scholarly journals Inhibition of the PI3 kinase cascade in corticolimbic circuit: temporal and differential effects on contextual fear and extinction

2013 ◽  
Vol 16 (4) ◽  
pp. 825-833 ◽  
Author(s):  
Milly Kritman ◽  
Mouna Maroun
Keyword(s):  
Fear Conditioning ◽  
Basolateral Amygdala ◽  
Fear Memory ◽  
Fear Learning ◽  
Contextual Fear ◽  
Pi3k Inhibition ◽  
Kinase Cascade ◽  
Differential Involvement ◽  
Phosphoinositide 3 Kinase

Abstract We studied the role of PI3K cascade in the basolateral amygdala (BLA) and the infralimbic region of the medial prefrontal cortex (IL-mPFC), in contextual fear learning and extinction in the rat. To that end, we micro-infused the phosphoinositide-3-kinase (PIK3) inhibitor LY294002 into either the mPFC or the BLA. Infusion of LY294002 into the BLA following fear conditioning was associated with enhanced freezing levels and impaired extinction in the subsequent sessions. Similarly, inhibition of PI3K in the BLA before the retrieval of fear memory was associated with impaired retrieval of the fear memory, which was expressed as reduced freezing levels that persisted over 2 d. In the IL-mPFC, only consolidation of fear extinction was impaired: micro-infusion of PI3K inhibitor following the retrieval of fear was associated with impaired extinction on the following days. These results indicate differences in the temporal parameters of the effects of PI3K inhibition in the IL-mPFC and in the BLA, which suggest differential involvement of these structures in long-term fear and in extinction of fear memory. Our findings provide additional evidence for the critical roles played by PI3K in intact formation of fear memory and in its extinction and add new evidence for a role of PI3K in consolidation of memory of extinction. Better understanding of the differential involvement of the PI3K cascade during acquisition and extinction of fear conditioning in the mPFC-amygdala circuit could potentially contribute to the understanding and treatment of anxiety disorders.

scholarly journals Fear Memory

2016 ◽  
Vol 96 (2) ◽  
pp. 695-750 ◽  
Author(s):  
Ivan Izquierdo ◽  
Cristiane R. G. Furini ◽  
Jociane C. Myskiw
Keyword(s):  
Fear Conditioning ◽  
Basolateral Amygdala ◽  
Inhibitory Avoidance ◽  
Long Term Potentiation ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Term Potentiation ◽  
Mechanisms Of Memory

Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general.

scholarly journals microRNA mir-598-3p mediates susceptibility to stress-enhancement of remote fear memory

2019 ◽  
Author(s):  
Meghan E Jones ◽  
Stephanie E. Sillivan ◽  
Sarah Jamieson ◽  
Gavin Rumbaugh ◽  
Courtney A. Miller
Keyword(s):  
Basolateral Amygdala ◽  
Differential Susceptibility ◽  
Anxiolytic Effect ◽  
Bioinformatic Analysis ◽  
Fear Memory ◽  
Fear Learning ◽  
Small Rna Sequencing ◽  
Female Mice ◽  
The Impact

ABSTRACTmicroRNAs (miRNAs) have emerged as potent regulators of learning, recent memory and extinction. However, our understanding of miRNAs directly involved in regulating complex psychiatric conditions perpetuated by aberrant memory, such as in posttraumatic stress disorder (PTSD), remains limited. To begin to address the role of miRNAs in persistent memory, we performed small-RNA sequencing on basolateral amygdala (BLA) tissue to identify miRNAs altered by auditory fear conditioning (FC) one month after training. mir-598-3p, a highly conserved miRNA previously unstudied in the brain, was downregulated in the BLA. Further decreasing BLA mir-598-3p levels did not alter the expression or extinction of the remote fear memory. Given that stress is a critical component in PTSD, we next assessed the impact of stress-enhanced fear learning (SEFL) on mir-598-3p levels, finding the miRNA is elevated in the BLA of male, but not female, mice susceptible to the effects of stress in SEFL. Accordingly, intra-BLA inhibition of mir-598-3p interfered with expression and extinction of the remote fear memory in male, but not female, mice. This effect could not be attributed to an anxiolytic effect of miRNA inhibition. Finally, bioinformatic analysis following quantitative proteomics on BLA tissue collected 30 days post-SEFL training identified putative mir-598-3p targets and related pathways mediating the differential susceptibility, with evidence for regulation of the actin cytoskeleton.

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 Hippocampus and amygdala fear memory engrams re-emerge after contextual fear reinstatement

2019 ◽  
Author(s):  
Yosif Zaki ◽  
William Mau ◽  
Christine Cincotta ◽  
Anahita Hamidi ◽  
Emily Doucette ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Basolateral Amygdala ◽  
Fear Memory ◽  
Neural Substrates ◽  
Memory Representation ◽  
Contextual Fear ◽  
Neuronal Ensembles ◽  
State Present ◽  
Insight Into

AbstractThe formation and extinction of fear memories represent two forms of learning that each engage the hippocampus and amygdala. How cell populations in these areas contribute to fear relapse, however, remains unclear. Here, we demonstrate that, in mice, cells active during fear conditioning in the dentate gyrus of hippocampus and basolateral amygdala exhibit decreased activity during extinction and are re-engaged after fear reinstatement. In vivo calcium imaging reveals that reinstatement drives population dynamics in the basolateral amygdala to revert to a network state similar to the state present during fear conditioning. Finally, we find that optogenetic inactivation of neuronal ensembles active during fear conditioning in either the hippocampus or amygdala is sufficient to disrupt fear expression after reinstatement. These results suggest that fear reinstatement triggers a partial re-emergence of the original fear memory representation, providing new insight into the neural substrates of fear relapse.

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 Independence of Cued and Contextual Components of Fear Conditioning is Gated by the Lateral Habenula

2020 ◽  
Author(s):  
Tomas E. Sachella ◽  
Marina R. Ihidoype ◽  
Christophe Proulx ◽  
Jorge H. Medina ◽  
Pablo Mendez ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Fear Conditioning ◽  
Neuronal Activity ◽  
Fear Memory ◽  
Fear Learning ◽  
Training Context ◽  
Lateral Habenula ◽  
Extreme Form ◽  
Pathological Conditions

AbstractFear is an extreme form of aversion that, if inappropriately generalized, initiates pathological conditions such as panic or anxiety disorders. Fear conditioning (FC) is the best understood model of fear learning. FC forms two associations that independently link the cue and the training context to fear responses. The lateral habenula (LHb) encodes aversive information. However, how the LHb participates in fear learning has not been intensively studied. Here we studied the role of the LHb in FC learning using optogenetics and pharmacological tools in rats. We found that disrupting neuronal activity of the LHb during training abolishes independent expression of contextual and cued memories, yet memory is normally expressed when the cue is played in the training context. Our results show that neuronal activity at the LHb regulates independent expression of sub-components of a fear memory, assigning to that structure a previously uncharacterized role as regulator of fear memories.

scholarly journals 4335 Role of PSD95 and nNOS interaction in gene regulation following fear conditioning and implications for molecular mechanisms underlying PTSD

2020 ◽  
Vol 4 (s1) ◽  
pp. 15-16
Author(s):  
Jheel Patel ◽  
Erik Dustrude ◽  
Melissa Haulcomb ◽  
Liangping Li ◽  
Guanglong Jiang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Fear Conditioning ◽  
Rna Sequencing ◽  
Basolateral Amygdala ◽  
Molecular Mechanisms ◽  
Conditioned Fear ◽  
Enrichment Analysis ◽  
Fear Learning ◽  
Post Traumatic Stress

OBJECTIVES/GOALS: Normal fear learning produces avoidance behavior that promotes survival, but excessive and persistent fear after trauma can lead to development of phobias and post-traumatic stress disorder (PTSD). Our goal is to understand the mechanism and identify novel genetic targets underlying fear responses. METHODS/STUDY POPULATION: Involvement of the amygdala in fear acquisition is well established and requires activation of N-methyl-D-aspartic acid receptors (NMDARs). At a cellular level, NMDAR activation leads to production of nitric oxide (NO) by a process mediated by interaction between postsynaptic density protein 95 (PSD95) and neuronal nitric oxide synthase (nNOS). To elucidate mechanisms underlying the role of the PSD95-nNOS-NO pathway in conditioned fear, here we use rodent behavioral paradigms, pharmacological treatment with a small molecular PSD95-nNOS inhibitor, co-immunoprecipitation, Western blotting, and RNA-sequencing. RESULTS/ANTICIPATED RESULTS: We show that fear conditioning enhances the PSD95-nNOS interaction and that the small-molecule ZL006 inhibits this interaction. Treatment with ZL006 also attenuates rodent cued-fear consolidation and prevents fear-mediated shifts in glutamatergic receptor and current densities in the basolateral amygdala (BLA). With RNA-sequencing, expression of 516 genes was altered in the BLA following fear expression; of these genes, 83 were restored by systemic ZL006 treatment. Network data and gene ontology enrichment analysis with Ingenuity Pathway Analysis and DAVID software found that cell-cell interaction, cognition-related pathways, and insulin-like growth factor binding were significantly altered. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results reveal novel genetic targets that underlie plasticity of fear-memory circuitry via their contribution of NMDAR-mediated fear consolidation and can inform future strategies for targeting fear related disorders like PTSD. CONFLICT OF INTEREST DESCRIPTION: Anantha Shekhar and Yvonne Lai are co-founders of Anagin, Inc., which is developing some of the related molecules for the treatment of PTSD.

Role of dorsal and ventral hippocampal muscarinic receptor activity in acquisition and retention of contextual fear conditioning.

2020 ◽  
Vol 134 (5) ◽  
pp. 460-470
Author(s):  
Claudia C. Pinizzotto ◽  
Nicholas A. Heroux ◽  
Colin J. Horgan ◽  
Mark E. Stanton
Keyword(s):  
Fear Conditioning ◽  
Muscarinic Receptor ◽  
Contextual Fear Conditioning ◽  
Receptor Activity ◽  
Contextual Fear

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.

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