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Functional interaction between a prefrontal and a thalamic nucleus for the consolidation of spatial memories

Periodic Reporting for period 1 - METHA (Functional interaction between a prefrontal and a thalamic nucleus for the consolidation of spatial memories)

Période du rapport: 2020-04-01 au 2022-03-31

Memory consolidation, the process by which memories become stronger over time, is still poorly understood. Much of what we know of this process involves mainly the hippocampus and the cortex. However, the thalamus, a region known to relay information to the cortex has started to become another important player in the memory consolidation process. In this project, we explored a cortico-thalamic circuit connecting the Laterodorsal Thalamus (LD) and the Retrosplenial Cortex (RSC), two areas of the brain that are believed to be involved in processing spatial information and that only recently have been proposed to play a role memory consolidation. Notably, both regions are part of the head direction cell system, meaning that neurons of these areas fire at specific orientations of the mouse head during exploration.

Then our overall objective was to study RSC to LD projections, a previously unexplored neural pathway for the recall of memory, and also to better describe the function of the Laterodorsal Thalamus and its contribution to spatial navigation and memory.
To achieve our objectives, we manipulated the activity of neurons connecting the RSC and the LD at the long-term recall of contextual fear memory. Briefly, we trained mice to associate a context with a negative experience, and then they are subjected to the same context without the negative stimulus 28 days later. During this period, we implanted optic fibers into their brains to manipulate the activity of their neurons with light, using a technique called “optogenetics”. We found that mice do retrieve this memory by assessing their “freezing” behavior, a well-established behavioral parameter associated to fear. Using a combination of free available and custom software we scored this behavior in an automatic and unbiased manner.
To study the kind of information the LD – RSC is processing, we also visualized and recorded the activity of neurons from both nuclei in mice performing contextual fear conditioning. We managed to extract data from hundreds of individual neurons and we implemented in-house analysis pipelines to find head direction cells. For this objective we also introduced a variation in the behavioral paradigm: we train mice in one context as mentioned above and assess the memory at recent (1 day after training) and remote (21 days) in the same context (A), but also in a different one (B). By doing this we found that, at recent recall, mice do freeze much more in context A, in which they were trained, and significantly less in the context B; Conversely, at a remote time point, mice do freeze to the same level in both contexts. This suggests there is a strong generalization effect over time. Furthermore, preliminary analysis show there is a portion of mice able to distinguish between contexts (“discriminators”), while other cannot (“generalizers”). The latter opens the opportunity to compare neuronal activity also between these two populations.
Preliminary results of these tasks as well as proofs of progress had been presented at internal seminars and scientific meetings. A more complete set of results is expected to be presented in a poster at Neuroscience Annual Meeting in November this year.
The role of the thalamus in the context of high cognitive functions such as memory had just started to be explored. Past and recent publications have only tangentially discussed its potential role beyond being a relay nucleus to the cortex. In this context, the LD, has recently shown to be involved in memory consolidation. However, little is known about its function either as part of the head direction cell system or regarding its connections with the cortex.
To our knowledge, only a few articles had shown the presence of head direction cells in the Laterodorsal Thalamus of the rodent brain, describing just a few neurons per animal. We can now better characterize its neuronal activity at both, single cell and population level, since we visualized and recorded the activity of hundreds of cells from the LD of freely behaving mice subjected to training, consolidation and recall of contextual fear memory. Furthermore, the miniscope technique we used, allow us to track the activity of neurons over time. Our findings will have an impact in the memory and spatial navigation field, opening new ways in the study of basic mechanisms involved in pathologies like post-traumatic stress disorder and dementia.
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