Johannes Gräff

École Polytechnique Fédérale de Lausanne

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José V. Sánchez‐Mut

Instituto de Neurociencias

Li‐Huei Tsai

Massachusetts Institute of Technology

Isabelle M. Mansuy

University of Zurich

Damien Rei

Institut Pasteur

Thorsten Ecke

Helios Hospital Bad Saarow

Roland Hake

St. Elisabeth-Hospital Bochum

Bianca A. Silva

Universidade Federal do Rio de Janeiro

Ralph M. Wirtz

St. Elisabeth-Hospital Bochum

Sebastian Eidt

St. Elisabeth-Hospital Bochum

Michael Waldner

St. Elisabeth-Hospital Bochum

Cooperative Institutions

École Polytechnique Fédérale de Lausanne

Massachusetts Institute of Technology

Harvard University

Howard Hughes Medical Institute

Heidelberg University

University of Zurich

University of Basel

Centre National de la Recherche Scientifique

University of Lausanne

Charité - Universitätsmedizin Berlin

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A novel pathway regulates memory and plasticity via SIRT1 and miR-134

Nature (2010)

Jun Gao Wen-Yuan Wang Yingwei Mao Johannes Gräff Ji‐Song Guan

Sirtuin 1

Mediator

10.1038/nature09271

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Citations (938)

A cortico-thalamic-hippocampal circuit for remote fear memory attenuation

Journal of Neural Transmission (2017)

Bianca A. Silva Michael Kintscher Ralf Schneggenburger Johannes Gräff

Source

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

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Nicolas Chiaruttini Carlo Castoldi Linda Maria Requie Carmen Camarena-Delgado B Bianco

Abstract 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.

Cytoarchitecture

10.1101/2024.09.06.611625

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Citations (2)

Pathological complete response and potential for bladder preservation by theranostic instillation therapy targeting CXCR4 in combination with systemic chemotherapy: The Bladder BRIDGister experience.

Journal of Clinical Oncology (2025)

Ralph M. Wirtz Enno Storz Melanie von Brandenstein Frank Friedersdorff Dimitri Barski

691 Background: Patients with muscle invasive urothelial carcinoma (MIBC) achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NACT) have improved prognosis. Previously we did show that luminal tumors respond better to NACT (Ecke et al 2022), while chemoresistant tumors express radioligand targets CXCR4 and FAP. First-in-Human treatment of chemotherapy resistant T4 MIBC using two cycles of Lu 177 FAP combined with one cycle of pembrolizumab results in durable complete response (Baum et al, submitted). The objective of this study was to eradicate treatment naïve T2a MIBC with limited probability to respond to chemotherapy by adding intravesical Lu 177 CXCR4 instillation into the bladder before first NACT cycle to justify subsequent adopted clinical trials. Methods: A reference cohort (n=100) for subtype classification was constructed. RNA from FFPE tissues was extracted, relative gene expression of luminal and non-luminal target were analyzed by RT-qPCR. FFPE tissue from initial TURB of MIBC patients under evaluation for subsequent therapy were analyzed accordingly and individual target mRNA were added to the cluster analysis to determine subtype and target expression level. PET/CT Imaging by Ga 68 CXCR4 was performed in selected patients. In case of tumor specific, high uptake subsequent Lu 177 CXCR4 was instilled one week before initiation of ddMVAC. Response was evaluated by Ga 68 CXCR4 PET/CT and control resections by TURB. Results: A luminal pT2 G3 MIBC patient with elevated CXCR4 expression level by RT-qPCR and validated by immunohistochemistry, who was predicted to be unresponsive to NACT, was selected for CXCR4 instillation therapy. Subsequent Ga 68 CXCR4 whole body PET/CT proved tumor specific uptake and excluded nodal involvement as well as distant metastasis. Thereafter 4GB Lu 177 CXCR4 was applied via catheter as intravesical Radio-Ligand-Therapy (iRLT) followed by three cycles ddMVAC. Thereafter a control Ga 68 CXCR4 was performed before starting the planned second cycle of iRLT and ddMVAC. Intravesical Ga 68 CXCR4 PET/CT revealed complete response, with no tumor uptake being visible anymore. TURB including muscle tissue revealed complete absence of malignancy with only inflammatory immune reaction being left after RLT based NACT. Conclusions: Combination of molecular in vitro diagnostics identifies high risk MIBC with elevated CXCR4 target gene expression, that exhibit high radioligand uptake in vivo and are amenable for intensified treatment by adding iRLT to systemic ddMVAC treatment. First clinical results are promising and justify clinical approaches as part of phase 1 / 2 clinical trials within the Bladder BRIDGister study group with the ultimate goal of bladder preservation after pCR to neoadjuvant combination therapies.

Systemic therapy

10.1200/jco.2025.43.5_suppl.691

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An epigenetic blockade of cognitive functions in the neurodegenerating brain

Nature (2012)

Johannes Gräff Damien Rei Ji‐Song Guan Wenyuan Wang Jinsoo Seo

Histone deacetylase inhibitor

Histone deacetylase 5

HDAC10

HDAC11

HDAC4

10.1038/nature10849

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Citations (774)

A modular toolbox for the optogenetic deactivation of transcription

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Philipp Muench Matteo Fiumara Nicholas Southern Davide Martino Coda Sabine Aschenbrenner

Abstract 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 ( l ight o ff- o perated m odular in ductor of transcriptional a ctivation), 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.

Transcription

Synthetic Biology

Toolbox

10.1101/2023.11.06.565805

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Citations (1)

A thalamo-amygdalar circuit underlying the extinction of remote fear memories

Nature Neuroscience (2021)

Bianca A. Silva Simone Astori Allison M. Burns Hendrik Heiser Lukas van den Heuvel

Extinction (optical mineralogy)

Basolateral amygdala

10.1038/s41593-021-00856-y

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Citations (65)

Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation

Nature Communications (2012)

Johannes Gräff Bisrat T. Woldemichael Dominik Berchtold Grégoire Dewarrat Isabelle M. Mansuy

Neuroanatomy of memory

10.1038/ncomms1997

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Citations (111)

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

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Lucie Dixsaut Johannes Gräff

Abstract 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.

Engram

Infralimbic cortex

Consolidation

Neuroanatomy of memory

10.1101/2022.03.16.484644

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Citations (1)

Protein phosphatase 1-dependent transcriptional programs for long-term memory and plasticity

Learning & Memory (2010)

Johannes Gräff Kyoko Koshibu Anne Jouvenceau P. Dutar Isabelle M. Mansuy

Gene transcription is essential for the establishment and the maintenance of long-term memory (LTM) and for long-lasting forms of synaptic plasticity. The molecular mechanisms that control gene transcription in neuronal cells are complex and recruit multiple signaling pathways in the cytoplasm and the nucleus. Protein kinases (PKs) and phosphatases (PPs) are important players in these mechanisms. Protein serine/threonine phosphatase 1 (PP1), in particular, was recently shown to be important for transcription-dependent memory by regulating chromatin remodeling. However, the impact of PP1 on gene transcription in adult neurons remains not fully delineated. Here, we demonstrate that the nuclear pool of PP1 is associated with transcriptional events involving molecular components of signaling cascades acting as positive and negative regulators of memory and brain plasticity. The data show that inhibiting this pool selectively in forebrain neurons improves memory performance, enhances long-term potentiation (LTP), and modulates gene transcription. These findings highlight an important role for PP1 in the regulation of gene transcription in LTM and synaptic plasticity in the adult brain.

Protein phosphatase 1

Forebrain

Long-term memory

10.1101/lm.1766510

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Citations (55)