Social Defeat: Impact on Fear Extinction and Amygdala-Prefrontal Cortical Theta Synchrony in 5-HTT Deficient Mice

Narayanan, Venu; Heiming, Rebecca S.; Jansen, Friederike; Lesting, Jörg; Sachser, Norbert; Pape, Hans‐Christian; Seidenbecher, Thomas

doi:10.1371/journal.pone.0022600

Cited by 110 publications

(96 citation statements)

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“…In contrast to PL, reversible inactivation of IL impairs extinction (Sierra-Mercado et al 2011) and single unit activity increases in IL neurons during extinction recall (Milad and Quirk 2002). Our finding of enhanced theta activity in IL during extinction agrees with recent evidence indicating a role for IL theta oscillations in extinction and its recall Narayanan et al 2011). Our results showing increased IL activity before extinction recall compared to before extinction also support evidence indicating enhanced synaptic efficacy in IL after extinction (Herry and Garcia 2002).…”

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“…Confidence intervals (95%) were used to quantify statistically significant differences in PL and IL activity during early and late extinction and extinction recall separately in males and females. Given the recently established role of mPFC theta oscillations in mediating fear extinction Narayanan et al 2011), we focused our analysis on this frequency band (4-12 Hz).In males, theta activity in PL showed a marked and significant decrease during late compared to early extinction (P , 0.05). Conversely, IL activity was significantly increased during late compared to early extinction (P , 0.05) (Fig.…”

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

et al. 2014

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Anxiety disorders, such as post-traumatic stress, are more prevalent in women and are characterized by impaired inhibition of learned fear and medial prefrontal cortex (mPFC) dysfunction. Here we examined sex differences in fear extinction and mPFC activity in rats. Females showed more learned fear expression during extinction and its recall, but not fear conditioning. They also showed more spontaneous fear recovery and more contextual fear before extinction and its recall. Moreover, enhanced learned fear expression in females was associated with sustained prelimbic (PL) cortex activity. These results suggest that sex differences in learned fear expression may involve persistent PL activation.Women are at increased risk of developing fear-related anxiety disorders compared to men. For example, the prevalence of posttraumatic stress disorder (PTSD) is twice as high in women as in men (Lebron-Milad and Milad 2012). These disorders are characterized by impaired inhibition of learned fear (Milad et al. 2009a;Jovanovic et al. 2010) and a growing number of studies in humans and animals have shown sex differences in fear extinction (Milad et al. 2006;Baran et al. 2009Baran et al. , 2010Glover et al. 2012;ter Horst et al. 2012;Baker-Andresen et al. 2013), the reduction in learned fear that occurs with repeated nonreinforced presentations of the conditioned stimulus (CS).The neural circuitry mediating fear extinction is dysfunctional in PTSD. The medial prefrontal cortex (mPFC) is a heterogeneous area that plays a crucial role in this circuit through its involvement in learned fear and extinction processing. The dorsal anterior cingulate cortex (dACC) in humans and its rodent homolog, the prelimbic cortex (PL), are important for conditioned fear expression. In contrast, the human ventromedial prefrontal cortex (vmPFC) and the homologous infralimbic cortex (IL) in rodents are involved in fear suppression and extinction (Vidal-Gonzalez et al. 2006;Sierra-Mercado et al. 2011;Linnman et al. 2012). Importantly, PTSD is associated with dACC and vmPFC dysfunction (Milad et al. 2009a;Shin et al. 2009). Although a role for mPFC in mediating sex differences in fear extinction is emerging (Baran et al. 2010;Zeidan et al. 2011;Merz et al. 2012), the potential contribution of individual mPFC subregions remains unknown.We examined sex differences in local field potential (LFP) activity in PL and IL during fear extinction in male and naturally cycling female Lister hooded rats (Harlan, UK). All experimental procedures were conducted with internal ethical approval and in accordance with the Animals (Scientific Procedures) Act 1986, UK. Electrodes (Teflon-coated stainless-steel wires, 50 mm diameter) were implanted into PL and IL (2.7 mm anterior and 0.5 mm lateral to bregma, 3.3 mm (PL) and 4.3 mm (IL) ventral to the brain surface) under isoflurane anesthesia. Rats received peri-and post-operative analgesia (buprenorphine and meloxicam) and were singly housed during recovery and behavioral testing, which started 10 -14 d after surgery. ...

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

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“…Other risk factors such as variation in 5-HTTLPR in humans, that affects the prevalence of several anxiety disorders including PTSD, can be assessed in this model as well [46][47][48] . 5-HTT knockout rats, displaying increased freezing and impaired fear extinction [49][50][51] or fear extinction recall [52][53][54] , have been used as model for the more PTSD-susceptible 5-HTTLPR genotype. The polymorphism results in differences in serotonin regulation that play an important role in anxiety disorders.…”

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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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“…Diese Erkenntnis konnte in Pawlow'schen Furchtkonditionier ungsexperimenten bestätigt werden (Narayanan et al 2011;vgl. Wotjak und Pape in dieser Ausgabe). Bereits bevor die Mäuse eine Verlierererfahrung gemacht hatten, unterschieden sich die drei SERT-Genotypen deutlich in Aspekten ihrer Furchtextinktion (genauer: dem Abruf ‚retrieval' des Extinktionsgedächtnisses; vgl.…”

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Das Zusammenspiel von Genotyp und Umwelt bei der Entwicklung von Furcht und Angst

Sachser¹,

Lesch²

2013

E-Neuroforum

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Zusammenfassung AbstractThe interplay of genotype and environment in the development of fear and anxiety. Individual differences in fear, anxiety and in the etiology of anxiety disorders develop during ontogeny. They are due to both, genetic and environmental factors. Concerning the role of the environment the organism is most susceptible to external influences during early development. Accordingly, stressors that impinge on the maternal organism during pregnancy evoke high levels of anxiety in the offspring later in life, as does an adverse early postnatal environment. However, anxiety-related circuits in the CNS retain their plasticity in adulthood, that is, levels of anxiety can be modified by experience also later in life. Notably, the effects of external stressors on the individual's level of anxiety are modulated by genotype. Such genotype-by-environment interactions are particularly well studied concerning a polymorphism that modulates the function of the serotonin-transporter-gene. Thus, this review focusses on this candidate gene to elucidate the interplay of genotype and environment in the development of fear and anxiety.

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Social Defeat: Impact on Fear Extinction and Amygdala-Prefrontal Cortical Theta Synchrony in 5-HTT Deficient Mice

Cited by 110 publications

References 93 publications

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

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

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

Das Zusammenspiel von Genotyp und Umwelt bei der Entwicklung von Furcht und Angst

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