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

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

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

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

Structural, Synaptic, and Epigenetic Dynamics of Enduring Memories

Our memories are the records of the experiences we gain in our everyday life. Over time, they slowly transform from an initially unstable state into a long-lasting form. Many studies have been investigating from different aspects how a memory could persist for sometimes up to decades. In this review, we highlight three of the greatly addressed mechanisms that play a central role for a given memory to endure: the allocation of the memory to a given neuronal population and what brain areas are recruited for its storage; the structural changes that underlie memory persistence; and finally the epigenetic control of gene expression that might regulate and support memory perseverance. Examining such key properties of a memory is essential towards a finer understanding of its capacity to last

Structure-Function Analysis of a Neuron-Specific Vesicular ATPase in Neurotransmission

Neurotransmission is central to neuronal communication, through which information is processed, stored, and retrieved. The vesicular ATPase (V-ATPase) protein is a proton pump that is implicated in neurotransmission. It acidifies synaptic vesicles to be consequently loaded with neurotransmitters prior to release through exocytosis. V100 is a neuron-specific vesicular ATPase subunit a1, and it is a major subunit that determines where the vesicular ATPase functions intracellularly. Previous studies characterized two putative functions for the V100 in neuronal cell biology; intracellular vesicle acidification, and membrane fusion. In this project, we set out to dissect the function of V100 genetically - using immunolabeling and electrophysiology- to understand acidification-dependent and -independent functions. The results cast some light on a potential regulation of the V100 by Ca2+/Calmodulin. This regulatory mechanism may be specifically required for spontaneous vesicle release independent of the proton pump function of the V-ATPase

The H50Q mutation enhances αα-synuclein aggregation, secretion, and toxicity

Background: A new SNCA mutation, H50Q, has been linked to familial Parkinson disease (PD). Results: The H50Q mutation does not affect the structure, membrane binding, or subcellular localization of α-Syn but alters its pathogenic properties. Conclusion: The H50Q mutation increases α-Syn aggregation, secretion, and extracellular toxicity. Significance: α-Syn mutations contribute to the pathogenesis of PD via multiple mechanisms