The opposite role of D-serine in immediate and retrieval extinction of contextual fear memory

Activity-dependent gene expression through activation of Ca2+-CREB signal transduction pathways has been thought to play a central role in fear memory formation. On the other hand, retrieval of fear memory triggers two time-dependent phases of reactivated memory; reconsolidation and extinction. To understand the mechanisms for determining the fate of the reactivated fear memory, we investigated roles of CREB in reconsolidation and extinction of contextual fear memory and then analyzed the brain-regions regulating reconsolidation and extinction by identifying regions where CREB-mediated gene expression is activated and then examining the role of protein synthesis in those regions on reconsolidation and extinction. We first showed that activation of CREB-mediated transcription is required for reconsolidation and long-term extinction of contextual fear memory. Using immunocytochemical analyses, we demonstrated that CREB is activated in the hippocampus/amygdala and amygdala/medial prefrontal cortex (mPFC) in the reconsolidation and extinction phases, respectively. Similar results were observed by analyzing the expression of a CREB-dependent gene, Arc. We finally showed that reconsolidation and long-term extinction of the contextual fear memory depended on new gene expression in the hippocampus/amygdala and amygdala/mPFC, respectively. Thus reactivated contextual fear memory is reconsolidated or extinguished through distinct CREB-mediated gene expression regulation in the hippocampus, amygdala and mPFC.

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Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity

Learning & Memory ◽

10.1101/lm.793008 ◽

2008 ◽

Vol 15 (4) ◽

pp. 252-260 ◽

Cited By ~ 26

Author(s):

C. Kluge ◽

C. Stoppel ◽

C. Szinyei ◽

O. Stork ◽

H.-C. Pape

Keyword(s):

Synaptic Plasticity ◽

Fear Memory ◽

Contextual Fear ◽

Contextual Fear Memory ◽

Hippocampal Synaptic Plasticity

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Contextual Fear Memory Maintenance Changes Expression of pMAPK, BDNF and IBA-1 in the Pre-limbic Cortex in a Layer-Specific Manner

Frontiers in Neural Circuits ◽

10.3389/fncir.2021.660199 ◽

2021 ◽

Vol 15 ◽

Author(s):

Nicholas Chaaya ◽

Joshua Wang ◽

Angela Jacques ◽

Kate Beecher ◽

Michael Chaaya ◽

...

Keyword(s):

Fear Conditioning ◽

Fear Memory ◽

Contextual Fear Conditioning ◽

Mitogen Activated Protein Kinase ◽

Limbic Cortex ◽

Pavlovian Fear Conditioning ◽

Bdnf Expression ◽

Contextual Fear ◽

Contextual Fear Memory

Post-traumatic stress disorder (PTSD) is a debilitating and chronic fear-based disorder. Pavlovian fear conditioning protocols have long been utilised to manipulate and study these fear-based disorders. Contextual fear conditioning (CFC) is a particular Pavlovian conditioning procedure that pairs fear with a particular context. Studies on the neural mechanisms underlying the development of contextual fear memories have identified the medial prefrontal cortex (mPFC), or more specifically, the pre-limbic cortex (PL) of the mPFC as essential for the expression of contextual fear. Despite this, little research has explored the role of the PL in contextual fear memory maintenance or examined the role of neuronal mitogen-activated protein kinase (pMAPK; ERK 1/2), brain-derived neurotrophic factor (BDNF), and IBA-1 in microglia in the PL as a function of Pavlovian fear conditioning. The current study was designed to evaluate how the maintenance of two different long-term contextual fear memories leads to changes in the number of immune-positive cells for two well-known markers of neural activity (phosphorylation of MAPK and BDNF) and microglia (IBA-1). Therefore, the current experiment is designed to assess the number of immune-positive pMAPK and BDNF cells, microglial number, and morphology in the PL following CFC. Specifically, 2 weeks following conditioning, pMAPK, BDNF, and microglia number and morphology were evaluated using well-validated antibodies and immunohistochemistry (n = 12 rats per group). A standard CFC protocol applied to rats led to increases in pMAPK, BDNF expression and microglia number as compared to control conditions. Rats in the unpaired fear conditioning (UFC) procedure, despite having equivalent levels of fear to context, did not have any change in pMAPK, BDNF expression and microglia number in the PL compared to the control conditions. These data suggest that alterations in the expression of pMAPK, BDNF, and microglia in the PL can occur for up to 2 weeks following CFC. Together the data suggest that MAPK, BDNF, and microglia within the PL of the mPFC may play a role in contextual fear memory maintenance.

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Molecular motor KIF3B in the prelimbic cortex constrains the consolidation of contextual fear memory

Molecular Brain ◽

10.1186/s13041-021-00873-9 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Nadine F. Joseph ◽

Aya Zucca ◽

Jenna L. Wingfield ◽

Isabel Espadas ◽

Damon Page ◽

...

Keyword(s):

Molecular Motor ◽

Fear Memory ◽

Contextual Fear Conditioning ◽

Prelimbic Cortex ◽

Spine Density ◽

Cellular Mechanisms ◽

Contextual Fear ◽

Contextual Fear Memory ◽

And Function

AbstractMolecular and cellular mechanisms underlying the role of the prelimbic cortex in contextual fear memory remain elusive. Here we examined the kinesin family of molecular motor proteins (KIFs) in the prelimbic cortex for their role in mediating contextual fear, a form of associative memory. KIFs function as critical mediators of synaptic transmission and plasticity by their ability to modulate microtubule function and transport of gene products. However, the regulation and function of KIFs in the prelimbic cortex insofar as mediating memory consolidation is not known. We find that within one hour of contextual fear conditioning, the expression of KIF3B is upregulated in the prelimbic but not the infralimbic cortex. Importantly, lentiviral-mediated knockdown of KIF3B in the prelimbic cortex produces deficits in consolidation while reducing freezing behavior during extinction of contextual fear. We also find that the depletion of KIF3B increases spine density within prelimbic neurons. Taken together, these results illuminate a key role for KIF3B in the prelimbic cortex as far as mediating contextual fear memory.

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The role of the cannabinoid system in fear memory and extinction in male and female mice

10.1101/2021.06.06.447281 ◽

2021 ◽

Author(s):

Ikumi Mizuno ◽

Shingo Matsuda ◽

Suguru Tohyama ◽

Akihiro Mizutani

Keyword(s):

Sex Differences ◽

Molecular Mechanisms ◽

Acid Amide ◽

Fear Memory ◽

Fear Extinction ◽

Male And Female ◽

Contextual Fear ◽

Contextual Fear Memory ◽

Female Mice

The prevalence of post-traumatic stress disorder (PTSD) is higher in women than in men. Among both humans and mice, females exhibit higher resistance to fear extinction than males, suggesting that differences between sexes in processes of fear extinction are involved in the pathophysiology of such fear-related diseases. Sex differences in molecular mechanisms for fear memory and extinction are unclear. The cannabinoid (CB) system is well known to be involved in fear memory and extinction, but this involvement is based mainly on experiments using male rodents. It has been unclear whether there are sex differences in the role of the CB system in fear memory and extinction. To explore the possibility of such differences, we investigated the effects of pharmacological manipulations of the CB system on the retrieval and extinction of contextual fear memory in male and female mice. WIN55,212-2, a CB receptor (CBR) agonist, augmented the retrieval of fear memory in both sexes, but SR141716 (a CB1R antagonist) did not affect it in either sex. An enhancement of 2-arachidonylglycerol (2-AG, one of the two major endocannabinoids) via JZL184 [an inhibitor of the 2-AG hydrolase monoacylglycerol lipase (MAGL)], augmented the retrieval of fear memory through the activation of CB1R but not CB2R in female mice. In contrast, the enhancement of N-arachidonylethanolamine (AEA, the other major endocannabinoid) via URB597, an inhibitor of an AEA hydrolase (fatty acid amide hydrolase-1) did not show any effects on the retrieval or extinction of fear memory in either sex. WIN55,212-2, SR141716, and JZL184 inhibited fear extinction irrespective of sex. These results suggest that although the role of CB1R in the retrieval and extinction of contextual fear memory is common among males and females, the effects of an increase in the 2-AG level on the retrieval of contextual fear memory differ between the sexes.

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