In the pursuit of the fear engram: identification of neuronal circuits underlying the treatment of anxiety disorder

Ossama Mohamed Salah El-Dien El-Sayed Ibrahim Khalaf
EPFL, 2017
Thèse EPFL

Résumé

Fear and other anxiety disorders are extraordinarily robust and difficult to treat. Among the most effective treatments for anxiety disorders are exposure-based therapies, during which a patient is repeatedly confronted with the originally fear-eliciting stimulus in a safe environment so that the once fearful stimulus can be newly interpreted as neutral or safe. A fundamental element for successful exposure-based therapies is the reactivation/recall of the traumatic memory, which initiates a time-limited process called memory reconsolidation, during which a memory becomes susceptible to disruption. Presently, the neuronal subpopulations and molecular mechanisms underlying successful fear memory attenuation remain completely unknown, which represents a big gap in memory research. Therefore, the aim of this work is to first identify the neuronal subpopulations that are causally implicated in effective attenuation of remote fear memories. This will help to determine whether the original traumatic memory trace has been permanently modified or a new memory trace of safety has been superimposed over the original one. The second aim is to develop a tool that allows for the isolation of the neuronal subpopulations causally implicated in remote memory attenuation, in order to be able to delineate the epigenetic and transcriptional mechanisms at play within these subpopulations. This will help to identify a molecular signature of effective remote fear memory attenuation. The results of my research suggest for the first time that there is a small population of neurons in the dentate gyrus - that was active during the recall of fear â that needs to be reactivated during extinction to attain successful remote fear attenuation. While the inactivation of such population during extinction impairs fear attenuation, its activation ameliorates behavioral extinction. Furthermore, I have successfully established a method to isolate this neuronal subpopulation from the brain, namely by fluorescence-activated cell sorting. This tool will allow follow up studies to pursue the quest for the molecular signature of successful remote memory attenuation. Overall, these findings could help us to better understand the intricate principles of effective remote fear memory attenuation, and thus to develop new strategies that improve the treatment of anxiety disorder.

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https://infoscience.epfl.ch/record/231938?ln=fr

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Ossama Mohamed Salah El-Dien El-Sayed Ibrahim Khalaf
EPFL, 2017
Thèse EPFL

Résumé

Official source

https://infoscience.epfl.ch/record/231938?ln=fr

À propos de ce résultat

Concepts associés (15)

Concepts associés

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Publications associées (10)

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Reactivation of Recall-Induced Neurons in the Infralimbic Cortex and the Basolateral Amygdala After Remote Fear Memory Attenuation

Johannes Gräff, Ossama Mohamed Salah El-Dien El-Sayed Ibrahim Khalaf

Whether the attenuation of traumatic memories is mediated through the suppression of the original memory trace of fear by a new memory trace of safety, or through an updating of the original fear trace towards safety has been a long-standing question at the interface of neuroscience and psychology. This matter is of particular importance for remote fear memories as they lie at the core of stress- and anxiety-related disorders. Recently, we have found that in the dentate gyrus, the effective attenuation of remote fear memories is accompanied by a reactivation of memory recall-induced neurons and that the continued activity of these neurons is critical for fear reduction. However, whether this also applies to other brain areas implicated in the storage of remote fear memories remains to be determined. Here, we show-by cellular compartment analysis of temporal activity using fluorescence in situ hybridization-that such reactivation also occurs in the basolateral amygdala and the infralimbic cortex, two brain areas known to be involved in fear memory attenuation. These results provide further experimental support for effective traumatic memory attenuation likely being mediated by an updating of the original fear trace towards safety.

FRONTIERS MEDIA SA2019

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Amygdala upregulation of NCAM polysialylation induced by auditory fear conditioning is not required for memory formation, but plays a role in fear extinction

Kamila Markram, Maria del Carmen Sandi Perez

There is much interest to understand the mechanisms leading to the establishment, maintenance, and extinction of fear memories. The amygdala has been critically involved in the processing of fear memories and a number of molecular changes have been implicated in this brain region in relation to fear learning. Although neural cell adhesion molecules (NCAMs) have been hypothesized to play a role, information available about their contribution to fear memories is scarce. We investigate here whether polysialylated NCAM (PSA-NCAM) contributes to auditory fear conditioning in the amygdala. First, PSA-NCAM expression was evaluated in different amygdala nuclei after auditory fear conditioning at two different shock intensities. Results showed that PSA-NCAM expression was increased 24 h post-training only in animals subjected to the highest shock intensity (1mA). Second, PSA-NCAM was cleaved in the basolateral amygdaloid complex through micro-infusions of the enzyme endoneuraminidase N, and the consequences of such treatment were investigated on the acquisition, consolidation, remote memory expression, and extinction of conditioned fear memories. Intra-amygdaloid cleavage of PSA-NCAM did not affect acquisition, consolidation or expression of remote fear memories. However, intra-amygdaloid PSA-NCAM cleavage enhanced fear extinction processes. These results suggest that upregulation of PSA-NCAM is a correlate of fear conditioning that is not necessary for the establishment of fear memory in the amygdala, but participates in mechanisms precluding fear extinction. These findings point out PSA-NCAM as a potential target for the treatment of psychopathologies that involve impairment in fear extinction.

2007

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Stress has been shown to modulate many aspects of physiology and behavior. In particular, substantial work has confirmed that stress is a strong modulator of learning and memory processes. It is more than a century that Yerkes and Dodson have shown that relationship between stress intensity and memory function follows an inverted-U-shaped curve; memory increases with stress to an optimal point, above or below which memory decreases. Despite the great popularity of the Yerkes-Dodson law, the validity of the law has been criticized due to significant methodological problems in the study performed by Yerkes and Dodson (1908) and their data being judged insufficient to substantiate conclusions, among other reasons. Moreover the existing evidence has not yet illustrated this phenomenon under the same experimental conditions for relational learning tasks. On the other hand, stress is not the only factor that modulates cognitive abilities. Different types of learning and memory might be affected by other factors such as individual differences in personality. While the relationship between personality and learning has been studied in human, animal studies addressed to understanding the relationship between personality and learning have been rare. In addition, exposure to stress during pregnancy can have deleterious emotional effects on women. However, the mechanisms underlying these emotional effects are not well understood, and the development of suitable animal models for stress-induced depression in females still remains scarce. The goal of this Thesis was to investigate how stress affects cognitive and emotional processes in different animal models, and to explore the importance of individual differences in the mediation of stress effects. On a first study, we investigated the relationship between stress intensity and memory function. For this purpose cognitive abilities of rats to learn a radial arm water maze were assessed under different stress intensities, using behavioural and endocrine approaches. Our results confirm, for the first time, the existence of an inverted-U-shape memory function according to stressor intensity during the early learning and memory phases in a hippocampus-dependent task. Furthermore, we present evidence that these stress effects are not shown uniformly by all individuals; rather, performance at either the high or the low stress intensities is differentially affected in individuals with different personality-like profiles. In a second study, we investigated whether different personality traits in the Wistar outbred strain of rats were associated with performance in specific types of learning and memory tasks that have been reported to depend on specific brain areas, such as the amygdala, hippocampus and prefrontal cortex (PFC). Using a wide variety of behavioral tests, we identified three personality factors: anxiety, exploration and locomotion. According to our results, the locomotion trait displayed no correlation with learning and memory. However curiosity trait predicted extinction of fear memories and spatial reversal learning, and the anxiety traits was related to extinction of fear. These results suggest that behavioral traits, anxiety and curiosity, might be linked to the functioning of specific brain areas (i.e. amygdala and PFC). Our findings are consistent with recent human studies showing that certain personality traits can predict academic achievement and point out the importance of constructing learning environments that could optimize individual strengths. In a third study, we used a model of stress during pregnancy in an attempt to mirror more closely than other experimental approaches based mainly on movement restraint procedures the human condition where stress is often persistently imposed by a male aggressive partner. For that purpose we used aggressive male rats that cohabitated with (and therefore can be considered a stressor) female rats during their pregnancy and, then, characterized the behaviour of these females after weaning. Similar to effects reported in humans, mother rats displayed anxiety-like and depressive-like behaviours, with the females presenting a high anxiety trait being the more vulnerable to the deleterious effects resulting from exposure to the aggressive male. These results propose an interesting animal model to study the effect of stress during pregnancy. Taken together, our results reinforce the view that stress has a strong impact on cognitive function and emotion. They also stress the importance of taking into account individual differences to characterize individuals with different vulnerability to be affected in both cognitive and emotional domain by exposure to stress. Our approach is novel and original in that it takes into account several behavioural (personality-like) traits simultaneously and shows the importance of different traits for different aspects of the relationship between stress, emotion and cognition. The approaches and findings provide valuable models to address the neurobiological mechanisms underlying stress effects on behavior.

EPFL2010

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EPFL2010