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 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 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 Cerebellar molecular layer interneurons are dispensable for cued and contextual fear conditioning

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Katy L. H. Marshall-Phelps ◽  
Gernot Riedel ◽  
Peer Wulff ◽  
Marta Woloszynowska-Fraser
Keyword(s):  
Fear Conditioning ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Conditioned Fear ◽  
Molecular Layer ◽  
Fear Memory ◽  
Memory Formation ◽  
Contextual Fear Conditioning ◽  
Contextual Fear

AbstractPurkinje cells are the only output cell of the cerebellar cortex. Their spatiotemporal activity is controlled by molecular layer interneurons (MLIs) through GABAA receptor-mediated inhibition. Recently, it has been reported that the cerebellar cortex is required for consolidation of conditioned fear responses during fear memory formation. Although the relevance of MLIs during fear memory formation is currently not known, it has been shown that synapses made between MLIs and Purkinje cells exhibit long term plasticity following fear conditioning. The present study examined the role of cerebellar MLIs in the formation of fear memory using a genetically-altered mouse line (PC-∆γ2) in which GABAA receptor-mediated signaling at MLI to Purkinje cell synapses was functionally removed. We found that neither acquisition nor recall of fear memories to tone and context were altered after removal of MLI-mediated inhibition.

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 AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

2015 ◽  
Vol 41 (7) ◽  
pp. 1849-1864 ◽  
Author(s):  
Ying Han ◽  
Yixiao Luo ◽  
Jia Sun ◽  
Zengbo Ding ◽  
Jianfeng Liu ◽  
...  
Keyword(s):  
Dorsal Hippocampus ◽  
Fear Memory ◽  
Memory Formation ◽  
Contextual Fear ◽  
Ampk Signaling ◽  
Contextual Fear Memory

scholarly journals Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory Formation

2021 ◽  
Vol 14 ◽  
Author(s):  
Kayla Farrell ◽  
Madeline Musaus ◽  
Shaghayegh Navabpour ◽  
Kiley Martin ◽  
W. Keith Ray ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Fear Conditioning ◽  
Degradation Process ◽  
Fear Memory ◽  
Memory Formation ◽  
Contextual Fear Conditioning ◽  
Female Rats ◽  
Protein Targets ◽  
Male And Female Rats ◽  
Ubiquitin Proteasome

Ubiquitin-proteasome mediated protein degradation has been widely implicated in fear memory formation in the amygdala. However, to date, the protein targets of the proteasome remain largely unknown, limiting our understanding of the functional significance for protein degradation in fear memory formation. Additionally, whether similar proteins are targeted by the proteasome between sexes has yet to be explored. Here, we combined a degradation-specific K48 Tandem Ubiquitin Binding Entity (TUBE) with liquid chromatography mass spectrometry (LC/MS) to identify the target substrates of the protein degradation process in the amygdala of male and female rats following contextual fear conditioning. We found that males (43) and females (77) differed in the total number of proteins that had significant changes in K48 polyubiquitin targeting in the amygdala following fear conditioning. Many of the identified proteins (106) had significantly reduced levels in the K48-purified samples 1 h after fear conditioning, suggesting active degradation of the substrate due to learning. Interestingly, only 3 proteins overlapped between sexes, suggesting that targets of the protein degradation process may be sex-specific. In females, many proteins with altered abundance in the K48-purified samples were involved in vesicle transport or are associated with microtubules. Conversely, in males, proteins involved in the cytoskeleton, ATP synthesis and cell signaling were found to have significantly altered abundance. Only 1 protein had an opposite directional change in abundance between sexes, LENG1, which was significantly enhanced in males while lower in females. This suggests a more rapid degradation of this protein in females during fear memory formation. Interestingly, GFAP, a critical component of astrocyte structure, was a target of K48 polyubiquitination in both males and females, indicating that protein degradation is likely occurring in astrocytes following fear conditioning. Western blot assays revealed reduced levels of these target substrates following fear conditioning in both sexes, confirming that the K48 polyubiquitin was targeting these proteins for degradation. Collectively, this study provides strong evidence that sex differences exist in the protein targets of the degradation process in the amygdala following fear conditioning and critical information regarding how ubiquitin-proteasome mediated protein degradation may contribute to fear memory formation in the brain.

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