Biology subjects

Ortega-de San Luis, C.

Publications and source records attributed to Ortega-de San Luis, C..

6 recordsLinked to original sources

bioRxiv2025

Memory engram synapse 3D molecular architecture visualized by cryoCLEM-guided cryoET

Memory is incorporated into the brain as physicochemical changes to engram cells. These are neuronal populations that form complex neuroanatomical circuits, are modified by experiences to store information, and allow for memory recall. At the molecular level, learning modifies synaptic communication to rewire engram circuits, a mechanism known as synaptic plasticity. However, despite its functional role on memory formation, the 3D molecular architecture of synapses within engram circuits is unknown. Here, we demonstrate the use of engram labelling technology and cryogenic correlated light and electron microscopy (cryoCLEM)-guided cryogenic electron tomography (cryoET) to visualize the in-tissue 3D molecular architecture of engram synapses of a contextual fear memory within the CA1 region of the mouse hippocampus. Engram cells exhibited structural diversity of macromolecular constituents and organelles in both pre- and postsynaptic compartments and within the synaptic cleft, including in clusters of membrane proteins, synaptic vesicle occupancy, and F-actin copy number. This engram to tomogram approach, harnessing in vivo functional neuroscience and structural biology, provides a methodological framework for testing fundamental molecular plasticity mechanisms within engram circuits during memory encoding, storage and recall.

neuroscience↗

bioRxiv2024

Plasticity of visual looming response reveals a dissociation of innate and learned components

Animals rely on innate and learned behaviour to respond to their environment, but how the brain balances hardwired responses with adaptive flexibility remains unclear. Here, we demonstrate that innate looming stimulus responses in mice can be attenuated via repeated unreinforced presentation. This attenuation is long-lasting and generalising, but is rapidly recovered when the stimulus is paired with an electric foot-shock. Fiber photometry recordings reveal attenuation of responses to visual looming stimuli in the SC and PAG, which do not recover following recovery of behavioural responses. Analysis of c-Fos expression uncovered a ventral CA1 (vCA1) ensemble that is active during both innate and learned looming fear responses. We report that this vCA1 engram is not necessary for innate defensive behaviour but is necessary for learned fear responses. These findings reveal a novel role of the hippocampus in adapting to looming stimuli, and provide a platform for understanding the interaction of memory and instinct.

neuroscience↗

bioRxiv2024

The PHD3-FOXO3 axis modulates the interferon type I response in microglia aggravating Alzheimer's disease progression

Microglia respond to Alzheimers disease (AD) with a variety of transcriptional responses. However, the regulation of specific transcriptional signatures and the contribution of each individual response to disease progression is only starting to be characterized. We have previously shown that hypoxia via hypoxia inducible factor 1 (HIF1) is a strong regulator of A{beta} plaque-associated microglia (A{beta}AM). Here, we characterize the role of HIF1-mediated transcription of Egln3, encoding for PHD3, in A{beta}AM. We show that oligomeric A{beta} treatment (oA{beta}) in vitro induces the expression of Hif1a and Egln3 in microglia, which correlates with the transcriptional activation of genes involved in the interferon type I signature (IFNS) in a PHD3-dependent manner. Mechanistically, we demonstrate FOXO3 to be an important repressor of IFNS in microglia, whose abundance decreases upon A{beta} presence, and, correspondingly, both in human single-nucleus (sn) and mouse A{beta}AM transcriptomics, FOXO3 DNA binding sites define the IFNS. FOXO3 repression of the IFNS is dependent on PHD3, with our results suggesting a physical interaction between both proteins in vitro. In vivo, loss of PHD3 correlate with abrogation of the IFNS and activation of the disease-associated microglia signature (DAM) in A{beta}AM. Transcriptional changes in microglia associate with increased microglia proximity to A{beta} plaques, augmented phagocytosis of A{beta} by microglia, reduced parenchymal levels of A{beta}, and an increase in small-sized plaques. PHD3 deficiency also reduced the A{beta} plaque-associated neuropathology and rescued behavioural deficits of an AD mouse model. Finally, we also demonstrate that microglial PHD3 overexpression during development in the absence of A{beta} pathology is sufficient to induce the IFNS and to behavioural alterations. Altogether, our data strongly indicate that the PHD3-FOXO3 axis controls the microglial IFNS in a cell autonomous manner, contributing to the progression of AD.

neuroscience↗

bioRxiv2023

Engram cell connectivity as a mechanism for information storage and memory function

Information derived from experiences is incorporated into the brain as changes to ensembles of cells, termed engram cells, that allow memory storage and recall. The mechanism by which those changes hold specific information is unclear. Here we test the hypothesis that the specific synaptic wiring between engram cells is the substrate of information storage. First, we monitor how learning modifies the connectivity pattern between engram cells at a monosynaptic connection involving the hippocampal vCA1 region and the amygdala. Then, we assess the functional significance of these connectivity changes by artificially activating or inhibiting its presynaptic and postsynaptic components respectively. Finally, we identify a synaptic plasticity mechanism mediated by PSD-95, which impacts the connectivity pattern among engram cells and contributes to the long-term stability of the memory. These findings impact our theory of learning and memory by helping us explain the translation of specific information into engram cells and how these connections shape brain function.

neuroscience↗

bioRxiv2023

Adaptive Expression of Engrams by Retroactive Interference

Long-term memories are stored as stable configurations of neuronal ensembles, termed engrams. While investigation of engram cell properties and functionality in memory recall has been extensive, less is known about how engram cells are affected by forgetting. We describe a form of interference-based forgetting using an object memory behavioral paradigm. By using activity-dependent cell labelling, we show that although retroactive interference results in decreased engram cell reactivation during recall trials, optogenetic stimulation of the labelled engram cells is sufficient to induce memory retrieval. Forgotten engrams may also be reinstated via the presentation of similar or related environmental information. Furthermore, we demonstrate that engram activity is necessary for interference to occur. Taken together, these findings indicate that retroactive interference modulates engram expression in a manner that is both reversible and updatable. Retroactive inference may constitute a form of adaptive forgetting, where in everyday life new perceptual and environmental inputs modulate the natural forgetting process.

neuroscience↗

bioRxiv2022

Immune activation state modulates retrieval of infant engrams

Infantile amnesia is possibly the most ubiquitous form of memory loss in mammals. Despite its widespread relevance, little is known about the biological conditions for infantile amnesia to occur and its effect on the engram cells that encode a memory. We investigated how memories are stored in the brain throughout development by integrating engram labeling technology with mouse models of infantile amnesia. Here, we discovered a phenomenon in which male offspring in maternal immune activation models of autism spectrum disorder do not experience infantile amnesia. We rescued the same apparently forgotten infantile memories in mice by optogenetically reactivating dentate gyrus engram cells labeled during complex infant development experiences. Further, we were able to permanently reinstate lost infantile memories by artificially updating the memory engram, demonstrating that infantile amnesia is a reversible process. Our findings suggest that immune activation during development modulates innate, and reversible, forgetting switches that determine whether infantile amnesia will occur.

neuroscience↗