Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder

Pibiri, Fabio; Nelson, Marianela; Guidotti, Alessandro; Costa, E.; Pinna, Graziano

doi:10.1073/pnas.0801853105

Cited by 229 publications

(290 citation statements)

References 44 publications

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“…Rather, dysfunction in clinically relevant brain circuitry seems to be already manifested shortly after massive traumatic events. Consistent with this idea, studies based on animal models have revealed that cortical GABA neurons can be modulated by allopregnanolone soon (3-4 weeks) after subjecting animals to experimental fearful stimuli (30). The increased GABA tone could increase regionally synchronized neuronal activity (31) and activity in ␥-band power (32), which has been found to be correlated with ALFF (15).…”

Section: Discussionmentioning

confidence: 61%

High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China

Lui¹,

Huang

Chen³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

114

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Besides the enormous medical and economic consequences, national disasters, such as the Wenchuan 8.0 earthquake, also pose a risk to the mental health of survivors. In this context, a better understanding is needed of how functional brain systems adapt to severe emotional stress. Previous animal studies have demonstrated the importance of limbic, paralimbic, striatal, and prefrontal structures in stress and fear responses. Human studies, which have focused primarily on patients with clinically established posttraumatic stress disorders, have reported abnormalities in similar brain structures. At present, little is known about potential alterations of brain function in trauma survivors shortly after traumatic events. Here, we show alteration of brain function in a cohort of healthy survivors within 25 days after the Wenchuan earthquake by a recently discovered method known as ''restingstate'' functional MRI. The current investigation demonstrates that regional activity in frontolimbic and striatal areas increased significantly and connectivity among limbic and striatal networks was attenuated in our participants who had recently experienced severe emotional trauma. Trauma victims also had a reduced temporal synchronization within the ''default mode'' of restingstate brain function, which has been characterized in humans and other species. Taken together, our findings provide evidence that significant alterations in brain function, similar in many ways to those observed in posttraumatic stress disorders, can be seen shortly after major traumatic experiences, highlighting the need for early evaluation and intervention for trauma survivors.neuroimaging ͉ stress ͉ anxiety ͉ depression ͉ posttraumatic stress disorder I n the afternoon on May 12, 2008, the epicenter of a devastating earthquake occurred in Wenchuan, in the Sichuan Province of China. It measured 8.0 on the Richter scale. The most severely affected geographical regions were Yingxiu, Wenchuan, Dujiangyan, and Shifang, where 45 million people were directly affected. Among them, 69,146 people were confirmed dead, 374,131 were seriously injured, and 17,516 are missing. A significant proportion of the survivors (Ϸ20%) (1) are likely to develop stress-related disorders, such as acute stress disorder (ASD) and posttraumatic stress disorder (PTSD). Given the serious and persistent impact of these highly prevalent psychiatric disorders, it is vital to develop a better understanding of the alterations of cerebral function evident in the early stages of adaptation to trauma. Such knowledge may lead to a better understanding of posttraumatic responses and the development of more effective early interventions.Studies of animal models of acute and chronic stress have provided evidence of physiological and morphological changes in several brain regions, including the amygdala, hippocampus, and prefrontal cortex (2, 3). Human studies (4-12) have focused primarily on patients who already have an established psychiatric disorder, such as ASD and PTSD. Despite some inconsis...

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Section: Discussionmentioning

confidence: 61%

High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China

Lui¹,

Huang

Chen³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

114

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“…Social instability: Just like the random cage cohort HI model, PTSD-like symptoms can be created using social isolation (SI). Isolation for at least 1 d in adult mice leads to more contextual freezing and impaired fear extinction during FS-like fear conditioning [69] . Overlap with the prior HI model was found in the form of increased anxiety and HPA changes, although the latter is formed by impaired suppression and higher baseline levels of corticosterone in the SI model [70] .…”

Section: Housing Instabilitymentioning

confidence: 99%

Animal models for posttraumatic stress disorder: An overview of what is used in research

Borghans¹,

Homberg²

2015

WJP

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Posttraumatic stress disorder (PTSD) is a common anxiety disorder characterised by its persistence of symptoms after a traumatic experience. Although some patients can be cured, many do not benefit enough from the psychological therapies or medication strategies used. Many researchers use animal models to learn more about the disorder and several models are available. The most-used physical stressor models are single-prolonged stress, restraint stress, foot shock, stress-enhanced fear learning, and underwater trauma. Common social stressors are housing instability, social instability, earlylife stress, and social defeat. Psychological models are not as diverse and rely on controlled exposure to the test animal's natural predator. While validation of these models has been resolved with replicated symptoms using analogous stressors, translating new findings to human patients remains essential for their impact on the field. Choosing a model to experiment with can be challenging; this overview of what is possible with individual models may aid in making a decision. Core tip: There are currently several widely accepted animal models being used in fundamental posttraumatic stress disorder (PTSD) research, and many publications using them have made valuable contributions to the collective knowledge on the subject. Still, the difference between models indicates that their suitability depends on the situation; each model has shown different amounts of success in replicating individual criteria or aspects of PTSD. Accordingly, the selection of the most suitable model for each experiment is important for optimally reliable results. This review offers relevant information to aid in that decision.Borghans B, Homberg JR. Animal models for posttraumatic REVIEW 387December 22, 2015|Volume 5|Issue 4|

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“…Because deuterated 3α-androstanediol is not available, deuterated 3β-androstanediol was used as the internal standard for 3α-androstanediol. Each steroid of interest was then derivatized for GC-MS (Pibiri et al, 2008;Pinna et al, 2000). Mass spectrometric analysis was conducted in the standard electron impact mode for all neuroactive steroid measurements.…”

Section: Hormone Analysismentioning

confidence: 99%

Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum

Dichtel

Lawson

Schorr

et al. 2017

Neuropsychopharmacol.

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3α-5α-Tetrahydroprogesterone, a progesterone metabolite also known as allopregnanolone, and 5α-androstane-3α,17β-diol, a testosterone metabolite also known as 3α-androstanediol, are neuroactive steroids and positive GABA A receptor allosteric modulators. Both anorexia nervosa (AN) and obesity are complicated by affective comorbidities and hypothalamic-pituitary-gonadal dysregulation. However, it is not known whether neuroactive steroid levels are abnormal at the extremes of the weight spectrum. We hypothesized that serum allopregnanolone and 3α-androstanediol levels would be decreased in AN compared with healthy controls (HC) and negatively associated with affective symptoms throughout the weight spectrum, independent of body mass index (BMI). Thirty-six women were 1 : 1 age-matched across three groups: AN, HC, and overweight/obese (OW/OB). AN were amenorrheic; HC and OW/OB were studied in the follicular phase. Fasting serum neuroactive steroids were measured by gas chromatography/mass spectrometry. Mean Hamilton depression and anxiety scores were highest in AN (po0.0001). Mean serum allopregnanolone was lower in AN and OW/OB than HC (AN 95.3 ± 56.4 vs OW/OB 73.8 ± 31.3 vs HC 199.5 ± 167.8 pg/ml, p = 0.01), despite comparable mean serum progesterone. Allopregnanolone levels, but not progesterone levels, were negatively associated with depression and anxiety symptom severity, independent of BMI. Serum 3α-androstanediol levels did not differ among groups and were not associated with depression or anxiety scores, despite a significant negative association between free testosterone levels and both anxiety and depression severity. In conclusion, women at both extremes of the weight spectrum have low mean serum allopregnanolone, which is associated with increased depression and anxiety severity, independent of BMI. Neuroactive steroids such as allopregnanolone may be potential therapeutic targets for depression and anxiety in traditionally treatment-resistant groups, including AN.

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Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder

Cited by 229 publications

References 44 publications

High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China

High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China

Animal models for posttraumatic stress disorder: An overview of what is used in research

Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum

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