Persistent prelimbic cortex activity contributes to enhanced learned fear expression in females

Fenton, Georgina E.; Pollard, Amelia K.; Halliday, David M.; Mason, Rob; Bredy, Timothy W.; Stevenson, Carl W.

doi:10.1101/lm.033514.113

Cited by 91 publications

(76 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, females should exhibit deficits in fear extinction relative to males only during periods of low estradiol, as was observed by Milad et al (2009Milad et al ( , 2010. These findings are also broadly consistent with other reports of impaired fear extinction in female mice and rodents relative to males in experiments that have not taken estrous cycle stage into account (Baran et al 2010;Baker-Andresen et al 2013;Fenton et al 2014). Furthermore, one study has reported sex differences in functional activation of limbic and cortical regions during extinction recall, despite an absence of sex differences in physiological arousal .…”

supporting

confidence: 89%

Inhibition of estradiol synthesis impairs fear extinction in male rats

Graham

Milad

2014

Learn. Mem.

View full text Add to dashboard Cite

Emerging research has demonstrated that the sex hormone estradiol regulates fear extinction in female rodents and women. Estradiol may also regulate fear extinction in males, given its role in synaptic plasticity in both sexes. Here we report that inhibition of estradiol synthesis during extinction training, via the aromatase inhibitor fadrozole, significantly impairs extinction recall in male rats. This deficit in extinction recall is not due to state-dependent memory formation and is completely abolished by coadministration of estradiol. Our data suggest that estradiol may be just as important in the regulation of fear extinction in males as it is in females.Fear extinction is a laboratory model of exposure therapy for anxiety disorders (Graham and Milad 2011;Milad and Quirk 2012;Parsons and Ressler 2013). During extinction training a feared conditioned stimulus (CS) is repeatedly presented in the absence of the aversive unconditioned stimulus (US), until fear responses decline. Long-term retention of extinction is tested the following day by presenting the extinguished CS and measuring fear responses. Although the vast majority of research on fear extinction has been conducted using male rodents, more recent research has focused on fear extinction in females. The key finding that has emerged is that fear extinction is subject to considerable control by sex hormones, particularly estradiol (Lebron-Milad and Milad 2012). For example, fluctuations in estradiol across the menstrual cycle are correlated with the success of extinction; women and female rats that undergo extinction learning during the low estradiol phase exhibit impaired extinction recall the following day, relative to those undergoing extinction learning during the high estradiol phase (Chang et al. 2009;Milad et al. 2009Milad et al. , 2010Zeidan et al. 2011;Glover et al. 2012;Graham and Milad 2013;Rey et al. 2013). A single dose of estradiol prior to extinction training abolishes these extinction deficits in healthy women (Graham and Milad 2013). Furthermore, in female rodents, estrogen agonists enhance, whereas estrogen antagonists impair, extinction consolidation (Chang et al. 2009;Milad et al. 2009). Finally, hormonal contraceptives, which inhibit estradiol synthesis, impair extinction in both rats and women (Graham and Milad 2013). Hormone-associated disruptions in extinction have been suggested as a potential mechanism contributing to women's increased vulnerability to anxiety disorders Graham and Milad 2013). Indeed, low estradiol levels have been associated with diminished extinction learning and increased symptom severity in women with posttraumatic stress disorder (Glover et al. 2012).Is the influence of estradiol on fear extinction unique to females, or could estradiol also regulate fear extinction in males? Studies that have demonstrated that, in both rats and humans, females exhibit similar extinction recall to males when they are extinguished during the high estradiol phase of the menstrual cycle, and exhibit impaired extinction recal...

show abstract

supporting

confidence: 89%

Inhibition of estradiol synthesis impairs fear extinction in male rats

Graham

Milad

2014

Learn. Mem.

View full text Add to dashboard Cite

show abstract

“…For example, alterations in PrLC function are important for modulating anxiety responses during stressful situations and gating of fear-related memories, the latter of which is associated with development of PTSD (Sotres-Bayon et al . 2012; Fenton et al . 2014).…”

Section: Discussionmentioning

confidence: 99%

Sex differences in GABABR-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex

et al. 2015

View full text Add to dashboard Cite

The medial prefrontal cortex (mPFC) has been implicated in multiple disorders characterized by clear sex differences, including schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, depression, and drug addiction. These sex differences likely represent underlying differences in connectivity and/or the balance of neuronal excitability within the mPFC. Recently, we demonstrated that signaling via the metabotropic γ-aminobutyric acid receptor (GABABR) and G proteingated inwardly-rectifying K+ (GIRK/Kir3) channels modulates the excitability of the key output neurons of the mPFC, the layer 5/6 pyramidal neurons. Here, we report a sex difference in the GABABR-GIRK signaling pathway in these neurons. Specifically, GABABR-dependent GIRK currents recorded in the prelimbic region of the mPFC were larger in adolescent male mice than in female counterparts. Interestingly, this sex difference was not observed in layer 5/6 pyramidal neurons of the adjacent infralimbic cortex, nor was it seen in young adult mice. The sex difference in GABABR-GIRK signaling is not attributable to different expression levels of signaling pathway components, but rather to a phosphorylation-dependent trafficking mechanism. Thus, sex differences related to some diseases associated with altered mPFC function may be explained in part by sex differences in GIRK-dependent signaling in mPFC pyramidal neurons.

show abstract

“…mPFC, amygdala, and hippocampus) may underlie the sex differences observed in fear conditioning and extinction, although the direction of these behavioral sex differences are not consistent. Some studies report that females do not perform as well as males in fear conditioning and extinction learning (Baker-Andresen, Flavell, Li, & Bredy, 2013; Baran et al, 2009, 2010; Fenton et al, 2014). Male rats exhibit more freezing to the conditioned stimulus in fewer trials during fear conditioning compared to females (Aguilar et al, 2003; Baran et al, 2009, 2010; Daviu, Andero, Armario, & Nadal, 2014; Maren, De Oca, & Fanselow, 1994; Pryce, Lehmann, & Feldon, 1999; Ribeiro et al, 2010).…”

Section: Sex Differences In Fear Extinctionmentioning

confidence: 99%

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

Maeng

Milad

2015

Hormones and Behavior

308

199

View full text Add to dashboard Cite

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.

show abstract

Persistent prelimbic cortex activity contributes to enhanced learned fear expression in females

Cited by 91 publications

References 38 publications

Inhibition of estradiol synthesis impairs fear extinction in male rats

Inhibition of estradiol synthesis impairs fear extinction in male rats

Sex differences in GABABR-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex

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

Contact Info

Product

Resources

About