A novel, integrated approach to the mechanisms and dynamics of episodic memory: from genes to cells and neural network properties. – MolCellCog

The strategy to achieve our aims was first to design and validate a new behavioural paradigm to probe episodic memory in rats. A new apparatus was built allowing us to expose rats to brief episodes of life during which a particular combination of odours, at specific spatial locations as a function of specific sensory contextual information present in their environment, can give them access to a sweet drinking solution. After having experienced two such episodes containing different odours, places and contexts, rats were probed for their long-term memory of these episodes. Different tasks allowed us to test their capacity to discriminate relatively similar events. A multi-disciplinary approach based on multisite population and unit in vivo electrophysiology recordings, pharmacological approaches, cellular imaging of the activation of genes involved in synaptic plasticity, and an ensemble of approaches allowing us to explore the role of new neurons generated in the adult brain by neurogenesis, was engaged to identify the neural circuits and the cellular and molecular mechanisms underlying episodic memory.

Novel results show that rats can form and recall long-term, flexible episodic memory with properties similar to that of human episodic memory. A neural network supporting episodic memory has been identified. The dynamic activity of this network as well as the activity of certain neurons in conditions of discrimination of similar events is analysed. Neurons with spatial and pattern separation properties have been discovered in the medio-dorsal geniculate thalamic nucleus. The functional role of newly born neurons generated in the adult and gene regulation mechanisms enabling the recruitment of these newly born neurons by memeory have been identified. Several questions extending the findings of this project continue to be explored by the partners

When dysfunctional, the neural mechanisms that underlie memory contribute to the ethiology of cognitive disorders associated with age or neurodegenerative diseases. Perspectives of the project are to achieve a better understanding of thge neural mechanisms underlying different forms of complex memories and to identify dysfunction of these mechanisms that can occur during ageing or in conditions of neurodegenerative, neuorlogical or psychiatric diseases associated with cognitive deficits. This understanding is crucial for the development and validation of novel therapeutic strategies designed to reduce or comensate these cognitive alterations. The neural mechanisms explored in this project will be prime candidates for future translational studies designed to explore ways of prevention or slowing down of cognitive decline.

Several articles have been published in high impact scientific journals and others should be published in the near future. Findings were also presented at scientific meetings and as material addressed to the general public. One Ph.D. has been achieved, another will be submitted soon, and two postdoctoral scientists working on this project have obtained academic positions at CNRS and University. Several technological developments have been achieved allowing us to carry on and extend research of the mechanisms of memory and of memory dysfunction.

One major question in contemporary neuroscience is how the dynamic activity of specific neurons and the mechanisms supporting brain plasticity gives rise to the lasting traces of experience that underlies memory. The past decade has witnessed tremendous advances in our understanding of some of the key cellular and molecular mechanisms of several forms of memory, and new insights have been gained on aspects of the neural codes of memory representations at the single cell and at the network level. Capitalising on these advances, the main ambition of this project is to develop a novel, integrated approach of the neural bases of a major, more complex form of memory: episodic memory, for which key features can be modelled in rodents to undertake a neurobiological analysis.
A first distinctive feature of this proposal is to attack some of the most central issues that are at the forefront of current debates on how episodic-type memories are formed, stabilized and recalled, such as how selected regions of the hippocampus and cortex participate in the storage of episodic memory; whether and how with time features of episodic memories are dynamically reorganized during systems consolidation when cortical regions gain growing control over recall; and what are the molecular, cellular and network mechanisms that support the formation, consolidation and recall of recent and remote episodic memory.
Facing the complexity of the brain where many interdependent levels of organisation are superimposed, a second distinctive feature is to undertake and integrated, multi-level analysis of the brain mechanisms that support episodic memory and its temporal dynamics, with the main ambition of bridging together ‘bottom’ levels and ‘higher’ levels of brain function to achieve a more comprehensive understanding of the mechanisms underlying the formation and dynamics of episodic-like memory. The overall aim is to work out the functional circuits, identify the representational codes and discover molecular and cellular mechanisms that give rise to features of episodic memory along the dynamic scale of its formation and maturation. For this, we will focus on two related key molecular and cellular mechanisms of plasticity involved in memory formation, activity-dependent transcriptional regulation mediated by the transcription factor zif268 as a key molecular mechanism of synaptic plasticity and memory consolidation, and the recruitment of new neurons in the hippocampus generated in the adult by neurogenesis. Our main objective is to decipher how these plasticity mechanisms in selected brain regions contribute to specific processes of memory (acquisition, initial and systems consolidation, recall and reconsolidation) fulfilled by these structures, how they influence representational codes of features of episodic memory at the single cell level, and how they influence the emergence of selective synchronized oscillatory activities at the network level.
To drive forward this understanding, we will use novel behavioural tasks, multiple-sites network oscillations recordings and synchronization analysis to uncover the formation of relevant dynamic networks supporting episodic memory, single-cell recording technology to characterize specific neural representational codes, cell activation imaging, experimental manipulation of hippocampal newborn neurons and gene targeting via RNA interference in vivo. For this, we have assembled teams with expertise in memory function and behaviour, multisite single cell activity and population oscillations recordings, gene targeting via viral vectors, and functional analysis of experience-driven adult neurogenesis, with the aim to combine a set of approaches that will allow us to bridge between molecular/cellular levels, single cell and network properties and dynamics, and behaviour in order to achieve an integrated, multilevel understanding of the neural mechanisms of the laying-down of episodic memory.