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 Chronic opioid pretreatment potentiates the sensitization of fear learning by trauma

2019 ◽  
Vol 45 (3) ◽  
pp. 482-490 ◽  
Author(s):  
Zachary T. Pennington ◽  
Jeremy M. Trott ◽  
Abha K. Rajbhandari ◽  
Kevin Li ◽  
Wendy M. Walwyn ◽  
...  
Keyword(s):  
Basolateral Amygdala ◽  
Traumatic Event ◽  
Fear Learning ◽  
Opioid Use ◽  
Physical Injuries ◽  
Opioid Administration ◽  
The Impact ◽  
First Time ◽  
Considerable Period

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.

scholarly journals microRNA regulation of persistent stress-enhanced memory

2018 ◽  
Author(s):  
Stephanie E. Sillivan ◽  
Sarah Jamieson ◽  
Laurence de Nijs ◽  
Meghan Jones ◽  
Clara Snijders ◽  
...  
Keyword(s):  
Quantitative Proteomics ◽  
Basolateral Amygdala ◽  
Traumatic Event ◽  
Inbred Mice ◽  
Differential Susceptibility ◽  
Fear Learning ◽  
Small Rna Sequencing ◽  
Microrna Regulation ◽  
Passenger Strand ◽  
Potential Biomarker

AbstractDisruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. Using a stress-enhanced fear learning protocol that results in differential susceptibility in inbred mice, we integrated small-RNA sequencing with quantitative proteomics on basolateral amygdala tissue collected one month after training. We identified persistently changed microRNAs, including mir-135b-5p, and predicted target proteins associated with PTSD-like heightened fear expression. Functional manipulations of mir-135b-5p bidirectionally modulated stress-associated memory. mir-135b-5p is expressed in human amygdala and its passenger strand was elevated in serum from a well-characterized military PTSD cohort. miR-135b-5p is a therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.One Sentence Summarymir-135 can be manipulated to weaken persistent, stress-associated memory and serve as a biomarker of PTSD.

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 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.

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.

Differential role of Rac in the basolateral amygdala and cornu ammonis 1 in the reconsolidation of auditory and contextual Pavlovian fear memory in rats

2014 ◽  
Vol 231 (15) ◽  
pp. 2909-2919 ◽  
Author(s):  
Ping Wu ◽  
Zeng-Bo Ding ◽  
Shi-Qiu Meng ◽  
Hao-Wei Shen ◽  
Shi-Chao Sun ◽  
...  
Keyword(s):  
Basolateral Amygdala ◽  
Fear Memory ◽  
Cornu Ammonis

Female mice mate preferentially with non-parasitized males

Parasitology ◽  
2002 ◽  
Vol 125 (5) ◽  
pp. 461-466 ◽  
Author(s):  
K. D. EHMAN ◽  
M. E. SCOTT
Keyword(s):  
Mate Choice ◽  
Parasitic Infection ◽  
Female Mate Choice ◽  
Hormonal Changes ◽  
Heligmosomoides Polygyrus ◽  
Female Mice ◽  
Female Mate ◽  
Intestinal Nematode ◽  
The Impact

If parasitic infection is a driving force in female mate choice, then females should preferentially select parasite-free males. The role of infection on female mate choice in mammals was assessed using a 3-chambered apparatus. A female CD-1 mouse was allowed to choose between 2 tethered male mice, 1 uninfected and 1 infected with 200 larvae (L3) of the intestinal nematode Heligmosomoides polygyrus. Both uninfected and infected males were equally receptive to the oestrous females, and females did not differ in the number of visits and time spent exploring the 2 males. Female time preference was not a useful predictor of ultimate mate choice, whereas first mount preference of the female was a reliable indicator. Results indicate that female mice preferentially mated with uninfected males as evidenced by first ejaculation choice, but that male infection status did not significantly affect female reproductive success. Interestingly, litters sired by infected males contained a significantly higher percentage of females suggesting that parasite-induced hormonal changes may alter the sex ratio of the offspring. This study provides the first direct evidence of the impact of parasitic infection on mammalian mate choice.

scholarly journals Differential Susceptibility to the Impact of the COVID-19 Pandemic on Working Memory, Empathy, and Perceived Stress: The Role of Cortisol and Resilience

2021 ◽  
Vol 11 (3) ◽  
pp. 348
Author(s):  
Shishir Baliyan ◽  
José Manuel Cimadevilla ◽  
Silvia de Vidania ◽  
Matías M. Pulopulos ◽  
Carmen Sandi ◽  
...  
Keyword(s):  
Working Memory ◽  
Perceived Stress ◽  
Memory Span ◽  
Differential Susceptibility ◽  
Well Being ◽  
Cognitive Empathy ◽  
Diurnal Cortisol ◽  
Potential Biomarker ◽  
The Impact

There are important individual differences in adaptation and reactivity to stressful challenges. Being subjected to strict social confinement is a distressful psychological experience leading to reduced emotional well-being, but it is not known how it can affect the cognitive and empathic tendencies of different individuals. Cortisol, a key glucocorticoid in humans, is a strong modulator of brain function, behavior, and cognition, and the diurnal cortisol rhythm has been postulated to interact with environmental stressors to predict stress adaptation. The present study investigates in 45 young adults (21.09 years old, SD = 6.42) whether pre-pandemic diurnal cortisol indices, overall diurnal cortisol secretion (AUCg) and cortisol awakening response (CAR) can predict individuals’ differential susceptibility to the impact of strict social confinement during the Coronavirus Disease 2019 (COVID-19) pandemic on working memory, empathy, and perceived stress. We observed that, following long-term home confinement, there was an increase in subjects’ perceived stress and cognitive empathy scores, as well as an improvement in visuospatial working memory. Moreover, during confinement, resilient coping moderated the relationship between perceived stress scores and pre-pandemic AUCg and CAR. In addition, in mediation models, we observed a direct effect of AUCg and an indirect effect of both CAR and AUCg, on change in perceived self-efficacy. These effects were parallelly mediated by the increase in working memory span and cognitive empathy. In summary, our findings reveal the role of the diurnal pattern of cortisol in predicting the emotional impact of the COVID-19 pandemic, highlighting a potential biomarker for the identification of at-risk groups following public health crises.

Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans

2021 ◽  
pp. 026988112110649
Author(s):  
Jaclyn N Highland ◽  
Cristan A Farmer ◽  
Panos Zanos ◽  
Jacqueline Lovett ◽  
Carlos A Zarate ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Plasma Concentrations ◽  
Gonadal Hormones ◽  
Treatment Resistant ◽  
Female Mice ◽  
Antidepressant Efficacy ◽  
Direct Administration ◽  
Resistant Depression ◽  
The Impact

Background: Ketamine is rapidly metabolized to norketamine and hydroxynorketamine (HNK) metabolites. In female mice, when compared to males, higher levels of ( 2R,6R;2S,6S)-HNK have been observed following ketamine treatment, and higher levels of ( 2R,6R)-HNK following the direct administration of ( 2R,6R)-HNK. Aim: The objective of this study was to evaluate the impact of sex in humans and mice, and gonadal hormones in mice on the metabolism of ketamine to form norketamine and HNKs and in the metabolism/elimination of ( 2R,6R)-HNK. Methods: In CD-1 mice, we utilized gonadectomy to evaluate the role of circulating gonadal hormones in mediating sex-dependent differences in ketamine and ( 2R,6R)-HNK metabolism. In humans (34 with treatment-resistant depression and 23 healthy controls) receiving an antidepressant dose of ketamine (0.5 mg/kg i.v. infusion over 40 min), we evaluated plasma levels of ketamine, norketamine, and HNKs. Results: In humans, plasma levels of ketamine and norketamine were higher in males than females, while ( 2R,6R;2S,6S)-HNK levels were not different. Following ketamine administration to mice (10 mg/kg i.p.), Cmax and total plasma concentrations of ketamine and norketamine were higher, and those of ( 2R,6R;2S,6S)-HNK were lower, in intact males compared to females. Direct ( 2R,6R)-HNK administration (10 mg/kg i.p.) resulted in higher levels of ( 2R,6R)-HNK in female mice. Ovariectomy did not alter ketamine metabolism in female mice, whereas orchidectomy recapitulated female pharmacokinetic differences in male mice, which was reversed with testosterone replacement. Conclusion: Sex is an important biological variable that influences the metabolism of ketamine and the HNKs, which may contribute to sex differences in therapeutic antidepressant efficacy or side effects.

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