Decrypting the dynamics of neuronal and vascular interactions within the hippocampal-cortical interface during memory formation and stabilization, two processes which are altered in neurodegenerative diseases
A fundamental question in Cognitive Neuroscience lies in understanding how our brain is capable of forming and maintaining enduring memories. In humans, memory for facts and events (declarative memory) is initially dependent on the hippocampus. Multidisciplinary approaches have elucidated crucial cellular and molecular mechanisms underlying the formation of declarative memories within hippocampal neuronal networks. As they mature over time, these memories progressively become independent of the hippocampus and increasingly dependent on cortical regions. However, our knowledge of the dynamics of hippocampal-cortical interactions underlying consolidation of information within distributed cortical networks and of forgetting processes still remains fragmentary. Elucidation of these cortical mechanisms is at the heart of our MemoryTrack project. The proposed experiments will enable to systematically examine behavioral, anatomical, electrophysiological and molecular factors underlying the formation of recent and remote memories. Integration of data from each of these levels will lead to a fundamental reshaping of our knowledge of how our brain manages to organize enduring memories and we anticipate that it will allow identification of molecular targets for novel pharmacological approaches to combat memory dysfunction associated with normal aging and neurodegenerative diseases.
Our project is built upon an integrative strategy of cognitive processes which combines correlative, causal and translational approaches. Innovative behavioral paradigms (associative spatial and nonspatial memory in rodents) coupled to brain imaging techniques of neuronal and vascular networks (activity-dependent genes, receptor expression…) and specific manipulations of these networks (intracerebral injections of pharmacological compounds, optogenetic control of neuronal activity) are used. Effects of these manipulations on memory performance (retrieval of recent and remote memories) are evaluated.
NMDA receptors play a crucial role in cerebral plasticity. We raised the hypothesis that a learning-induced synaptic redistribution of the two predominant subunits of these receptors present in the adult neocortex, GluN2A and GluN2B, could control the progressive embedding and stabilization of remote associative memories within cortical networks during the course of the memory consolidation process. We found that this process was accompanied by a progressive increase in the GluN2A/GluN2B ratio at glutamatergic synapses of the cortex, indicating a preferential role of GluN2A subunits in the stabilization of cortical-cortical connections underlying the long-term maintenance of remote memories. Conceptually, this molecular switch in the subunit composition of NMDA receptors could orchestrate the cortical dependency of remote memories, favouring memory stabilization and protecting synapses from interferences and forgetting. At the vascular level, we have observed soon after encoding a rapid increase in the density of vascular networks in cortical regions that will be later in charge of ensuring retrieval of remote memories. These early changes in the architecture of the cortical microvasculature suggest an angiogenic mechanism that acts as a prerequisite for the subsequent maturation of neuronal networks in charge of ensuring successful retrieval of consolidated memories.
Our experiments aim at examining and comparing behavioral, anatomical, cellular and molecular factors underlying the organization of recent and remote memory. Integration of data from these different levels of analysis is expected to provide major conceptual advances on how our brain processes, forms and stores enduring memories. We hope to identify novel mechanisms which will serve as therapeutic targets for the treatment of memory dysfunctions associated with normal and pathological aging.
A manuscript on the behavioral paradigm used to model associative memory in the rat (social transmission of food preference task) has been submitted (Bessières B., Nicole O. and Bontempi B. Assessing recent and remote associative olfactory memory in rats using the social transmission of food preference paradigm). Some of our results have been presented in oral form at the Neuroscience in Intensive Care International Symposium (NICIS, Institut Pasteur, Paris, June 18-19, 2015).
A fundamental question in Cognitive Neuroscience is how our brain forms enduring memories. In humans, memories for facts and events (declarative memories) initially depend on the medial temporal lobe system, including the hippocampus (HPC). Multidisciplinary approaches have enabled to elucidate many cellular and molecular and mechanisms underlying the formation of such memories in hippocampal networks. However, as these memories mature, they eventually become independent of the HPC and are thought to become dependent on other brain areas such as cortical regions. While the early role of the HPC has been extensively studied, much less is known about the hippocampal-cortical interactions allowing memories to be transformed into lifelong memories in distributed cortical networks. This still hotly debated issue is central to this 4-year project.
Building upon solid preliminary findings and validated innovative tools, its first objective is to unravel the key constraints and mechanisms which govern the spatio-temporal dynamics of hippocampal-cortical interactions during remote memory formation. Its second objective consists in manipulating selectively the functioning of the hippocampal-cortical interface during specific stages of memory formation to determine the impact on the fate of the memory. The proposed experiments, organized in the form of 7 interdependent tasks, will benefit from a consortium of 2 partners with a high level of complementary expertise in the fields of cognitive and molecular Neuroscience. Task 1 will provide insights into the experiential factors which modulate the contribution of the hippocampus and cortex to remote memory storage. It will 1) determine whether all memories can become hippocampal-independent once embedded into cortical networks, 2) establish whether memories can remain vivid and flexible without the HPC and 3) examine the content (identical versus transformed) of memories once consolidated in the cortex. These three related issues will rely on a set of innovative but already validated memory apparatuses and paradigms in rodents and humans (use of virtual environments mimicking rodent paradigms). Task 2 will explore the intriguing possibility that cortical regions modulate hippocampal function upon remote memory retrieval depending on the status of existing cortical knowledge. Task 3, more mechanistic, will unravel the differential contribution of NMDA receptor composition to the formation and stabilization of enduring memories. Task 4 will consist in manipulating neuronal plasticity (intracerebral injections of NMDA antagonists and novel peptides or antibodies affecting neuronal remodelling and receptor trafficking) and in determining the impact on memory performance and forgetting. Task 5 will be dedicated to examining the largely unexplored, but crucial contribution, of the cerebral vascular sphere (architecture, density, reactivity) to remote memory formation and determining whether vascular changes constitute a permissive mechanism controlling subsequent structural remodelling of hippocampal-cortical neuronal networks. In Task 6, we will modulate selectively the activity of vascular networks and determine the outcomes on memory performance and structural neuronal plasticity. Task 7 will disseminate the results in meetings and in the form of publication in peer-reviewed journals.
Together, the experiments described will be the first to systematically examine and compare behavioural, anatomical, electrophysiological, molecular and experiential factors underlying the formation of recent and remote memories. The integration of data from each of these levels will lead to a fundamental reshaping of our knowledge of how our brain manages to form enduring memories and we anticipate that it will allow identification of molecular targets for novel pharmacological approaches to combat memory dysfunction associated with normal aging and neurodegenerative diseases.
Monsieur Bruno Bontempi (Institut des Maladies Neurodégénératives (IMN))
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CNRS UMR 5297 Institut Interdisciplinaire en Neurosciences (IINS)
CNRS UMR 5293 Institut des Maladies Neurodégénératives (IMN)
Help of the ANR 510,207 euros
Beginning and duration of the scientific project: March 2015 - 48 Months