Biology subjects

Graeff, J.

Publications and source records attributed to Graeff, J..

6 recordsLinked to original sources

bioRxiv2026

Hippocampal recruitment of cortical engrams underlies remote memory generalization

Time-dependent generalization of remote fear memories is generally viewed as a passive and progressive loss of contextual precision, yet its underlying mechanisms remain poorly understood. Here, we investigated the neurobiological correlates of remote generalization using a combination of engram and projection-specific manipulation technologies in mice. Our results show that remote fear generalization results in an increased recruitment of learning-associated engrams into recall ensembles in the medial prefrontal cortex (mPFC), a crucial brain area for remote memory storage. Moreover, we find that this recruitment, and concomitantly remote generalization, requires ventral hippocampal (vCA1) inputs conveying contextual information to the mPFC, for which activity of parvalbumin-expressing interneurons proves necessary. Together, our findings suggest that time-dependent fear generalization arises from active hippocampal-prefrontal circuit mechanisms rather than passive loss of contextual information.

neuroscience↗

bioRxiv2024

ABBA, a novel tool for whole-brain mapping, reveals brain-wide differences in immediate early genes induction following learning

Unbiased characterization of whole-brain cytoarchitecture represents an invaluable tool for understanding brain function. For this, precise mapping of histological markers from 2D sections onto 3D brain atlases is pivotal. Here, we present two novel software tools facilitating this process: Aligning Big Brains and Atlases (ABBA), designed to streamline the precise and efficient registration of 2D sections to 3D reference atlases, and BraiAn, an integrated suite for multi-marker automated segmentation, whole-brain statistical analysis, and data visualisation. Combining these tools, we performed a comprehensive comparative study of the whole-brain expression of three of the most widely used immediate early genes (IEGs). Thanks to their neural activity-dependent expression, IEGs have been used for decades as a proxy of neural activity to generate unbiased mapping of activity following behaviour, but their respective induction in response to neuronal activation across the entire brain remains unclear. To address this question, we systematically compared the brain-wide expression cFos, Arc and NPAS4, three abundantly used IEGs, across three different behavioural conditions related to memory. Our results highlight major differences in both their distribution and induction patterns, indicating that they do not represent equivalent markers across brain areas or activity states, but can provide instead complementary information.

neuroscience↗

bioRxiv2024

Cell type and locus-specific epigenetic editing of memory expression

Epigenetic modifications parallel multiple memory processes, but evidence that the epigenetic makeup of a single site can guide learnt behaviors has so far been lacking. Here, we developed CRISPR-based epigenetic editing tools to address this question in a cell type-specific, locus-restricted and temporally controllable manner in the adult mouse brain. Focusing on learning-induced neuronal populations, we provide a proof-of-principle that site-specific epigenetic dynamics are causally implicated in memory expression.

neuroscience↗

bioRxiv2023

A modular toolbox for the optogenetic deactivation of transcription

Light-controlled transcriptional activation is a commonly used optogenetic strategy that allows researchers to regulate gene expression with high spatiotemporal precision. The vast majority of existing tools are, however, limited to light-triggered induction of gene expression. Here, we inverted this mode of action and created two complementary optogenetic systems capable of efficiently terminating transcriptional activation in response to blue light. First, we designed highly compact regulators, by photo-controlling VP16 transactivation peptide exposure. Then, applying a two-hybrid strategy, we engineered LOOMINA (light off-operated modular inductor of transcriptional activation), a versatile transcriptional control platform for mammalian cells that is highly adaptable and compatible with various effector proteins. Leveraging the flexibility of CRISPR systems, we integrated LOOMINA with Cas9 as a DNA-binding domain to control transcription from various endogenous promoters with exceptionally high dynamic ranges in multiple cell lines, including neuron-like cells. Both functionally and mechanistically, LOOMINA represents a valuable addition to the optogenetic repertoire for transcriptional regulation.

synthetic biology↗

bioRxiv2022

Brain-wide screen of prelimbic cortex inputs reveals a functional shift during early fear memory consolidation

Memory formation and storage rely on multiple interconnected brain areas, the contribution of which varies during memory consolidation. The medial prefrontal cortex, in particular the prelimbic cortex (PL), was traditionally found to be involved in remote memory storage, but recent evidence points towards its implication in early consolidation as well. Nevertheless, the inputs to the PL governing these dynamics remain unknown. Here, we first performed a brain-wide, rabies-based retrograde tracing screen of PL engram cells activated during contextual fear memory formation to identify relevant PL input regions. Next, we assessed the specific activity pattern of these inputs across different phases of memory consolidation, from fear memory encoding to recent and remote memory recall. Using projection-specific chemogenetic inhibition, we then tested their functional role in memory consolidation, which revealed a hitherto unknown contribution of claustrum to PL inputs at encoding, and of insular cortex to PL inputs at recent memory recall. Both of these inputs further impacted how PL engram cells were reactivated at memory recall, testifying to their relevance for establishing a memory trace in the PL. Collectively, this data identify a spatiotemporal shift in PL inputs important for early memory consolidation, and thereby help to refine the working model of memory formation.

neuroscience↗

bioRxiv2021

The HDAC inhibitor CI-994 acts as a molecular memory aid by facilitating synaptic and intra-cellular communication after learning

Long-term memory formation relies on synaptic plasticity, activity-dependent transcription and epigenetic modifications. Multiple studies have shown that HDAC inhibitor (HDACi) treatments can enhance individual aspects of these processes, and thereby act as putative cognitive enhancers. However, their mode of action is not fully understood. In particular, it is unclear how systemic application of HDACis, which are devoid of substrate specificity, can target pathways that promote memory formation. In this study, we explore the electrophysiological, transcriptional and epigenetic responses that are induced by CI-994, a class I HDAC inhibitor, combined with contextual fear conditioning (CFC) in mice. We show that CI-994-mediated improvement of memory formation is accompanied by enhanced long-term potentiation in the hippocampus, a brain region recruited by CFC, but not in the striatum, a brain region not primarily implicated in contextual memory formation. Furthermore, using a combination of bulk and single cell RNA sequencing, we find that synaptic plasticity-promoting gene expression cascades are more strongly engaged in the hippocampus than in the striatum, but only when HDACi treatment co-occurred with CFC, and not by either treatment alone. Lastly, using ChIP-sequencing, we show that the combined action of HDACi application and conditioning is required to elicit enhancer histone acetylation in pathways that may underlie improved memory performance. Together, our results indicate that systemic HDACi administration amplifies brain-region specific processes that are naturally induced by learning. These findings shed light onto the mode of action of HDACis as cognitive enhancers. Significance StatementMemory formation relies on a plethora of functions, including epigenetic modifications. Over the past years, multiple studies have indicated the potential of HDAC inhibitors (HDACi) to act as cognitive enhancers, but their mode of action is not fully understood. Here, we tested whether HDACi treatment improves memory formation via "cognitive epigenetic priming", stipulating that HDACis - without inherent target specificity - specifically enhance plasticity-related processes. We found that combining HDACi with fear learning, but not either treatment alone, enhances synaptic plasticity as well as memory-promoting transcriptional signaling in the hippocampus, a brain area known to be recruited by fear learning, but not in others. These results lend experimental support to the theory of "cognitive epigenetic priming".

neuroscience↗