Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder

Takei, Shiro; Morinobu, Shigeru; Yamamoto, Sadaki; Fuchikami, Manabu; Matsumoto, Tomoya; Yamawaki, Shigeto

doi:10.1016/j.jpsychires.2010.08.009

Cited by 104 publications

(75 citation statements)

References 45 publications

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“…As discussed earlier, epigenetic regulation of the BDNF gene has been implicated in the establishment of contextual fear memories in the hippocampus and changes in BDNF transcript levels have been described in the amygdala during consolidation of cued fear memory (Ou and Gean, 2007). Altered histone acetylation at specific loci on the BDNF gene has also been noted with stress-based models of PTSD (Bredy et al, 2007;Takei et al, 2011;see Box 2), indicating that epigenetic regulation of BDNF expression occurs in response to a range of aversive stimuli. Studies of predatorstress based models of PTSD have also found that BDNF expression is regulated by exposure to traumatic stimuli long after the fear-inducing stimulus has passed (Kozlovsky et al, 2007;Ou and Gean, 2007), indicating that BDNF regulation may be important for the persistence of pathological fear.…”

Section: Role Of Bdnf In Ptsdmentioning

confidence: 93%

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Epigenetic Mechanisms in Learned Fear: Implications for PTSD

Zovkic

Sweatt

2012

Neuropsychopharmacol

168

106

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One of the most exciting discoveries in the learning and memory field in the past two decades is the observation that active regulation of gene expression is necessary for experience to trigger lasting functional and behavioral change, in a wide variety of species, including humans. Thus, as opposed to the traditional view of 'nature' (genes) being separate from 'nurture' (environment and experience), it is now clear that experience actively drives alterations in central nervous system (CNS) gene expression in an ongoing fashion, and that the resulting transcriptional changes are necessary for experience to trigger altered long-term behavior. In parallel over the past decade, epigenetic mechanisms, including regulation of chromatin structure and DNA methylation, have been shown to be potent regulators of gene transcription in the CNS. In this review, we describe data supporting the hypothesis that epigenetic molecular mechanisms, especially DNA methylation and demethylation, drive long-term behavioral change through active regulation of gene transcription in the CNS. Specifically, we propose that epigenetic molecular mechanisms underlie the formation and stabilization of context-and cue-triggered fear conditioning based in the hippocampus and amygdala, a conclusion reached in a wide variety of studies using laboratory animals. Given the relevance of cued and contextual fear conditioning to post-traumatic stress, by extension we propose that these mechanisms may contribute to post-traumatic stress disorder (PTSD) in humans. Moreover, we speculate that epigenetically based pharmacotherapy may provide a new avenue of drug treatment for PTSD-related cognitive and behavioral function.

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Section: Role Of Bdnf In Ptsdmentioning

confidence: 93%

“…proximal fear-inducing stimuli in various paradigms of aversive learning Ou and Gean, 2007), and altered levels of the gene product are evident long after the fear-inducing stimulus has passed (Bredy et al, 2007;Takei et al, 2011). Each of these points are discussed in greater detail below.…”

Section: Role Of Bdnf In Ptsdmentioning

confidence: 99%

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

Zovkic

Sweatt

2012

Neuropsychopharmacol

168

106

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“…There is also a well-documented role for the hippocampus in stress responsivity, and although significant controversy regarding hippocampal volume abnormalities in PTSD existed in the literature, accumulating evidence confirms hippocampal abnormalities in PTSD. Various studies of animal models of PTSD have consistently implicated hippocampal abnormalities in PTSD, and the changes in brain-derived neurotropic factor (BDNF) and its receptor (TrkB) signaling in the hippocampus have been reported both in SPS (Takei et al, 2011) and predatorexposure models (Roth et al, 2011). Cohen et al (2011) further extended these findings by reporting increases in BDNF and a decrease in glucocorticoid receptor expression in the hippocampus with increased NPY expression.…”

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confidence: 90%

Expanding Our Understanding of Neurobiological Mechanisms of Resilience by Using Animal Models

Liberzon

2011

Neuropsychopharmacol

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The original conceptualization of stress and the stress response has been developed based on the understanding that certain environmental exposures and life events can be both detrimental to individual's health and wellbeing, and also promote physiological responses that can be adaptive. Interestingly, until recently, the majority of translational research focused on neurobiological processes involved in the abnormal or altered stress response, on the vulnerability to stress, or the negative consequences of stress. Only recently the field started focusing on the concept of resilience, exploring the possibility that, similarly to stress vulnerability, there could be unique mechanisms involved in resilience to stress. Defining resilience has not been easy and within clinical research, resilience often refers to the ability of an organism to deal with, or adapt to, the pathological effects of stress. This seemingly subtle shift in research focus actually has immediate and substantial implications to stress research, as it suggests that some individuals are particularly adept to dealing with stressful situations, and if we examine this subgroup of individuals, we are likely to find different or compensatory changes, or changes in biological processes that are diametrically opposed to those found in stress-vulnerable individuals.It has long been known that significant individual variability in vulnerability to severe stress or trauma exists with respect to the development of psychiatric consequences like post-traumatic stress disorder (PTSD), however, the resilience perspective might suggest that this can be accounted for by individual variability in resilience. Insofar as the mechanisms of vulnerability and resilience do not overlap completely, the study of the neurobiology of resilience is not simply a mirror of the study of stress vulnerability, but it could offer new perspectives on pathophysiology or treatment of stress-induced anxiety disorders such as PTSD and depression. Together with the study of stress vulnerability, understanding the neurobiology of resilience could provide a more comprehensive picture in the service of understanding pathophysiology, development of new treatments for stress-induced psychiatric disorders, and identifying markers for primary and secondary prevention. More importantly, if individuals who have low levels of resilience can be treated in such a manner so as to increase their levels of resilience, this could greatly reduce the incidence of stress-induced psychiatric disorders.Understanding the neurobiology of resilience in clinical research can be hindered by ethical constraints, but can be readily explored by employing animal models of stress and trauma. One promising approach for studying the neurobiology of resilience is the use of the cut-off behavioral criteria (CBC), as proposed by Cohen et al. This method, here applied to predator-odor-exposed animals that are later tested for startle and anxiety behavior, allows for identification of not only vulnerable groups (extreme be...

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“…Other studies have shown that histone modifications that increase transcription of Bdnf and Homer1a in the hippocampus and amygdala promote fear learning (Lubin et al 2008;Takei et al 2011;Mahan et al 2012).…”

Section: The Neuroepigenetics Of Fear Memorymentioning

confidence: 97%

“…This is not surprising, given that HDAC inhibitors increase acetylation to support extinction learning and decrease anxiety in animal stress paradigms (Yamawaki et al 2012;Valvassori et al 2014). The perseverant nature of these stress-enhanced traumatic memories may be due to a very strong epigenetic-regulated learning experience, as this model can also result in "overconsolidation" and enhanced acetylation of the Bdnf promoter by histones H3 and H4 (Takei et al 2011).…”

Section: The Neuroepigenetics Of Stress-enhanced Fear Learningmentioning

confidence: 99%

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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Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder

Cited by 104 publications

References 45 publications

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

Expanding Our Understanding of Neurobiological Mechanisms of Resilience by Using Animal Models

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

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