Towards a better preclinical model of PTSD: Characterizing animals with weak extinction, maladaptive stress responses and low plasma corticosterone

Reznikov, Roman; Diwan, Mustansir; Nóbrega, José N.; Hamani, Clement

doi:10.1016/j.jpsychires.2014.12.017

Cited by 33 publications

(51 citation statements)

References 40 publications

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“…This higher freezing behavior could simply result from the low locomotor response in a novel environment characteristic of LR rats, however, no freezing behavior was detected in LR animals during their first exposure to context A, which then was a novel environment. Although the interference of the low locomotor response of LR rats in a novel environment cannot be ruled out, this observation suggests that LR individuals present with heightened anxiety levels following fear conditioning that would be in line with lower extinction rates (Reznikov et al, 2015), and denote generalization of fear.…”

Section: Discussionmentioning

confidence: 95%

“…Interestingly, the segregation of rats based on their extinction rates revealed that weak extinction was associated with high anxiety-like behaviors, although anxiety levels prior to fear conditioning were not predictive of a weak extinction phenotype (Reznikov et al, 2015). Considering that heightened anxiety levels following fear conditioning is closely related to fear generalization in PTSD (Dunsmoor and Paz, 2015), it is particularly interesting to note that we observed a substantial freezing behavior in the habituation to the novel context B in shocked LR, but not HR animals, supported by a significant negative predictive link with locomotion score.…”

Section: Discussionmentioning

confidence: 99%

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Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine

et al. 2016

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Only a portion of the population exposed to trauma will develop persistent emotional alterations characteristic of posttraumatic stress disorder (PTSD), which illustrates the necessity for identifying vulnerability factors and novel pharmacotherapeutic alternatives. Interestingly, clinical evidence suggests that novelty seeking is a good predictor for vulnerability to the development of excessive and persistent fear. Here, we first tested this hypothesis by analyzing contextual and cued fear responses of rats selected for their high (high responders, HR) or low (low responders, LR) exploration of a novel environment, indicator of novelty seeking. While HR and LR rats exhibited similar sensitivity to the shock and cued fear memory retention, fewer extinction sessions were required in HR than LR animals to reach extinction, indicating faster contextual and cued memory extinction. In a second part, we found an effective disruption of contextual fear reconsolidation by the N-methyl-D-aspartate receptor antagonist ketamine, associated with a down-regulation of early growth response 1 (Egr1) in the hippocampal CA1 area, and up-regulation of brain-derived neurotrophic factor (Bdnf) mRNA levels in the prelimbic and infralimbic cortices. Altogether, these data demonstrate a link between novelty seeking and conditioned fear extinction, and highlight a promising novel role of ketamine in affecting established fear memory.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine

et al. 2016

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“…Rodent subpopulations with maladaptive stress responses have been used by different investigators to mimic PTSD-like states (Bush et al, 2007;Cohen et al, 2004). Similar to PTSD, we have found that ∼ 20-30% of outbred rats show impaired fear extinction after undergoing stress (Reznikov et al, 2015). These rats, which we refer to as 'weak extinction' (WE), also develop long-lasting anxiety traits and have low baseline corticosterone levels (Reznikov et al, 2015), a feature that is commonly reported in PTSD (Yehuda et al, 1990).…”

Section: Introductionmentioning

confidence: 81%

Prefrontal Cortex Deep Brain Stimulation Improves Fear and Anxiety-Like Behavior and Reduces Basolateral Amygdala Activity in a Preclinical Model of Posttraumatic Stress Disorder

Reznikov

Bambico

Diwan

et al. 2017

Neuropsychopharmacol.

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Deep brain stimulation (DBS) is being investigated for a number of psychiatric indications, including posttraumatic stress disorder (PTSD). Preclinical studies continue to be a cornerstone for the development of new DBS applications. We investigate whether DBS delivered to the infralimbic cortex (IL), a region involved in mechanisms of stress resiliency, may counter behavioral abnormalities in rats that present persistent extinction deficits and long-term anxiety after exposure to fear conditioning. Rats undergoing fear conditioning/extinction were segregated into weak and strong extinction groups (WE >70% or SE <30% of freezing during extinction). Following 2 weeks of DBS, animals were exposed to novel recall sessions and tested in the open field, novelty-suppressed feeding, and elevated plus maze. zif268 expression was measured in structures involved in mechanisms of fear and stress. In vivo electrophysiology was used to record activity from the basolateral amygdala (BLA). We found that DBS improved extinction deficits and anxiety-like behavior in WE animals, having no significant effects in SE rats. No major differences in absolute zif268 levels were recorded across groups. However, correlation between zif268 expression in the IL and BLA was disrupted in WE animals, a deficit that was countered by DBS treatment. Electrophysiology experiments have shown that DBS reduced BLA firing of both putative principal cells and interneurons in WE rats, with no significant differences being detected between SE and SE DBS animals. In summary, IL DBS mitigated fear, partially improved anxiety-like behavior, reversed neurocircuitry abnormalities, and reduced BLA cell firing in a preclinical model of PTSD.

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“…This may have a protective effect on the nervous system because chronic exposure to high corticosterone impairs new learning in several other aversive and non-aversive contexts (Wolf, 2003). One potential mechanism is that attenuated cortisol leads to an exaggerated catecholaminergic response during a traumatic event, which may result in an over-consolidation of fear (Yehuda et al, 1990; Cabib and Puglisi-Allegra, 1996; Reznikov et al, 2015). Hypocortisolism has been reported in several pathological conditions, including post-traumatic stress disorder, burnout with physical complaints, chronic fatigue syndrome, fibromyalgia, chronic pelvic pain, and asthma (Demitrack et al, 1991; Hellhammer and Wade, 1993; Crofford et al, 1994; Yehuda, 1997; Heim et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

A Window on the Study of Aversive Instrumental Learning: Strains, Performance, Neuroendocrine, and Immunologic Systems

Oliveira

Gouveia

Castro

et al. 2016

Front. Behav. Neurosci.

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The avoidance response is present in pathological anxiety and interferes with normal daily functions. The aim of this article is to shed light on performance markers of active avoidance (AA) using two different rat strains, Sprague-Dawley (SD) and Wistar. Specifically, good and poor performers were evaluated regarding anxiety traits exhibited in the elevated plus maze (EPM) and corticosterone levels and motor activity in the open field test. In addition, the plasma levels of Interleukin-6 (IL-6), Interleukin-1Beta (IL-1beta), Nerve Growth Factor Beta (NGF-beta), Tumor Necrosis Factor-Alpha (TNF-alpha) and cytokine-induced neutrophil chemoattractant 1 (CINC-1) were compared in the good and poor performers to better understand the role of the immunologic system in aversive learning. Behavioral criteria were employed to identify subpopulations of SD and Wistar rats based on their behavioral scores during a two-way AA test. The animals were tested for anxiety-like behavior in the EPM and motor activity in the open-field test. Plasma corticosterone levels were measured at the end of the avoidance test. Cytokine levels of IL-6, IL-1beta, NGF-beta, TNF-alpha, and CINC-1 were measured in the plasma of the Wistar rats. Sixty-six percent of the Wistar rats and 35% of the SD rats exhibited a poor performance. This feature was associated with a decrease in anxiety-like behavior in the EPM. The poor and good performers exhibited lower levels of corticosterone compared with the control animals, which suggests that training alters corticosterone levels, thereby leading to hypocortisolism, independent of the performance. The CINC-1 levels were increased in the poor performers, which reinforces the role of immunologic system activation in learning deficits. Our study provides a better understanding of the complex interactions that underlie neuroimmune consequences and their implications for performance.

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Towards a better preclinical model of PTSD: Characterizing animals with weak extinction, maladaptive stress responses and low plasma corticosterone

Cited by 33 publications

References 40 publications

Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine

Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine

Prefrontal Cortex Deep Brain Stimulation Improves Fear and Anxiety-Like Behavior and Reduces Basolateral Amygdala Activity in a Preclinical Model of Posttraumatic Stress Disorder

A Window on the Study of Aversive Instrumental Learning: Strains, Performance, Neuroendocrine, and Immunologic Systems

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