Exploring Epigenetic Regulation of Fear Memory and Biomarkers Associated with Post-Traumatic Stress Disorder

AbstractThe relationships among neuropeptide, calcitonin gene-related peptide (CGRP), and memory formation remain unclear. Here, we showed that the intracerebroventricular administration of CGRP impaired the traumatic fear memories, in a widely studied animal model of post-traumatic stress disorder. We found that CGRP administration suppressed fear memory by increasing neuronal PAS domain protein 4 (Npas4), phosphorylated histone deacetylase 5 (HDAC5), and protein kinase D (PKD). We also discovered that Npas4 knockdown inhibited CGRP-mediated fear memory. CGRP decreased the binding between HDAC5 and the Npas4 enhancer site and increased the binding between acetylated histone H3 and the Npas4 enhancer site. The pharmacological inhibition or knockdown of PKD attenuated the CGRP-mediated impairment of fear memory and the increased phosphorylation of HDAC5 and Npas4 expression. Our findings demonstrated that the CGRP-PKD pathway was associated with the histone H3 acetylation-Npas4 pathway. These results suggested a novel function for CGRP on fear memory, through epigenetic regulation.

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Npas4 impairs fear memory via phosphorylated HDAC5 induced by CGRP administration in mice

10.21203/rs.3.rs-53022/v1 ◽

2020 ◽

Author(s):

Narumi Hashikawa-Hobara ◽

Shuta Mishima ◽

Chihiro Okujima ◽

Youdai Shitanishi ◽

Naoya Hashikawa

Keyword(s):

Post Traumatic Stress Disorder ◽

Traumatic Stress ◽

Stress Disorder ◽

Histone H3 ◽

Fear Memory ◽

Protein Kinase D ◽

Post Traumatic Stress ◽

Calcitonin Gene ◽

Post Traumatic ◽

H3 Acetylation

Abstract The relationships among neuropeptide, calcitonin gene-related peptide (CGRP), and memory formation remain unclear. Here, we showed that the intracerebroventricular administration of CGRP impaired the traumatic fear memories, in a widely studied animal model of post-traumatic stress disorder. We found that CGRP administration suppressed fear memory by increasing neuronal PAS domain protein 4 (Npas4), phosphorylated histone deacetylase 5 (HDAC5), and protein kinase D (PKD). We also discovered that Npas4 knockdown inhibited CGRP-mediated fear memory. CGRP decreased the binding between HDAC5 and the Npas4 enhancer site and increased the binding between acetylated histone H3 and the Npas4 enhancer site. The pharmacological inhibition or knockdown of PKD attenuated the CGRP-mediated impairment of fear memory and the increased phosphorylation of HDAC5 and Npas4 expression. Our findings demonstrated that the CGRP-PKD pathway was associated with the histone H3 acetylation-Npas4 pathway. These results suggested a novel function for CGRP on fear memory, through epigenetic regulation.

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Electroconvulsive Shock Does Not Impair the Reconsolidation of Cued and Contextual Pavlovian Threat Memory

International Journal of Molecular Sciences ◽

10.3390/ijms21197072 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7072

Author(s):

Hajira Elahi ◽

Veronica Hong ◽

Jonathan E. Ploski

Keyword(s):

Electroconvulsive Shock ◽

Post Traumatic Stress Disorder ◽

Traumatic Stress ◽

Memory Retrieval ◽

Memory Trace ◽

Stress Disorder ◽

Fear Memory ◽

Post Traumatic Stress ◽

Post Traumatic ◽

Electroconvulsive Seizure

Existing memories, when retrieved under certain circumstances, can undergo modification through the protein synthesis-dependent process of reconsolidation. Disruption of this process can lead to the weakening of a memory trace, an approach which is being examined as a potential treatment for disorders characterized by pathological memories, such as Post-Traumatic Stress Disorder. The success of this approach relies upon the ability to robustly attenuate reconsolidation; however, the available literature brings into question the reliability of the various drugs used to achieve such a blockade. The identification of a drug or intervention that can reliably disrupt reconsolidation without requiring intracranial access for administration would be extremely useful. Electroconvulsive shock (ECS) delivered after memory retrieval has been demonstrated in some studies to disrupt memory reconsolidation; however, there exists a paucity of literature characterizing its effects on Pavlovian fear memory. Considering this, we chose to examine ECS as an inexpensive and facile means to impair reconsolidation in rats. Here we show that electroconvulsive seizure induction, when administered after memory retrieval, (immediately, after 30 min, or after 1 h), does not impair the reconsolidation of cued or contextual Pavlovian fear memories. On the contrary, ECS administration immediately after extinction training may modestly impair the consolidation of fear extinction memory.

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Faculty Opinions recommendation of Brexpiprazole blocks post-traumatic stress disorder-like memory while promoting normal fear memory.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738528566.793579477 ◽

2020 ◽

Author(s):

Alan Frazer ◽

Flavia Carreno

Keyword(s):

Post Traumatic Stress Disorder ◽

Traumatic Stress ◽

Stress Disorder ◽

Fear Memory ◽

Post Traumatic Stress ◽

Post Traumatic

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A review of epigenetic contributions to post-traumatic stress disorder

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2019.21.4/kressler ◽

2019 ◽

Vol 21 (4) ◽

pp. 417-428 ◽

Cited By ~ 6

Keyword(s):

Gene Expression ◽

Genetic Code ◽

Epigenetic Regulation ◽

Post Traumatic Stress Disorder ◽

Traumatic Stress ◽

Stress Disorder ◽

Regulation Of Gene Expression ◽

Direct Result ◽

Post Traumatic Stress ◽

Post Traumatic

Post-traumatic stress disorder (PTSD) is a syndrome which serves as a classic example of psychiatric disorders that result from the intersection of nature and nurture, or gene and environment. By definition, PTSD requires the experience of a traumatic exposure, and yet data suggest that the risk for PTSD in the aftermath of trauma also has a heritable (genetic) component. Thus, PTSD appears to require both a biological (genetic) predisposition that differentially alters how the individual responds to or recovers from trauma exposure. Epigenetics is defined as the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself, and more recently it has come to refer to direct alteration of DNA regulation, but without altering the primary sequence of DNA, or the genetic code. With regards to PTSD, epigenetics provides one way for environmental exposure to be “written” upon the genome, as a direct result of gene and environment (trauma) interactions. This review provides an overview of the main currently understood types of epigenetic regulation, including DNA methylation, histone regulation of chromatin, and noncoding RNA regulation of gene expression. Furthermore, we examine recent literature related to how these methods of epigenetic regulation may be involved in differential risk and resilience for PTSD in the aftermath of trauma.

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Fear not: recent advances in understanding the neural basis of fear memories and implications for treatment development

F1000Research ◽

10.12688/f1000research.20053.1 ◽

2019 ◽

Vol 8 ◽

pp. 1948

Author(s):

Amy L. Milton

Keyword(s):

Post Traumatic Stress Disorder ◽

Traumatic Stress ◽

Neural Circuits ◽

Stress Disorder ◽

Fear Memory ◽

Post Traumatic Stress ◽

Neural Basis ◽

Treatment Development ◽

Technological Advances ◽

Post Traumatic

Fear is a highly adaptive emotion that has evolved to promote survival and reproductive fitness. However, maladaptive expression of fear can lead to debilitating stressor-related and anxiety disorders such as post-traumatic stress disorder. Although the neural basis of fear has been extensively researched for several decades, recent technological advances in pharmacogenetics and optogenetics have allowed greater resolution in understanding the neural circuits that underlie fear. Alongside conceptual advances in the understanding of fear memory, this increased knowledge has clarified mechanisms for some currently available therapies for post-traumatic stress disorder and has identified new potential treatment targets.

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Characterizing changes in glucocorticoid receptor internalization in the fear circuit in an animal model of post traumatic stress disorder

10.1101/424101 ◽

2018 ◽

Author(s):

Emly Moulton ◽

Marisa Chamness ◽

Dayan Knox

Keyword(s):

Post Traumatic Stress Disorder ◽

Traumatic Stress ◽

Glucocorticoid Receptors ◽

Stress Disorder ◽

Dorsal Hippocampus ◽

Fear Memory ◽

Receptor Internalization ◽

Post Traumatic Stress ◽

Post Traumatic ◽

Individual Nodes

AbstractGlucocorticoid receptors (GRs) shuttle from the cytoplasm (cy) to the nucleus (nu) when bound with glucocorticoids (i.e. GR internalization) and alter transcriptional activity. GR activation within the fear circuit has been implicated in fear memory and post traumatic stress disorder (PTSD). However, no study to date has characterized GR internalization within the fear circuit during fear memory formation or examined how traumatic stress impacts this process. To address this, we assayed cy and nu GR levels at baseline and after auditory fear conditioning (FC) in the single prolonged stress (SPS) model of PTSD. Cy and nu GRs within the medial prefrontal cortex (mPFC), dorsal hippocampus (dHipp), ventral hippocampus (vHipp), and amygdala (AMY) were assayed using western blot. The distribution of GR in the cy and nu (at baseline and after FC) was varied across individual nodes of the fear circuit. At baseline, SPS enhanced cyGRs in the dHipp, but decreased cyGRs in the AMY. FC only enhanced GR internalization in the AMY and this effect was attenuated by SPS exposure. SPS also decreased cyGRs in the dHipp after FC. The results of this study suggests that GR internalization is varied across the fear circuit, which in turn suggests GR activation is selectively regulated within individual nodes of the fear circuit. The findings also suggest that changes in GR dynamics in the dHipp and AMY modulate the enhancing effect SPS has on fear memory persistence.

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