scholarly journals Interfering with contextual fear memories by post-reactivation administration of propranolol in mice: a series of null findings

2021 ◽  
Author(s):  
Wouter R Cox ◽  
Leonidas Faliagkas ◽  
Rolinka van der Loo ◽  
Sabine Spijker ◽  
Merel Kindt ◽  
...  
Keyword(s):  
Boundary Conditions ◽  
Behavioral Outcomes ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Mouse Strains ◽  
Conditioning Paradigm ◽  
Contextual Fear ◽  
Contextual Fear Memory ◽  
Series Of Experiments ◽  
Genetic And Environmental Factors

Post-reactivation amnesia of contextual fear memories by blockade of noradrenergic signaling has been shown to have limited replicability in rodents. This is usually attributed to several boundary conditions that gate the destabilization of memory during its retrieval. However, how these boundary conditions can be overcome, and what neural mechanisms underlie post-reactivation changes in contextual fear memory remain largely unknown. Here, we report a series of experiments in a contextual fear conditioning paradigm in mice, that were aimed at elucidating these matters. Towards this overarching goal, we first attempted to obtain a training paradigm that would consistently result in a contextual fear memory that could be destabilized upon reactivation, enabling robust amnesia by administration of propranolol. Unexpectedly, our attempts were unsuccessful to this end. Specifically, over a series of 11 experiments (including replicates) in which we varied different parameters of the fear acquisition procedure and administered propranolol or anisomycin, at best small and inconsistent effects were observed. These null findings are surprising, given that the training paradigms we implemented were previously shown to be vulnerable to post-reactivation amnestic agents. Additionally, we found that propranolol did not alter memory retrieval-induced neural activity, as measured by the number of c-Fos+ cells in the hippocampal dentate gyrus. Together, our findings illustrate the elusive nature of reactivation-dependent changes of non-human fear memory and underscore the need for better control over genetic and environmental factors that may influence behavioral outcomes of commonly used mouse strains.

scholarly journals Parvalbumin-positive interneurons mediate neocortical-hippocampal interactions that are necessary for memory consolidation

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Frances Xia ◽  
Blake A Richards ◽  
Matthew M Tran ◽  
Sheena A Josselyn ◽  
Kaori Takehara-Nishiuchi ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Fear Conditioning ◽  
Medial Prefrontal Cortex ◽  
Memory Consolidation ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Contextual Fear ◽  
Contextual Fear Memory ◽  
Spiking Activity

Following learning, increased coupling between spindle oscillations in the medial prefrontal cortex (mPFC) and ripple oscillations in the hippocampus is thought to underlie memory consolidation. However, whether learning-induced increases in ripple-spindle coupling are necessary for successful memory consolidation has not been tested directly. In order to decouple ripple-spindle oscillations, here we chemogenetically inhibited parvalbumin-positive (PV+) interneurons, since their activity is important for regulating the timing of spiking activity during oscillations. We found that contextual fear conditioning increased ripple-spindle coupling in mice. However, inhibition of PV+ cells in either CA1 or mPFC eliminated this learning-induced increase in ripple-spindle coupling without affecting ripple or spindle incidence. Consistent with the hypothesized importance of ripple-spindle coupling in memory consolidation, post-training inhibition of PV+ cells disrupted contextual fear memory consolidation. These results indicate that successful memory consolidation requires coherent hippocampal-neocortical communication mediated by PV+ cells.

scholarly journals Limited replicability of drug-induced amnesia after contextual fear memory retrieval in rats

2019 ◽  
Author(s):  
Natalie Schroyens ◽  
Joaquin Matias Alfei Palloni ◽  
Anna Elisabeth Schnell ◽  
Laura Luyten ◽  
Tom Beckers
Keyword(s):  
Memory Retrieval ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Memory Retention ◽  
Conditioning Context ◽  
Drug Induced ◽  
Systemic Injection ◽  
Contextual Fear ◽  
Contextual Fear Memory ◽  
Systemic Drug

With the ultimate goal of investigating boundary conditions for post-reactivation amnesia, we set out to replicate studies in which systemic, post-reactivation administration of midazolam, propranolol, or cycloheximide resulted in amnesia for contextual fear memories. Our experiments involved conceptual as well as exact replications of previously published studies. In most of our experiments, we adopted a procedure that conformed to the standard 3-day protocol typically used in the literature, with contextual fear conditioning on day 1, unreinforced re-exposure to the conditioning context followed by systemic injection of the amnestic drug on day 2, and a memory retention test on day 3. Given the plethora of successful studies with large effects sizes and the absence of any failed replications in the literature, we were surprised to find that we were generally unable to replicate those findings. Our results suggest that post-reactivation amnesia by systemic drug administration in rats is more difficult to obtain than what would be expected based on published empirical reports. At present, it remains unclear which conditions determine the success of this procedure.

scholarly journals Contextual Fear Memory Formation and Destabilization Induce Hippocampal RyR2 Calcium Channel Upregulation

2018 ◽  
Vol 2018 ◽  
pp. 1-11
Author(s):  
Jamileth More ◽  
María Mercedes Casas ◽  
Gina Sánchez ◽  
Cecilia Hidalgo ◽  
Paola Haeger
Keyword(s):  
Spatial Memory ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Male Rats ◽  
Endoplasmic Reticulum Membrane ◽  
Memory Retention ◽  
Contextual Fear ◽  
Memory Processes ◽  
Contextual Fear Memory ◽  
Protein Levels

Hippocampus-dependent spatial and aversive memory processes entail Ca2+ signals generated by ryanodine receptor (RyR) Ca2+ channels residing in the endoplasmic reticulum membrane. Rodents exposed to different spatial memory tasks exhibit significant hippocampal RyR upregulation. Contextual fear conditioning generates robust hippocampal memories through an associative learning process, but the effects of contextual fear memory acquisition, consolidation, or extinction on hippocampal RyR protein levels remain unreported. Accordingly, here we investigated if exposure of male rats to contextual fear protocols, or subsequent exposure to memory destabilization protocols, modified the hippocampal content of type-2 RyR (RyR2) channels, the predominant hippocampal RyR isoforms that hold key roles in synaptic plasticity and spatial memory processes. We found that contextual memory retention caused a transient increase in hippocampal RyR2 protein levels, determined 5 h after exposure to the conditioning protocol; this increase vanished 29 h after training. Context reexposure 24 h after training, for 3, 15, or 30 min without the aversive stimulus, decreased fear memory and increased RyR2 protein levels, determined 5 h after reexposure. We propose that both fear consolidation and extinction memories induce RyR2 protein upregulation in order to generate the intracellular Ca2+ signals required for these distinct memory processes.

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

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.

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

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.

scholarly journals Optogenetic inhibition of medial entorhinal cortex inputs to the hippocampus during a short period of time right after learning disrupts contextual fear memory formation

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Min Soo Kang ◽  
Jin-Hee Han
Keyword(s):  
Entorhinal Cortex ◽  
Dorsal Hippocampus ◽  
Fear Memory ◽  
Memory Formation ◽  
Contextual Fear Conditioning ◽  
Temporal Association ◽  
Medial Entorhinal Cortex ◽  
Contextual Fear ◽  
Contextual Fear Memory ◽  
Short Period

AbstractFormation of temporal association memory and context-specific fear memory is thought to require medial entorhinal cortex (MEC) inputs to the hippocampus during learning events. However, whether the MEC inputs are also involved in memory formation during a post-learning period has not been directly tested yet. To examine this possibility, we optogenetically inhibited axons and terminals originating from bilateral dorsal MEC excitatory neurons in the dorsal hippocampus for 5 min right after contextual fear conditioning (CFC). Mice expressing eNpHR3.0 exhibited significantly less freezing compared to control mice expressing EGFP alone during retrieval test in the conditioned context 1 day after learning. In contrast, the same optogenetic inhibition of MEC inputs performed 30 min before retrieval test did not affect freezing during retrieval test, excluding the possibility of non-specific deleterious effect of optical inhibition on retrieval process. These results support that contextual fear memory formation requires MEC inputs to the hippocampus during a post-learning period.

scholarly journals Ca2+/Calmodulin Kinase Kinase α Is Dispensable for Brain Development but Is Required for Distinct Memories in Male, though Not in Female, Mice

2006 ◽  
Vol 26 (23) ◽  
pp. 9094-9104 ◽  
Author(s):  
Keiko Mizuno ◽  
Laurence Ris ◽  
Amelia Sánchez-Capelo ◽  
Emile Godaux ◽  
K. Peter Giese
Keyword(s):  
Brain Development ◽  
Mrna Expression ◽  
Fear Conditioning ◽  
Fear Memory ◽  
Memory Formation ◽  
Contextual Fear Conditioning ◽  
Cam Kinase ◽  
Contextual Fear ◽  
Contextual Fear Memory ◽  
Kinase Cascade

ABSTRACT In neurons, the Ca2+/calmodulin (CaM) kinase cascade transduces Ca2+ signaling into gene transcription. The CaM kinase cascade is known to be important for brain development as well as memory formation in adult brain, although the functions of some cascade members remain unknown. Here we have generated null and hypomorphic mutants to study the physiological role of CaM kinase kinase α (CaMKKα), which phosphorylates and activates both CaM kinase I (CaMKI) and CaMKIV, the output kinases of the cascade. We show that CaMKKα is dispensable for brain development and long-term potentiation in adult hippocampal CA1 synapses. We find that CaMKKα is required for hippocampus-dependent contextual fear memory, but not spatial memory, formation. Surprisingly, CaMKKα is important for contextual fear memory formation in males but not in females. We show that in male mice, contextual fear conditioning induces up-regulation of hippocampal mRNA expression of brain-derived neurotrophic factor (BDNF) in a way that requires CaMKKα, while in female mice, contextual fear conditioning induces down-regulation of hippocampal BDNF mRNA expression that does not require CaMKKα. Additionally, we demonstrate sex-independent up-regulation in hippocampal nerve growth factor-inducible gene B mRNA expression that does not require CaMKKα. Thus, we show that CaMKKα has a specific complex role in memory formation in males.

scholarly journals Effects of post-training novelty exposure on contextual fear memory: An attempt to translate behavioral tagging to humans

2018 ◽  
Author(s):  
Mason McClay ◽  
Joseph E. Dunsmoor
Keyword(s):  
Virtual Reality ◽  
Time Window ◽  
Critical Time ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Contextual Fear ◽  
Contextual Fear Memory ◽  
Null Result ◽  
Adult Humans

AbstractIn rodents, poorly formed hippocampal memories can be improved by novelty exploration within a critical time window, in line with the “behavioral tagging” hypothesis. Here, we sought to establish an analogue protocol to investigate if novelty exploration similarly operates to rescue weak hippocampal-dependent memories in humans. Adult humans underwent suboptimal contextual fear conditioning, followed 10 minutes later by open field novelty exploration in immersive 3D virtual reality. Novelty exploration did not improve long-term contextual fear memory, contrary to a behavioral tagging hypothesis. Despite this null result, we suggest further attempts to translate behavioral tagging from rodents to humans is warranted.

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