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

Allison Marie Burns, Johannes Gräff, Jose Vicente Sanchez Mut, Giulia Santoni

Long-term memory formation relies on synaptic plasticity, neuronal activity-dependent gene 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 HDACi, 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 fear learning. Furthermore, using a combination of bulk and single-cell RNA-sequencing, we find that, when paired with CFC, HDACi treatment engages synaptic plasticity-promoting gene expression more strongly in the hippocampus, specifically in the dentate gyrus (DG). Finally, using chromatin immunoprecipitation-sequencing (ChIP-seq) of DG neurons, we show that the combined action of HDACi application and conditioning is required to elicit enhancer histone acetylation in pathways that underlie improved memory performance. Together, these results indicate that systemic HDACi administration amplifies brain region-specific processes that are naturally induced by learning.

2022

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

Lucie Pauline Dixsaut, Johannes Gräff

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 toward 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 in male mice 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, these data identify a spatiotemporal shift in PL inputs important for early memory consolidation, and thereby help to refine the working model of memory formation.

2022

Where does the engram come from? Study of prefrontal cortex inputs during memory consolidation

Lucie Pauline Dixsaut

The formation and storage of memories has been under deep investigation for several decades. Nevertheless, the precise contribution of each brain region involved in this process and the interplay between them across memory consolidation is still largely debated. Although memory encoding requires the hippocampus (HPC), it is becoming apparent that other brain regions are also important in early phases of memory formation, such as the medial prefrontal cortex (mPFC). In addition, engram cells have been found in the mPFC at memory encoding: these cells represent a close approximation of the "memory trace" insofar as they are activated at the time of learning, as they undergo enduring molecular modifications after learning, and as their reactivation drives memory recall. In contrast to HPC engram cells, mPFC engram cells are thought to be kept silent during a recent recall and until the memory is fully consolidated, becoming active only at remote recall. To explain the dynamics of these mPFC engram cells, we hypothesized that inputs to the mPFC could be differentially activated over the course of memory consolidation.We first determined that the prelimbic cortex (PL), a subregion of the mPFC, was specifically activated during the encoding phase of a fear memory in mice by measuring the expression of the Immediate Early Gene cFos, transcribed upon neuronal activation. We then traced the inputs of PL cells that were active during encoding, the putative PL engram cells, in order screen for relevant connections for further investigations. To achieve this, we used an activity-dependent monosynaptic retrograde tracing method based on rabies tracing. Then, to determine the activation patterns of these specific PL inputs, we measured their activity throughout consolidation of a contextual fear memory using an unbiased retrograde tracer coupled with cFos immunostaining. We further tested their functional relevance by chemogenetically inhibiting these projections during the different learning phases. This approach confirmed the roles of the Entorhinal Cortex and the Basolateral Amygdala inputs during the encoding phase of a fear memory to later recall remote memories. In addition, we found that the Claustrum (CLA) to PL projection was also required during the encoding phase, but to recall recent memories specifically. Moreover, the Insular Cortex (INS) to PL projection was necessary during recent recall. Eventually, we observed that the CLA and INS manipulations led to a modification of PL engram cells reactivation during recent recall.Overall, our results suggest that there is a functional shift in PL inputs during the course of memory consolidation, which is also impacting how PL engram cells are reactivated. In addition, we observed that the activity of PL inputs is part of a broader brain network, both through the presence of axon collaterals targeting other brain regions and by the existence of parallel and perhaps redundant pathways that could ensure efficient memory consolidation.Collectively, our data help to further refine the working model of memory formation by deciphering the interplay between brain regions during the process of systems consolidation of a fear memory, and open several questions for future investigations.

EPFL2022

Where does the engram come from? Study of prefrontal cortex inputs during memory consolidation

Lucie Pauline Dixsaut

EPFL2022