Periodic Reporting for period 4 - RECENT-TO-REMOTE (Remote Memory Consolidation Based on Activity, Connectivity and Stability; Contribution of Neurons and Astrocytes.)
Période du rapport: 2023-05-01 au 2023-10-31
"We are nothing more than the sum of our memories"(Michael Scott).
Our remote memories, weeks to decades long, define who we are and how we experience the world, hence remote memory impairments have devastating consequences. Only a minority of recent memories (minutes to days long) will undergo a transition to remote memory, and those are usually the ones most important to the organism, as the longevity of a memory is tightly connected to its significance. Despite that, the vast majority of research was dedicated to recent memory, leaving the most basic questions unanswered: how and when are remote memories selected? How are they physically different from recent ones? What processes mediate the transition from recent to remote memory?
This project aims to address these questions, under the novel hypothesis that hippocampal neurons prioritized for remote consolidation are more likely to be connected to the anterior cingulate cortex (ACC), which in turn will be recruited for the long-term storage of memory. I further suggest a mechanistic investigation of the fundamental theoretical framework of 'systems consolidation' describing the transition from recent to remote memory, hypothesizing it is implemented by continuous interactions between brain regions, e.g. the hippocampus and the ACC. Finally, I propose a novel function for hippocampal astrocytes in the independent representation of the environment.
We have tested these hypotheses comprehensively by combining complementary conceptual and technical approaches, as explained in the next section.
Our remote memories, weeks to decades long, define who we are and how we experience the world, hence remote memory impairments have devastating consequences. Only a minority of recent memories (minutes to days long) will undergo a transition to remote memory, and those are usually the ones most important to the organism, as the longevity of a memory is tightly connected to its significance. Despite that, the vast majority of research was dedicated to recent memory, leaving the most basic questions unanswered: how and when are remote memories selected? How are they physically different from recent ones? What processes mediate the transition from recent to remote memory?
This project aims to address these questions, under the novel hypothesis that hippocampal neurons prioritized for remote consolidation are more likely to be connected to the anterior cingulate cortex (ACC), which in turn will be recruited for the long-term storage of memory. I further suggest a mechanistic investigation of the fundamental theoretical framework of 'systems consolidation' describing the transition from recent to remote memory, hypothesizing it is implemented by continuous interactions between brain regions, e.g. the hippocampus and the ACC. Finally, I propose a novel function for hippocampal astrocytes in the independent representation of the environment.
We have tested these hypotheses comprehensively by combining complementary conceptual and technical approaches, as explained in the next section.
During the 5 years of the project we have made a tremendous progress in understanding recent and remote memory and the role of astrocytes in behavior. We have established the experimental systems essential for implementation of the project, and completed all 3 objectives outlined in the grant proposal. Our results were published in the best journals.
The major efforts and accomplishments are the following:
A. The parts of the project investigating the role of astrocytes in projection-specific effects on memory acquisition and the role of the CA1 and ACC projection in remote memory acquisition were completed. By employing connectivity-based tagging, to label specific populations of hippocampal based on their projection target, we have causally demonstrated the functional significance of specific projections to memory acquisition, and defined a precise time-window for this process. This objective is published in Kol et al., Nature Neuroscience 2020, and is also a part of Refaeli et al, Current Biology, 2023.
B. Our 2-photon microscope was upgraded (by ERC funding) to allow parallel 2-channel imaging of astrocytes and neurons. We have imaged astrocytic activity in mice navigating a virtual environment (Aim 3C), and made very exciting discoveries: whereas single astrocytes do not encode specific locations (as opposed to neurons), it is possible to design an encoder that will infer the location of the mouse based on the activity of the astrocytic population. Furthermore, there is a clear difference in astrocytic activity when mice are navigating a familiar or a novel environment. The work, describing how hippocampal astrocytes encode reward location was published in Nature (Doron et al, 2022).
C. Objective 1, revolve around ensembles, their activity and connectivity. We have employed activity-based fluorescent tagging to label recent and remote memory recall ensembles. To determine how they differ in their activity we checked the overlap of these populations between acquisition, recent, and remote. We found that the recent and remote populations are relatively stable, and the recent engram is necessary for remote recall. To look for changes in connectivity we employed CLARITY-based detection of the output and input projections from/to the hippocampus in a single-cell resolution. We hypothesize that remote recall ensemble cells in CA1 will be preferentially connected to frontal regions, and indeed, this is what we found (Refaeli et al, Current Biology, 2023).
D. We made a 3D, CLARITY based, spatial description of neurons and astrocytes in the hippocampus, as a basis for our future investigations in this aim. This paper about astrocyte morphology is published, Refaeli et al, Glia, 2021, accompanied by a method paper Refaeli et al, JoVE, 2022.
The major efforts and accomplishments are the following:
A. The parts of the project investigating the role of astrocytes in projection-specific effects on memory acquisition and the role of the CA1 and ACC projection in remote memory acquisition were completed. By employing connectivity-based tagging, to label specific populations of hippocampal based on their projection target, we have causally demonstrated the functional significance of specific projections to memory acquisition, and defined a precise time-window for this process. This objective is published in Kol et al., Nature Neuroscience 2020, and is also a part of Refaeli et al, Current Biology, 2023.
B. Our 2-photon microscope was upgraded (by ERC funding) to allow parallel 2-channel imaging of astrocytes and neurons. We have imaged astrocytic activity in mice navigating a virtual environment (Aim 3C), and made very exciting discoveries: whereas single astrocytes do not encode specific locations (as opposed to neurons), it is possible to design an encoder that will infer the location of the mouse based on the activity of the astrocytic population. Furthermore, there is a clear difference in astrocytic activity when mice are navigating a familiar or a novel environment. The work, describing how hippocampal astrocytes encode reward location was published in Nature (Doron et al, 2022).
C. Objective 1, revolve around ensembles, their activity and connectivity. We have employed activity-based fluorescent tagging to label recent and remote memory recall ensembles. To determine how they differ in their activity we checked the overlap of these populations between acquisition, recent, and remote. We found that the recent and remote populations are relatively stable, and the recent engram is necessary for remote recall. To look for changes in connectivity we employed CLARITY-based detection of the output and input projections from/to the hippocampus in a single-cell resolution. We hypothesize that remote recall ensemble cells in CA1 will be preferentially connected to frontal regions, and indeed, this is what we found (Refaeli et al, Current Biology, 2023).
D. We made a 3D, CLARITY based, spatial description of neurons and astrocytes in the hippocampus, as a basis for our future investigations in this aim. This paper about astrocyte morphology is published, Refaeli et al, Glia, 2021, accompanied by a method paper Refaeli et al, JoVE, 2022.
Now, at the end of the project, I can say confidently that it did make a mark on the state of the art.
Here are 4 major changes that we made:
* We provided the first chronic astrocyte imaging in the hippocampus, describing how hippocampal astrocytes encode reward location only in familiar environments, and astrocytes activity can be used to decode the location of the mouse. The importance of these results, had justified publication in Nature (Doron et al, 2022).
* We showed that astrocytes have a projection-specific effects on memory acquisition, by employing connectivity-based tagging, to label specific projections from the hippocampus. This work was published in Nature Neuroscience (Kol et al., 2020).
* We were the first to show stability between recent and remote engrams on one hand, and their maturation on the other (Refaeli et al, Current Biology, 2023).
* We provided a 3D, CLARITY based, spatial description of neurons and astrocytes in the hippocampus (Refaeli et al, Glia, 2021).
Here are 4 major changes that we made:
* We provided the first chronic astrocyte imaging in the hippocampus, describing how hippocampal astrocytes encode reward location only in familiar environments, and astrocytes activity can be used to decode the location of the mouse. The importance of these results, had justified publication in Nature (Doron et al, 2022).
* We showed that astrocytes have a projection-specific effects on memory acquisition, by employing connectivity-based tagging, to label specific projections from the hippocampus. This work was published in Nature Neuroscience (Kol et al., 2020).
* We were the first to show stability between recent and remote engrams on one hand, and their maturation on the other (Refaeli et al, Current Biology, 2023).
* We provided a 3D, CLARITY based, spatial description of neurons and astrocytes in the hippocampus (Refaeli et al, Glia, 2021).