxiety disorders: Interactions between fear, stress, and gonadal hormones

Maeng

Milad

2015

Hormones and Behavior

308

199

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Women are more vulnerable to stress- and fear-based disorders, such as anxiety and post-traumatic stress disorder. Despite the growing literature on this topic, the neural basis of these sex differences remains unclear, and the findings appear inconsistent. The neurobiological mechanisms of fear and stress in learning and memory processes have been extensively studied, and the crosstalk between these systems is beginning to explain the disproportionate incidence and differences in symptomatology and remission within these psychopathologies. In this review, we discuss the intersect between stress and fear mechanisms and their modulation by gonadal hormones and discuss the relevance of this information to sex differences in anxiety and fear-based disorders. Understanding these converging influences is imperative to the development of more effective, individualized treatments that take sex and hormones into account.

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“…In terms of sex differences in fear memory, the results are mixed and difficult to extrapolate to the human condition of PTSD. For instance, male rats freeze more than female rats in memory retention tests of cued fear conditioning (Maren et al 1994), and female rats extinguish faster than their male counterparts (Dalla and Shors 2009;Glover et al 2015). This picture is complicated by recent work showing that female mice cope differently in behavioral assays such as fear conditioning, which may confound interpretation of their behavioral output (Jones and Monfils 2016).…”

Section: Implications For Ptsdmentioning

confidence: 63%

The potential of epigenetics in stress-enhanced fear learning models of PTSD

et al. 2016

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Prolonged distress and dysregulated memory processes are the core features of post-traumatic stress disorder (PTSD) and represent the debilitating, persistent nature of the illness. However, the neurobiological mechanisms underlying the expression of these symptoms are challenging to study in human patients. Stress-enhanced fear learning (SEFL) paradigms, which encompass both stress and memory components in rodents, are emerging as valuable preclinical models of PTSD. Rodent models designed to study the long-term mechanisms of either stress or fear memory alone have identified a critical role for numerous epigenetic modifications to DNA and histone proteins. However, the epigenetic modifications underlying SEFL remain largely unknown. This review will provide a brief overview of the epigenetic modifications implicated in stress and fear memory independently, followed by a description of existing SEFL models and the few epigenetic mechanisms found to date to underlie SEFL. The results of the animal studies discussed here highlight neuroepigenetics as an essential area for future research in the context of PTSD through SEFL studies, because of its potential to identify novel candidates for neurotherapeutics targeting stress-induced pathogenic memories.Post-traumatic stress disorder (PTSD) is triggered by experiencing or witnessing a traumatic event and is characterized by pathogenic memory (e.g., recurrent, involuntary memories that trigger intense stress), avoidance of reminders, hyperarousal and reactivity, negative mood, cognitive alterations, and a persistence of symptoms for at least 1 mo. Although only a fraction of people exposed to trauma develop PTSD, a history of stress exposure prior to witnessing a traumatic event increases the risk (Breslau et al. 2014). Therefore, some animal models of PTSD use multidimensional stress and fear memory paradigms to model the disorder. In stress-enhanced fear learning (SEFL), a rodent is exposed to a stressor or combination of stressors prior to undergoing classical fear conditioning. Models that utilize SEFL closely reproduce many core symptoms of PTSD, including enhanced fear learning, generalized anxiety, heightened startle, and impaired extinction.

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Estrogen and Extinction of Fear Memories:Implications for Posttraumatic Stress Disorder Treatment

Cited by 100 publications

References 95 publications

Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats

Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats

Sex differences in anxiety disorders: Interactions between fear, stress, and gonadal hormones

The potential of epigenetics in stress-enhanced fear learning models of PTSD

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