Fear | EPFL Graph Search

Fear is an intensely unpleasant emotion in response to perceiving or recognizing a danger or threat. Fear causes physiological changes that may produce behavioral reactions such as mounting an aggressive response or fleeing the threat. Fear in human beings may occur in response to a certain stimulus occurring in the present, or in anticipation or expectation of a future threat perceived as a risk to oneself. The fear response arises from the perception of danger leading to confrontation with or escape from/avoiding the threat (also known as the fight-or-flight response), which in extreme cases of fear (horror and terror) can be a freeze response. In humans and other animals, fear is modulated by the process of cognition and learning. Thus, fear is judged as rational and appropriate, or irrational and inappropriate. An irrational fear is called a phobia. Fear is closely related to the emotion anxiety, which occurs as the result of threats that are perceived to be uncontrollable or u

Genetic selection for low glucocorticoid responsiveness recapitulates PTSD-related phenotypes: a behavioral, neuroimaging and sleep-physiology study

Silvia Monari

Humans show inter-individual differences in vulnerability to develop post-traumatic stress disorder (PTSD) following exposure to trauma. Several critical biobehavioral features have been consistently described in PTSD patients, including blunted cortisol levels, smaller hippocampal size, sleep disturbances. However, because of the delay between trauma exposure and the onset of symptoms characteristic of PTSD, only a few longitudinal studies have tried to dissect whether these features constitute pre-trauma risk factors or consequences of the trauma. Enormous effort in animal and human studies has been dedicated to understanding mechanisms of conditioned fear and fear extinction, processes that are at the core of PTSD. However, the same progress has not been translated into psychiatric practice for PTSD. Deepening our understanding of the contribution of key factors to PTSD-related alterations can serve to develop effective treatments.In particular, with regard to low cortisol levels in PTSD pathophysiology, a causative role for blunted glucocorticoid responsiveness in PTSD has not been demonstrated yet.Here, we have addressed this question in lines of Wistar rats genetically-selected for their differential habituation of glucocorticoid responses to stress (LOW-, INTER-, HIGH-CORT Responder rats) and focused on fear extinction, a hallmark of PTSD symptomology, as one of the key features. As a first step, we looked whether divergent trajectories of glucocorticoid responsiveness were associated with brain volume abnormalities, prompted by the influential role of glucocorticoid in brain development. Notably, rats with low or high corticosterone responsiveness exhibit smaller hippocampi, regardless of trauma exposure, compared to rats with normative corticosterone levels. Similarly, the distribution of corticosteroid receptors in the hippocampus presented similarities between the LOW-CR and the HIGH-CR rats with higher mineralocorticoid receptors (MR) and less glucocorticoid receptors (GR). Although LOW- and HIGH-CR rats displayed a similar hippocampal profile at the structural and molecular levels, only LOW-CR male rats exhibited strong deficits in extinction consolidation compared to rats with 'normative' glucocorticoid responses (INTER-CR rats), and showed higher fear response both at few days and at several weeks after trauma exposure. We next tested the causal involvement of corticosterone in the fear extinction consolidation, and found that post-extinction corticosterone treatment markedly prevented the deficits in extinction memory and attenuated fear relapse. In addition, pharmacological inhibition of corticosterone levels during extinction memory consolidation, but not during training, in the INTER-CR rats led to extinction deficits at retrieval one day later. These results indicate that blunted corticosterone levels contribute to confer major vulnerability than having a small hippocampus, and that consolidation processes following extinction are mainly affected by low corticosterone levels.It is well known that glucocorticoids play an important role in memory consolidation processes and that sleep disturbances are a diagnostic criterion of PTSD. Therefore, we investigated in greater detail the sleep architecture in undisturbed condition and during the consolidation period of the extinction phase, which is known to be supported by sleep-dependent processes. In polysomnographic recordings, we found that rats with blunted corticos

EPFL2022

Hyper-emotional neurophysiology in a rat model of autism

Mônica Regina Favre

Autism is a pervasive neurodevelopmental disorder of unknown etiology, characterized by a spectrum of symptoms of social impairment, abnormal communication, and unusual restricted, inflexible behaviors. Patients also frequently present various levels of sensory, learning, memory and attention abnormalities, anxiety and phobias, in addition to disturbances in gastrointestinal, sleep, metabolic and immune functions, also with higher rates of physical malformations and seizures. There is currently no empirically based consensus on the causes of symptoms and their remarkable heterogeneity. It is also unknown if associated symptoms are directly linked to autism etiology or if they represent parallel comorbidities. In consequence of our incomplete understanding of the disease process, treatment options are vast and not equally efficacious across all diagnosed individuals. Thus, autism today leads to a lifelong disability that requires significant assistance from health care providers, educational systems and family members. Ultimately, improved diagnostic indicators and personalized therapies should allow the autistic individual to live with reduced costs and more independently. Prenatal exposure to compounds such as valproic acid (VPA) has been associated with higher risk for development of autistic features. The teratogenic and neurodevelopmental effects of VPA in humans are replicated in rodents exposed early in embryonic development, at the time neural tube closure. Thus, the VPA-rat has emerged as a well validated model of autism for controlled investigations of the neurobiological basis of autistic-like symptoms and individual response to environmental interventions. Our laboratory previously demonstrated in the model that the primary sensory cortical, frontal cortical, and amygdala microcircuits are hyper-functional in the pup, in parallel to excessive conditioned fear responses, over-generalization of fear to non-conditioned stimuli, and resistance to fear extinction, in the adult. Together with the full range of autistic symptoms and increasing evidence for local hyper-functional connections and cortical minicolumnpathy in patients, data from the VPA model inspired the hypothesis of autism as an Intense World Syndrome. The theory proposes that the polygenetic background of each individual sets the threshold for susceptibility to their prenatal and post natal environments. At the event of a biological insult, be it exogenous such as VPA-exposure, or genetic, such as a rare set of polymorphisms, a cascade of molecular events would lead to hyper-plastic and hyper-reactive neural microcircuits creating a hyper-functional endophenotype. Depending on the developmental trajectory of each individual, this would lead to abnormalities in four dimensions: hyper-attention, hyper-memory and hyper-perception, and hyper-emotionality. Different patterns of hyper-functional outcomes in each individual would then create a fragmented, intense and even aversive experience of the world, and explain the wide heterogeneity in symptom severity and most, if not all, characteristics of autistic people. Thus, inherent to the theory is the description of autistic individuals as highly biologically sensitive and thus that a predictable, positive, safe and calm environment is an essential feature of early postnatal life for positive outcomes in the child. For my doctoral dissertation, I addressed if embryonic exposure to VPA in the rat leads to hyper-functional emotion system, and if this leads to differential response of individuals to postnatal environment. In Chapter 1, I introduce the clinical characteristics of autism and the brain systems involved in emotion and cognition through modulation of fear, anxiety learning and memory. Then I introduce the research rationale for this project. In Chapter 2, I present our published manuscript describing physical malformations, and other teratogenic and developmental health effects in the VPA-rat. This study further validates the VPA-rat as a model of effects in humans, and summarizes important outstanding questions in the VPA-model, in view of the variability in protocols for model generation. We emphasize that such general health parameters could serve as indicators of the precise time and location of toxic event, and thus as potential predictors of differential symptom dimensions and severities. In Chapter 3, I present our study of predictability in the environment of VPA animals as an essential feature for beneficial effects of enrichment, on autism-like hyper-emotionality. This study provides an elegant and computationally accessible method for multivariate analysis of group effects and individual-based effects. In support of the Intense World Theory, our results suggest that VPA-exposed animals are particularly sensitive to their environment, and point to the hippocampus and amygdala as candidate targets of environmental enrichment predictability effects in reducing fear and anxiety in certain VPA exposed individuals. Finally, in Chapter 4, I present some concluding remarks on the implications of this project and future perspectives.

EPFL2013

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

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.

EPFL2017