Neurons are highly elongated cells in the brain that must survive and function for a lifetime. To keep these complex cells healthy, proteins must be continuously supplied to their furthest extensions, which is a massive logistical challenge. Instead of shipping finished proteins all the way from the cell body, neurons transport the genetic blueprints (mRNAs) directly to where they are needed. However, how these traveling mRNAs know exactly where to stop and where local protein production is activated remains a mystery.
Her project investigates the new concept that local protein production is managed at specific control hubs where the cell’s transport system and protein factories converge. Using live-cell imaging, proximity proteomics and RNA sequencing, Tabitha will study these dynamic cellular interactions in real time to understand how these hubs function.
While driven by a fundamental curiosity about healthy brain cells, this work also holds important clues for understanding disease. Disruptions in mRNA transport and protein production are central events in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). By uncovering the cellular changes that lead to ALS, she hopes to lay an essential scientific foundation for future therapeutic strategies.
Tabitha is a PostDoc in the group of Max Koppers at FGA. More information on this VENI project can be found on: J. Tabitha Hees receives Veni grant for research on brain cells and ALS – Vrije Universiteit Amsterdam.

Postdocs Miodrag Mitrić and Sanne Beerens, in collaboration with PhD student Panthea Nemat and other members of the teams of Michel van den Oever and Priyanka Rao, genetically labelled cortical engram neurons in mice that were fear conditioned with 1 or 3 foot-shocks (1US – mild threat vs. 3US – strong threat, respectively) and compared them with mice that did not receive foot-shocks during conditioning. First, they found that cortical engram neurons are functionally involved in remote memory expression only after mild conditioning. Next, in a set of electrophysiological recordings and structural analyses of engram versus non-engram neurons, they observed that after mild, but not strong, conditioning, cortical engram neurons show a time-dependent increase in the density of long thin spines on their oblique dendrites, aligning with the selective causal contribution of these neurons to retrieval of a mild threat memory.

Together, this demonstrates that synaptic adaptations in cortical engram cells exhibit three key characteristics: they depend on (1) threat intensity, (2) the passage of time, and (3) develop in a dendritic segment-specific manner. As such, these findings provide strong support for (1) the functional engagement of cortical engram cells in expression of a mild threat memory, (2) their contribution to remote, but not recent, memory expression, and (3) increased potential for enhanced connectivity with afferents innervating oblique dendrites of these memory-encoding cortical neurons.

The image above shows examples of 3D reconstructions of dendrites and spines of engram (tdTom+) and non-engram (tdTom-) neurons.

Source: Threat intensity shapes cortical engram architecture supporting remote memory retrieval. Nature Commun 2026 Jun 11. DOI: 10.1038/s41467-026-74231-5

Memories are thought to be stored in specific brain cells that strengthen their synaptic connections during learning. But while these connections must remain stable for memories to persist, the proteins that make up synapses are constantly replaced. Janina will investigate how the brain resolves this apparent paradox.

Her project focuses on whether epigenetic mechanisms, which regulate gene activity, help memory-encoding neurons maintain stable synaptic changes over time. To address this, she will combine imaging of memory-encoding cells with molecular analyses of their nuclei and synapses.

Beyond its fundamental neuroscience relevance, this work may also help explain what goes wrong in disorders involving altered memory persistence, such as traumatic memories in PTSD or memory decline in Alzheimer’s disease.

Janina is a postdoc in the Molecular Engrams team of Priyanka Rao and Memory Circuits team of Michel van den Oever (collaborative Brainscapes project).

A small population of hippocampal neurons, known as engram cells, is activated during learning and is responsible for memory formation. While it is known that enhanced synaptic connectivity onto these cells supports memory storage and recall, the molecular composition of these specific synapses has remained largely unexplored due to their sparse distribution.

In this collaborative study, published in Science Advances, first author Biswajit Moharana, together with colleagues from the MCN, Complex Trait Genetics (CTG), and the MCCF core facility (Amsterdam UMC–Location VUmc), generated a comprehensive proteomic dataset of hippocampal engram cell synapses 72 h after learning occurs. Their findings shed new light on how aversive and neutral contextual memories are uniquely represented at the synaptic level during memory maintenance.

By combining in vivo circuit-specific labeling of engram cell synapses, sorting to enrich this synaptic sub-population, and highly sensitive mass spectrometry, the authors identified how these synapses adapt their protein composition in parallel with the strengthening of structural and physiological connectivity. In addition, they identified distinct protein expression signatures that dominate when contextual memories are more salient through negative valence, suggesting molecular features associated with memory strength and emotional modulation. Notably, this differential engram cell synapse proteome also showed an enrichment for genes linked to human cognitive phenotypes and related disorders.

By capturing these protein-level shifts, this dataset provides a crucial, hypothesis-generating resource for the research community. It opens up new avenues to investigate the molecular basis of memory, offering a clearer picture of how distinct experiences alter the synapses that encode them.

Image: Left: labelled hippocampal memory engram cells (red) and their synapses (yellow). Right: Sunburst plot detailing the localization of engram cell synaptic proteins by sub-compartment.

Source: GRASPing experience-dependent protein expression signatures enriched for hippocampal engram cell synapses. Sci Adv. 2026 May 15;12(20):eadv3557. doi: 10.1126/sciadv.adv3557

A new study, led by Laura Supiot in collaboration with Danai Riga (FGA, CNCR), Rogier Poorthuis and Frank Meye (UMC Utrecht), elucidated how stress promotes overeating by reshaping a specific neural network. Published in Nature Communications, the findings reveal that stress alters a multi-branched circuit running from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LHA). These results open up important new avenues for understanding and potentially treating stress-induced eating behaviours.

How stress flips the switch on fat intake

The LHA is a well-known hub for feeding, but how stress hijacks this system has remained unclear. Using in-vivo electrophysiological recordings and advanced circuit dissection and manipulation techniques the researchers first demonstrated that direct stimulation of this mPFC-LHA pathway increases fat intake. However, in the context of stress-induced fat intake, the circuit behaves differently. The team found that stress leads to a weakening of mPFC inputs onto LHA glutamatergic neurons. Crucially, they discovered that inhibiting these LHA glutamatergic neurons during stress completely prevents the binge eating response.

Opposing forces bias the brain toward binging

Importantly, the study reveals that these stress-induced changes are not uniform across the glutamatergic population in the LHA. Instead, stress modulates the mPFC-LHA glutamatergic connection depending strictly on their downstream target areas: VTA-projecting LHA glutamatergic neurons are strengthened, consistent with their role in promoting food intake; peri-PVN-projecting LHA glutamatergic neurons, which are known to reduce food intake, are weakened. These opposing forms of plasticity ultimately bias the entire circuit toward increased food intake after stress.

Overall, this work identifies a complex, multi-branched mPFC-LHA network that is indispensable for stress-induced eating, highlighting a precise circuit-level mechanism for how the brain responds to adversity by altering dietary habits.

 

Image from Supiot et al., Nat Commun 17, 4620 (2026). https://doi.org/10.1038/s41467-026-71073-z Stress-recruited mPFC neurons project to the lateral hypothalamus. Viral targeting and optogenetic manipulation of this neuronal ensemble leads to overconsumption of palatable food, mimicking the effects of stress on feeding behaviors. 

The funded projects address several complementary therapeutic strategies. Ruud Wijdeven (Candidate center) and Iwan de Esch (VU AIMMS) focus on compounds that may block the cellular uptake of toxic APOE4, a major genetic risk factor for Alzheimer’s disease. Iwan de Esch (VU AIMMS) and Wiep Scheper (Molecular Neurodegeneration group) are working on dual inhibition of PDE4 and PDE7, with the aim of combining anti-inflammatory and cognition-supporting effects in a single therapeutic strategy. Rik van der Kant (Dementia Discovery group) is investigating whether existing drugs can reduce fibronectin levels and help protect the blood–brain barrier in APOE4 carriers.

Outside of the CNCR, a fourth collaborative project between Rob Leurs (VU AIMMS) and Elga de Vries (Amsterdam UMC, MCBI) investigates ACKR3 as a target to reduce harmful immune cell entry into the brain and limit neuroinflammation.

The awarded projects highlight the urgency for development of novel and more effective therapies for AD, and the need for cross-disciplinary approaches spanning both chemistry and biology to develop such therapies.

The HypoGluTx project centers on disorders associated with genes including GRIN2B, SHANK3, STXBP1, and CACNG2, which converge on disrupted glutamatergic neurotransmission. By targeting this shared biological mechanism, the consortium aims to identify scalable treatment strategies across genetically distinct conditions.

Neurospector contributes its platform of human iPSC-derived neuronal models and high-content functional readouts to evaluate compound efficacy in a clinically relevant context. The project will assess both established compounds and new candidates identified through data-driven approaches, prioritizing molecules with known safety profiles to enable rapid translation.

“We see this as a step toward a new generation of precision therapies, where shared biology across rare disorders can unlock broader impact for patients,” says Claudia Persoon, Head of Neurospector.

This collaboration highlights Neurospector’s role as a translational partner in bridging discovery science and preclinical drug development, supporting the generation of IND-ready data packages for rare neurological indications.

SNAREopathies are a group of recently recognized rare neurodevelopmental disorders caused by mutations in eight genes that together drive secretion of chemical signals in the brain. Within 20 years, SNAREopathy incidence rose from zero to one of the most prevalent rare diseases to date (1:30k), producing a phenomenal unmet need.

The iSNARE consortium aims to change this situation by combining cellular assays based on available IPSC-derived SNAREopathy patient neurons with in vivo assays using available SNAREopathy mouse models. These in vitro and in vivo assays are combined in a standardized, integrated framework to systematically test and compare candidate treatments in three phases of development:

(i) four small molecules currently tested off label in small patient cohorts (replication study)

(ii) 6-10 emerging candidates (small molecule, antisense oligonucleotides)

(iii) novel compounds designed de novo by iSNARE in silico modeling using validated SNARE protein templates.

This systematic, multi-level approach will produce a unique data set that quantitatively compares effectivity and potency of most candidate treatments currently on the radar and firmly establishes the most promising ones. The strong connection to national treatment sites in nine EU countries + Israel ensures their rapid dissemination to clinical practice. The standardized array of in vivo and in vitro assays developed here provides a valuable framework for the assessment of future candidate therapies.

The iSNARE consortium (3 female, 4 male partners, 6 countries) brings together some of the best-cited scientists in the SNARE field and human neuron pioneers with experienced SNAREopathy mouse model experts, in silico modelling experts and patient organizations in nine EU countries + Israel. Together, this complementary expertise and patient participation warrant a project design that exploits the most recent scientific advances to promote new therapy development that maximally serves the patients’ needs.