Distributed coding in auditory thalamus and basolateral amygdala upon associative fear learning

AbstractDespite the large comorbidity between PTSD and opioid use disorders, as well as the common treatment of physical injuries resulting from trauma with opioids, the ability of opioid treatments to subsequently modify PTSD-related behavior has not been well studied. Using the stress-enhanced fear learning (SEFL) model for PTSD, we characterized the impact of chronic opioid regimens on the sensitization of fear learning seen following traumatic stress in mice. We demonstrate for the first time that chronic opioid pretreatment is able to robustly augment associative fear learning. Highlighting aversive learning as the cognitive process mediating this behavioral outcome, these changes were observed after a considerable period of drug cessation, generalized to learning about multiple aversive stimuli, were not due to changes in stimulus sensitivity or basal anxiety, and correlated with a marker of synaptic plasticity within the basolateral amygdala. Additionally, these changes were not observed when opioids were given after the traumatic event. Moreover, we found that neither reducing the frequency of opioid administration nor bidirectional manipulation of acute withdrawal impacted the subsequent enhancement in fear learning seen. Given the fundamental role of associative fear learning in the generation and progression of PTSD, these findings are of direct translational relevance to the comorbidity between opioid dependence and PTSD, and they are also pertinent to the use of opioids for treating pain resulting from traumas involving physical injuries.

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Fear Memory

Physiological Reviews ◽

10.1152/physrev.00018.2015 ◽

2016 ◽

Vol 96 (2) ◽

pp. 695-750 ◽

Cited By ~ 150

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.

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Fear learning induces structural and functional plasticity at GABAergic synapses in the basolateral amygdala

BMC Pharmacology ◽

10.1186/1471-2210-11-s2-a42 ◽

2011 ◽

Vol 11 (Suppl 2) ◽

pp. A42

Author(s):

Yu Kasugai ◽

Elisabeth Vogel ◽

Markus Hauschild ◽

Ramon O Tasan ◽

Yvan Peterschmitt ◽

...

Keyword(s):

Basolateral Amygdala ◽

Fear Learning ◽

Functional Plasticity ◽

Gabaergic Synapses

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Synaptic NMDA receptors in basolateral amygdala principal neurons are triheteromeric proteins: physiological role of GluN2B subunits

Journal of Neurophysiology ◽

10.1152/jn.00176.2012 ◽

2013 ◽

Vol 109 (5) ◽

pp. 1391-1402 ◽

Cited By ~ 26

Author(s):

Andrew J. Delaney ◽

Petra L. Sedlak ◽

Elenora Autuori ◽

John M. Power ◽

Pankaj Sah

Keyword(s):

Nmda Receptors ◽

Basolateral Amygdala ◽

Physiological Role ◽

Long Term Potentiation ◽

Subunit Composition ◽

Fear Learning ◽

Term Potentiation ◽

Nmda Current ◽

Synaptic Receptors ◽

Kinetics Of

N-methyl-d-aspartate (NMDA) receptors are heteromultimeric ion channels that contain an essential GluN1 subunit and two or more GluN2 (GluN2A–GluN2D) subunits. The biophysical properties and physiological roles of synaptic NMDA receptors are dependent on their subunit composition. In the basolateral amygdala (BLA), it has been suggested that the plasticity that underlies fear learning requires activation of heterodimeric receptors composed of GluN1/GluN2B subunits. In this study, we investigated the subunit composition of NMDA receptors present at synapses on principal neurons in the BLA. Purification of the synaptic fraction showed that both GluN2A and GluN2B subunits are present at synapses, and co-immunoprecipitation revealed the presence of receptors containing both GluN2A and GluN2B subunits. The kinetics of NMDA receptor-mediated synaptic currents and pharmacological blockade indicate that heterodimeric GluN1/GluN2B receptors are unlikely to be present at glutamatergic synapses on BLA principal neurons. Selective RNA interference-mediated knockdown of GluN2A subunits converted synaptic receptors to a GluN1/GluN2B phenotype, whereas knockdown of GluN2B subunits had no effect on the kinetics of the synaptically evoked NMDA current. Blockade of GluN1/GluN2B heterodimers with ifenprodil had no effect, but knockdown of GluN2B disrupted the induction of CaMKII-dependent long-term potentiation at these synapses. These results suggest that, on BLA principal neurons, GluN2B subunits are only present as GluN1/GluN2A/GluN2B heterotrimeric NMDA receptors. The GluN2B subunit has little impact on the kinetics of the receptor, but is essential for the recruitment of signaling molecules essential for synaptic plasticity.

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Respiration and brain neural dynamics associated with interval timing during odor fear learning in rats

10.1101/2020.07.31.228866 ◽

2020 ◽

Author(s):

Maryne Dupin ◽

Samuel Garcia ◽

Belkacem Messaoudi ◽

Valérie Doyère ◽

Anne-Marie Mouly

Keyword(s):

Fear Conditioning ◽

Basolateral Amygdala ◽

Piriform Cortex ◽

Respiratory Rhythm ◽

Interval Timing ◽

Fear Learning ◽

Gamma Activity ◽

Time Interval ◽

Scalar Property ◽

Learned Fear

ABSTRACTIn fear conditioning, where a conditioned stimulus predicts the arrival of an aversive stimulus, the animal encodes the time interval between the two stimuli. Freezing, the most used index to assess learned fear, lacks the temporal resolution required to investigate interval timing at the early stages of learning. Here we monitored respiration to visualize anticipatory behavioral responses in an odor fear conditioning in rats, while recording theta (5-15Hz) and gamma (40-80Hz) brain oscillatory activities in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), dorsomedial striatum (DMS) and olfactory piriform cortex (PIR). We investigated the temporal patterns of respiration frequency and of theta and gamma activity power during the odor-shock interval. We found that akin to respiration patterns, theta temporal curves were modulated by the duration of the odor-shock interval in the four recording sites, and respected scalar property in mPFC and DMS. In contrast, gamma temporal curves were modulated by the interval duration only in the mPFC, and in a manner that did not respect scalar property. This suggests a preferential role for theta rhythm in interval timing. In addition, our data bring the novel idea that the respiratory rhythm might take part in the setting of theta activity dynamics.

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Fear Learning Induces Long-Lasting Changes in Gene Expression and Pathway Specific Presynaptic Growth

10.1101/571331 ◽

2019 ◽

Author(s):

Blythe C. Dillingham ◽

Peter Cameron ◽

Simon Pieraut ◽

Leonardo M. Cardozo ◽

Eun J. Yoo ◽

...

Keyword(s):

Gene Expression ◽

Basolateral Amygdala ◽

Contextual Fear Conditioning ◽

Fear Learning ◽

Neural Ensembles ◽

Examine Gene Expression ◽

Initial Learning ◽

Long Time ◽

Transcriptional Changes ◽

New Gene

AbstractThe stabilization or consolidation of long-term memories lasting more than a few hours requires new gene expression. While neural activity has been shown to induce expression of a variety of genes within several hours of learning, whether this leads to persistent changes in gene expression that lasts for days or weeks remains unclear. We developed a novel mouse line which expresses Cre recombinase in an inducible manner and used it to examine gene expression in learning-activated neurons of the medial prefrontal cortex (mPFC) one month following contextual fear conditioning. The mPFC is not required for the initial retrieval of contextual memory but becomes necessary after one month, suggesting a slowly developing plasticity. We found a variety of changes in gene expression in learning-activated neural ensembles that were specific to the mPFC. One group of transcriptional changes observed was the coordinated upregulation of presynaptic proteins suggesting a potential learning-induced elaboration of presynaptic terminals. We tested this idea by labeling the projections of mPFC neurons active during initial learning and found an increase in the number of terminals in neurons projecting to the basolateral amygdala at 1 month following training. These results suggest a presynaptic growth mechanism that could account for the enhanced role of the mPFC in fear memory retrieval at long time points after learning.

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

10.1101/584326 ◽

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.

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