Glucocorticoids Can Induce PTSD-Like Memory Impairments in Mice

Kaouane, Nadia; Porte, Yves; Vallée, Monique; Brayda-Bruno, Laurent; Mons, Nicole; Calandreau, Ludovic; Marighetto, Aline; Piazza, Pier Vincenzo; Desmedt, Aline

doi:10.1126/science.1207615

Cited by 218 publications

(265 citation statements)

References 31 publications

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“…Much like exposure therapy is applied to PTSD patients in the clinic, this phenomenon is commonly modeled in rodents using fear extinction (Kaouane et al, 2012;McGuire et al, 2010;Rau et al, 2005). Consistent with our data showing more severe PTSD symptoms in E2+ veterans, we confirmed deficits in fear extinction in E2/E2 mice (Olsen et al, 2012), suggesting that an abnormal processing of fear memory may underlie the apparent sensitivity of E2+ individuals to trauma.…”

Section: Discussionsupporting

confidence: 88%

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

Johnson

Zuloaga

Bidiman

et al. 2015

Neuropsychopharmacol

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Apolipoprotein E (apoE) is an essential component of lipoprotein particles in both the brain and periphery, and exists in three isoforms in the human population: E2, E3, and E4. ApoE has numerous, well-established roles in neurobiology. Most notably, E4 is associated with earlier onset and increased risk of Alzheimer's disease (AD). Although possession of E2 is protective in the context of AD, E2 appears to confer an increased incidence and severity of posttraumatic stress disorder (PTSD). However, the biological processes underlying this link remain unclear. In this study, we began to elucidate these associations by examining the effects of apoE on PTSD severity in combat veterans, and on PTSD-like behavior in mice with human apoE. In a group of 92 veterans with PTSD, we observed significantly higher Clinician-Administered PTSD Scale and PTSD Checklist scores in E2+ individuals, as well as alterations in salivary cortisol levels. Furthermore, we measured behavioral and biological outcomes in mice expressing human apoE after a single stressful event as well as following a period of chronic variable stress, a model of combat-related trauma. Mice with E2 showed impairments in fear extinction, and behavioral, cognitive, and neuroendocrine alterations following trauma. To the best of our knowledge, these data constitute the first translational demonstration of PTSD severity in men and PTSD-like symptoms in mice with E2, and point to apoE as a novel biomarker of susceptibility, and potential therapeutic target, for PTSD.

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Section: Discussionsupporting

confidence: 88%

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

Johnson

Zuloaga

Bidiman

et al. 2015

Neuropsychopharmacol

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“…The three gray-gradient arrows represent mild, moderate, and severe stress. Recently, intra-hippocampal infusion of CORT has been shown to induce PTSD-like memory impairment; i.e., low levels of freezing to a shock-predicting context, but high levels of freezing to a nonshock-predicting discrete cue (Kaouane et al 2012), implicating glucocorticoids in mediating detrimental effects of stress. CORT has also been shown to interact with catecholamines in the basolateral amygdala to intensify long-term memory consolidation of emotional events .…”

Section: Glucocorticoid Hypothesis Of Stress: Compatible and Incompatmentioning

confidence: 99%

Stress effects on the hippocampus: a critical review

2015

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Uncontrollable stress has been recognized to influence the hippocampus at various levels of analysis. Behaviorally, human and animal studies have found that stress generally impairs various hippocampal-dependent memory tasks. Neurally, animal studies have revealed that stress alters ensuing synaptic plasticity and firing properties of hippocampal neurons. Structurally, human and animal studies have shown that stress changes neuronal morphology, suppresses neuronal proliferation, and reduces hippocampal volume. Since the inception of stress research nearly 80 years ago, much focus has been on the varying levels of hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine hormones, namely glucocorticoids, as mediators of the myriad stress effects on the hippocampus and as contributing factors to stress-associated psychopathologies such as post-traumatic stress disorder (PTSD). However, reports of glucocorticoid-produced alterations in hippocampal functioning vary widely across studies. This review provides a brief history of stress research, examines how the glucocorticoid hypothesis emerged and guides contemporary stress research, and considers alternative approaches to understanding the mechanisms underlying stress effects on hippocampal functioning.

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“…Kaouane et al (2012) have recently shown that infusion of glucocorticoids-which are secreted naturally in response to stressors-directly into the dorsal hippocampus both impairs the processing of memory and results in generalized fear memory and hyperreactive amygdala activity that also typically characterizes PTSD. Further, stressors also result in methylation of the Bdnf gene and decreased BDNF gene expression in the dorsal hippocampus (Kozlovsky et al, 2007;Roth et al, 2011).…”

Section: A Default-mode Network-based Posterior Hippocampus Circuitrymentioning

confidence: 99%

Hippocampal Network Connectivity and Activation Differentiates Post-Traumatic Stress Disorder From Generalized Anxiety Disorder

Chen

Etkin

2013

Neuropsychopharmacol

192

178

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Anxiety disorders are a diverse group of clinical states. Post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), eg, share elevated anxiety symptoms, but differ with respect to fear-related memory dysregulation. As the hippocampus is implicated in both general anxiety and fear memory, it may be an important brain locus for mapping the similarities and differences among anxiety disorders. Anxiety and fear also functionally associate with different subdivisions of the hippocampus along its longitudinal axis: the human posterior (rodent dorsal) hippocampus is involved in memory, through connectivity with the medial prefrontal-medial parietal defaultmode network, whereas the anterior (rodent ventral) hippocampus is involved in anxiety, through connectivity with limbic-prefrontal circuits. We examined whether differential hippocampal network functioning may help account for similarities and differences in symptoms in PTSD and GAD. Network-sensitive functional magnetic resonance imaging-based resting-state intrinsic connectivity methods, along with task-based assessment of posterior hippocampal/default-mode network function, were used. As predicted, in healthy subjects resting-state connectivity dissociated between posterior hippocampal connectivity with the default-mode network, and anterior hippocampal connectivity to limbic-prefrontal circuitry. The posterior hippocampus and the associated default-mode network, across both resting-state connectivity and task-based measures, were perturbed in PTSD relative to each of the other groups. By contrast, we found only modest support for similarly blunted anterior hippocampal connectivity across both patient groups. These findings provide new insights into the neural circuit-level dysfunctions that account for similar vs different features of two major anxiety disorders, through a translational framework built on animal work and carefully selected clinical disorders.

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Glucocorticoids Can Induce PTSD-Like Memory Impairments in Mice

Cited by 218 publications

References 31 publications

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

Stress effects on the hippocampus: a critical review

Hippocampal Network Connectivity and Activation Differentiates Post-Traumatic Stress Disorder From Generalized Anxiety Disorder

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