scholarly journals Molecularly-Defined Hippocampal Inputs Regulate Population Dynamics in the Prelimbic Cortex to Suppress Context Fear Memory Recall

2019 ◽  
Author(s):  
Henry L. Hallock ◽  
Henry M. Quillian ◽  
Kristen R. Maynard ◽  
Yishan Mai ◽  
Huei-Ying Chen ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Fear Memory ◽  
Fear Learning ◽  
Memory Recall ◽  
Post Traumatic Stress ◽  
Memory Processing ◽  
Expression Of Genes ◽  
Post Traumatic ◽  
Genetic Targeting

AbstractAssociating fearful events with the context in which they occur is critical for survival. Dysregulation of context-fear memory processing is a hallmark symptom of several neuropsychiatric disorders, including generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Both the hippocampus and prelimbic subregion (PrL) of the medial prefrontal cortex (mPFC) have been linked with context fear memory recall in rodents, but the mechanisms by which hippocampal-prelimbic circuitry regulates this process remains poorly understood. Spatial and genetic targeting of this circuit in mice allowed us to use molecular profiling to show that hippocampal neurons with projections to the PrL (vHC-PrL projectors) are a transcriptomically-distinct sub-population that is enriched for expression of genes associated with both GAD and PTSD. We further show that stimulation of this population of vHC-PrL projectors suppresses context fear memory recall and impairs the ability of PrL neurons to dynamically distinguish between distinct phases of fear learning. Using transgenic and circuit-specific molecular targeting approaches, we demonstrate that unique patterns of activity-dependent gene transcription within vHC-PrL projectors causally regulate excitatory/inhibitory balance in the PrL during context fear memory recall. Together, our data illuminate the molecular mechanisms by which hippocampal-prelimbic circuitry regulates the retrieval of contextually-mediated fear memories.

scholarly journals Ketamine—50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms

2021 ◽  
Vol 73 (2) ◽  
pp. 323-345
Author(s):  
Samuel Kohtala
Keyword(s):  
Traumatic Stress ◽  
Molecular Mechanisms ◽  
Post Traumatic Stress ◽  
Active Metabolites ◽  
The Past ◽  
Antidepressant Effects ◽  
Post Traumatic ◽  
Pharmacologically Active ◽  
Dose Dependent ◽  
Different Doses

AbstractOver the past 50 years, ketamine has solidified its position in both human and veterinary medicine as an important anesthetic with many uses. More recently, ketamine has been studied and used for several new indications, ranging from chronic pain to drug addiction and post-traumatic stress disorder. The discovery of the rapid-acting antidepressant effects of ketamine has resulted in a surge of interest towards understanding the precise mechanisms driving its effects. Indeed, ketamine may have had the largest impact for advancements in the research and treatment of psychiatric disorders in the past few decades. While intense research efforts have been aimed towards uncovering the molecular targets underlying ketamine’s effects in treating depression, the underlying neurobiological mechanisms remain elusive. These efforts are made more difficult by ketamine’s complex dose-dependent effects on molecular mechanisms, multiple pharmacologically active metabolites, and a mechanism of action associated with the facilitation of synaptic plasticity. This review aims to provide a brief overview of the different uses of ketamine, with an emphasis on examining ketamine’s rapid antidepressant effects spanning molecular, cellular, and network levels. Another focus of the review is to offer a perspective on studies related to the different doses of ketamine used in antidepressant research. Finally, the review discusses some of the latest hypotheses concerning ketamine’s action.

scholarly journals Environmental enrichment prevents the late effect of acute stress-induced fear extinction deficit: the role of hippocampal AMPA-GluA1 phosphorylation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Leonardo Santana Novaes ◽  
Letícia Morais Bueno-de-Camargo ◽  
Carolina Demarchi Munhoz
Keyword(s):  
Environmental Enrichment ◽  
Basolateral Amygdala ◽  
Acute Stress ◽  
Fear Memory ◽  
Fear Extinction ◽  
Post Traumatic Stress ◽  
Related Disorder ◽  
Memory Extinction ◽  
Post Traumatic

AbstractThe persistence of anxiety and the deficit of fear memory extinction are both phenomena related to the symptoms of a trauma-related disorder, such as post-traumatic stress disorder (PTSD). Recently we have shown that single acute restraint stress (2 h) in rats induces a late anxiety-related behavior (observed ten days after stress), whereas, in the present work, we found that the same stress impaired fear extinction in animals conditioned ten days after stress. Fourteen days of environmental enrichment (EE) prevented the deleterious effect of stress on fear memory extinction. Additionally, we observed that EE prevented the stress-induced increase in AMPA receptor GluA1 subunit phosphorylation in the hippocampus, but not in the basolateral amygdala complex and the frontal cortex, indicating a potential mechanism by which it exerts its protective effect against the stress-induced behavioral outcome.

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

2021 ◽  
Vol 11 (1) ◽  
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

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.

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

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.

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

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.

Behavioral Neuroscience of Circuits Involved in Fear Processing

2016 ◽  
Author(s):  
Elizabeth P. Bauer ◽  
Denis Paré
Keyword(s):  
Fear Conditioning ◽  
Post Traumatic Stress Disorder ◽  
Traumatic Stress ◽  
Current Knowledge ◽  
Brain Structures ◽  
Fear Learning ◽  
Post Traumatic Stress ◽  
Post Traumatic ◽  
The Brain ◽  
Insight Into

Normal fear regulation includes the ability to learn by experience that some circumstances predict danger. This process, which can be modeled in the laboratory using Pavlovian fear conditioning, appears to be disrupted in individuals with post-traumatic stress disorder (PTSD). Understanding of the mechanisms underlying fear learning has progressed tremendously in the last 25 years, and constitutes a promising paradigm to study the neural bases of PTSD. This chapter first reviews current knowledge of the brain structures involved in fear learning, expression and extinction, including the contributions of the amygdala and prefrontal cortex. It then addresses how these circuits are affected by PTSD and how fear processing is altered in PTSD. Understanding PTSD within a fear-conditioning and extinction framework provides insight into why certain individuals are susceptible to developing PTSD and suggests potential therapies.

scholarly journals Optogenetic sleep enhancement improves fear-associated memory processing following trauma exposure in rats

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Christopher J. Davis ◽  
William M. Vanderheyden
Keyword(s):  
Sleep Duration ◽  
Post Traumatic Stress Disorder ◽  
Traumatic Stress ◽  
Stress Disorder ◽  
Trauma Exposure ◽  
Dark Phase ◽  
Post Traumatic Stress ◽  
Memory Processing ◽  
Optogenetic Stimulation ◽  
Post Traumatic

Abstract Sleep disturbances are commonly found in trauma-exposed populations. Additionally, trauma exposure results in fear-associated memory impairments. Given the interactions of sleep with learning and memory, we hypothesized that increasing sleep duration following trauma exposure would restore overall function and improve trauma-induced fear-associated memory dysfunction. Here, we utilized single prolonged stress, a validated rodent model of post-traumatic stress disorder, in combination with optogenetic activation of hypothalamic melanin-concentrating hormone containing cells to increase sleep duration. The goal of this work was to ascertain if post-trauma sleep increases are sufficient to improve fear-associated memory function. In our laboratory, optogenetic stimulation after trauma exposure was sufficient to increase REM sleep duration during both the Light and Dark Phase, whereas NREM sleep duration was only increased during the Dark Phase of the circadian day. Interestingly though, animals that received optogenetic stimulation showed significantly improved fear-associated memory processing compared to non-stimulated controls. These results suggest that sleep therapeutics immediately following trauma exposure may be beneficial and that post-trauma sleep needs to be further examined in the context of the development of post-traumatic stress disorder.

scholarly journals The Many Faces of FKBP51

Biomolecules ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 35 ◽  
Author(s):  
Andreas Hähle ◽  
Stephanie Merz ◽  
Christian Meyners ◽  
Felix Hausch
Keyword(s):  
Stress Responses ◽  
Molecular Mechanisms ◽  
Post Traumatic Stress ◽  
Interacting Protein ◽  
Fk506 Binding Protein ◽  
Obesity And Diabetes ◽  
Protein Partners ◽  
Interaction Partners ◽  
Post Traumatic ◽  
The Many

The FK506-binding protein 51 (FKBP51) has emerged as a key regulator of endocrine stress responses in mammals and as a potential therapeutic target for stress-related disorders (depression, post-traumatic stress disorder), metabolic disorders (obesity and diabetes) and chronic pain. Recently, FKBP51 has been implicated in several cellular pathways and numerous interacting protein partners have been reported. However, no consensus on the underlying molecular mechanisms has yet emerged. Here, we review the protein interaction partners reported for FKBP51, the proposed pathways involved, their relevance to FKBP51’s physiological function(s), the interplay with other FKBPs, and implications for the development of FKBP51-directed drugs.

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