Periodic Reporting for period 4 - INFANT MEMORIES (Dissecting hippocampal circuits for the encoding of early-life memories)
Okres sprawozdawczy: 2024-07-01 do 2024-12-31
Even though the developing brain has enormous potential for plasticity and learning, memories of personal experiences from infancy can’t be recalled later in life – a phenomenon known as Infantile Amnesia. This apparent paradox has induced scientists to question the ability of the infant hippocampus to perform the exact computations that, during adulthood, support the encoding and long-term storage of memories. Recent experiments in animal models, however, have shown that, though its circuits are still immature, the hippocampus is involved in the formation of memories of early life events already during infancy. Those memories are not lost during development but persist as “silent” traces that can be reinstated later in life. This knowledge opens new research frontiers and raises fundamental questions about the valence and function of maintaining silent memory traces in the brain, together with questions associated with the physiological and pathological impact of reactivating infant memories in adults. Our aim was to elucidate how developing hippocampal circuits support the formation of infant memories, how these memories drift into quiescence with time, what might be the physiological role of silent infant memories in the adult brain, and how infant memory traces might guide learning processes later in life. Our experiments revealed that in the adult hippocampus, multiple memory traces are established within neurogenesis-defined and functionally distinct neuronal subpopulations. The divergent recruitment of these subpopulations to memory traces supports the progression of dynamic memories over time, and defines the propensity of a memory towards updating. This divergent recruitment appears progressively during development in association with cognitive milestones such as the possibility to encode persistent memories. Last, infant memory traces persist in adults despite the apparent memory loss, and their activity is necessary to reinstate a forgotten infantile memory.
In the first phase of the project, we have been focused on establishing methods to perform recordings of large populations of neurons in the developing mouse hippocampus, on developing behavioural paradigms that can be learned with similar efficacy by both infant and adult mice, on establishing robust and reliable setups for the artificial stimulation or silencing of targeted populations of neurons, and on developing and streamlining analysis pipelines for the quantitative interrogation of data acquired with the previous techniques. These efforts have been essential for performing the experiments related to the second phase of the project. In the first line of research, we have recorded the activity of a large fraction of the neural network comprising the CA3 area of the hippocampus longitudinally, through stages of development that are associated with distinct learning potential – i.e. with a mouse's ability to learn more and more complex cognitive tasks. These experiments have allowed us to compare changes in the statistics of network activity and connectivity with a developing animal's performance in spatial learning tasks, and dissect the mechanisms by which developmentally-driven network remodelling underpins the increase in cognitive flexibility of a developing animal. In the second line of research, we have mapped the recruitment of neurons characterised by specific developmental trajectories (i.e. neurogenesis) into memory traces at different stages of an animal's life, to reveal a time-dependent change in the circuitry involved in encoding and storage of memories during the development and adulthood. In the third line of research, we have targeted neurons involved in memory formation during infancy for their reactivation later in life and investigated how the activity of neurons associated with memories that are inaccessible for recall in the adult brain would influence learning processes and the behaviour of the animal.
Our experiments indicate that in the adult hippocampus, multiple memory traces form within distinct neuronal subpopulations defined by neurogenesis and functional specialization. The separate recruitment of these subpopulations drives the evolving nature of memories, ultimately determining whether a memory remains open to modification over time. This divergence gradually emerges during development in conjunction with cognitive milestones, such as the capacity to create enduring memories. Finally, we observed that infant memory traces remain intact in the adult brain despite their apparent loss and that their activation is essential for reinstating a forgotten early-life memory.
This research has been repeatedly disseminated at national and international conferences through the years by both the principal investigator and the PhD Students and Postdocs who took part in the work. While one line of research has led to a publication led by PhD student Vilde Aamodt Kveim in 2024 (Kveim et al., Science 2024), the others are currently in preparation for submission to scientific journals.
Our experiments indicate that in the adult hippocampus, multiple memory traces form within distinct neuronal subpopulations defined by neurogenesis and functional specialization. The separate recruitment of these subpopulations drives the evolving nature of memories, ultimately determining whether a memory remains open to modification over time. This divergence gradually emerges during development in conjunction with cognitive milestones, such as the capacity to create enduring memories. Finally, we observed that infant memory traces remain intact in the adult brain despite their apparent loss and that their activation is essential for reinstating a forgotten early-life memory.
This research has been repeatedly disseminated at national and international conferences through the years by both the principal investigator and the PhD Students and Postdocs who took part in the work. While one line of research has led to a publication led by PhD student Vilde Aamodt Kveim in 2024 (Kveim et al., Science 2024), the others are currently in preparation for submission to scientific journals.
By relying on methodologies and principles from both systems and developmental neuroscience, the experiments of this project represent an innovative approach to the dissection of biological underpinnings of the assembly and functions of neuronal networks centred around high-end cortices, which are endowed with computations for the internal representations of variables associated with experience and support the formation and long-term storage of memories. This project is among the first to be able to record the activity of large populations of neurons longitudinally through development in awake, behaving mice, and to associate changes in network connectivity and dynamics with the developmental trajectory of learning processes. In this context, the ability to study functional correlates of memory processes by simultaneously recording the activity of neuronal populations and quantitatively dissecting the animal’s behaviour holds great promises for the causal interrogation of the contribution of specific subpopulations of neurons to cognitive processes like spatial navigation and the encoding, consolidation, and recall of memories through development. By the end of the project, we have been able to first, identify changes in network dynamics that are related to the increase in cognitive potential associated with development and reveal key neuronal players driving such changes; second, to dissect circuitry and processes underpinning the encoding and long-term storage of memories of personal experience during development, and to relate such circuitry to the encoding and consolidation of memories in the adult; last, to reveal the mechanisms by which physical traces associated with specific memories are maintained in the adult brain despite the apparent memory loss of Infantile Amnesia, and how these silent traces can be reactivated and lead to the reinstatement of the associated memories.