Outreach and Awards Foundation BrainAid/IZN Dissertation Award

2024

Janina Kupke (Oliveira lab)

Memories are more than just recollections of past events; they shape our personality and define who we are. The formation of memory begins at the tiny connections between neurons, called synapses, where activity triggers signals that travel all the way into the cell nucleus, altering gene expression and consequently neuron connections. A memory is stored in “engram neurons” that function like puzzle pieces; the more pieces flipped (engram neurons reactivated during the retrieval of a memory), the clearer the puzzle picture is (better memory). We know relatively well how a memory is formed, but we know very little how it is maintained for years. For example, you likely remember what you had for lunch, but in two weeks this will be forgotten. However, I bet you remember your prom night. Why do we form the memory of both, but only one memory persists? We know that the hippocampus is the main brain area crucial for forming and recalling early memories. Persistent memory storage however involves the neocortex and the information transfer from the hippocampus to the cortex.
I found that overexpressing an enzyme responsible for DNA methylation (Dnmt3a2) in the hippocampus of mice converted a short-lasting memory (e.g. lunch) to a persistent memory (prom night). Strikingly, this memory conversion did not affect the engram neurons (puzzle pieces) in the hippocampus. However, it facilitated the memory transfer from the hippocampus to the neocortex with better engram reactivation in the cortex (e.g. more puzzle pieces flipped to recognize the picture). This demonstrates a new function of epigenetic mechanisms and how modifying DNA methylation can cement memories over time.
Another focus was on how different DNA methyltransferase isoforms, Dnmt3a1 and Dnmt3a2, affect memory. While both are crucial, they operate through a distinct transcriptional programme. I uncovered a new protein with previous unknown function for memory: Neuropilin 1 – a downstream target of Dnmt3a1 but not Dnmt3a2. This highlights the potential for targeting isoform-specific pathways for therapeutic interventions.
Lastly, not all memories are helpful; some can lead to unwanted behaviours, e.g. too high fear that leads to be un-adaptable and un-functioning. I discovered that a protein called Npas4 helps the brain dial down certain memories. It responds to the intensity of situations, particularly fearful ones, and its levels adjust to help suppress the memory, aiding in behavioural flexibility. This could be key in preventing disorders where people are haunted by intense, unwanted memories.
My research has significantly advanced our understanding of the molecular and cellular mechanisms involved in memory formation, persistence, and suppression, paving the way for innovative therapies that enhance memory function and cognitive flexibility.

2023

Jose Ricardo da Cruz Vieira (Ruiz de Almodóvar lab)

The generation of a single organism requires the precise construction of multiple systems, all inter-connected and functionally driven by the unique characteristics and functions developed by every single cell. And, for every cell to successfully accomplish its task, it requires to be in a constant conversation with all the neighboring cells. This is indispensable for achieving a precise development and homeostasis program. In my PhD thesis, I focused on understanding how two important systems, the central nervous system and the vascular system, communicate during embryonic development and pathology.
During embryonic development, just like in a carefully choreographed dance, neurons and vessels need to coordinate well to prevent that they get in each other’s way. In my thesis, I present a new mechanism specifically used by motor neurons to coordinate their dance with vessels. Motor neurons inform the vessels that it is their turn to grow and develop by releasing into their surroundings a protein called semaphorin 3C (Sema3C), acting like a stop message. This signal reaches the vascular cells by binding to a receptor (acting like an ‘ear’ to hear the signal) called PlexinD1, making vessels to not overstep into the motor neurons area. When we block this message by stopping the production of Sema3C in neurons or we remove the receptor PlexinD1 in vascular cells, vessels do not ‘hear’ that they should stop and start growing into the territory that should be occupied only by neurons, disturbing motor neurons and their development, and affecting their function.
In the second part of my thesis, I show that the neurovascular unit, and in particular ECs, is involved in the development of chronic pain. I found that the blood vessels are not completely tight in two different pain models, allowing toxic molecules or immune cells to enter from the bloodstream into the spinal cord. Additionally, I identified a specific protein called Lrg1 to be excessively increased in several pain models, and that is a likely candidate contributing for chronic pain.
In summary, the work of my PhD thesis shows that neural-vascular cells communication is not only required to fine-tune embryonic development, but that it might also contribute for the development and maintenance of pain.

2022

David Brito (Oliveira lab)

We are what we remember. Without memories we are left with a void, living similar experiences over and over for the first time. This becomes clear in instances where memory is disrupted, such as during aging or memory-related disorders. Understanding the molecular mechanisms that orchestrate memory formation and persistency is therefore necessary to develop future therapeutic strategies. The capability of the brain to acquire and retain memories depends on specialized cells such as neurons that after learning, communicate using several strategies. Upon receiving new information at neuronal contact points, proteins transmit this information to the nucleus to induce gene expression. However, these processes are tightly controlled by several mechanisms such as modifications on signaling proteins (e.g., phosphorylation), or changes in gene products that ultimately affect protein expression required for memory. To date it is unclear what molecules control these diverse levels of regulation, that are essential for the formation and maintenance of memories over time.
The goal of my PhD thesis was to identify molecules that crucially regulate synapse-to-nucleus communication and gene expression required for memory formation and persistency. I identified three proteins that regulate these processes in the mouse brain. First, a DNA-damage-associated protein, whose expression levels are compromised during human and rodent aging and that is required for proper neuronal communication pathways, gene expression and memory. These findings suggest that compromised function of this protein during aging leads to memory defects. Second, I found a DNA methylation regulator that primes neurons for increasing gene function associated with neuronal structure, a mechanism possibly involved in the devastating neurodevelopmental disorder of Rett syndrome. Third, I identified an inducible transcription factor that when expressed accelerated memory decay. This finding expands our understanding on how memories that persist short periods (days) differ from long-lasting memories (months, years). Altogether, my PhD work allowed for a better understanding of the molecular basis for cognition and opened new therapeutic directions into targeting these molecules to ameliorate memory-associated disorders and aging.

2021

Jing Yan (Bading lab)

Neurodegenerative diseases are characterized as a progressive degeneration of the structure and function of neurons in the central or peripheral nervous system. Previous studies have shown that glutamate neurotoxicity is the crucial contributor to neuronal death in various neurodegenerative diseases, especially in Alzheimer’s disease, amyotrophic lateral sclerosis, and stroke. Although it is well known that glutamate neurotoxicity is mainly mediated by the extrasynaptically localized N-methyl-D-aspartate receptor (NMDAR), the molecular basis remains unclear. In the presented work, we have revealed the toxic signaling of extrasynaptic NMDARs in the central nervous system, which is depending on the physical interaction between NMDAR and the transient receptor potential cation channel subfamily M member 4 (TRPM4), a calcium-impermeable ion channel localized outside synapses. Extrasynaptic NMDARs and TRPM4 could form a death complex and result in neuronal death in neurodegenerative disease where glutamate levels are elevated. Based on this knowledge, we have developed NMDAR/TRPM4 interface inhibitors, which provide robust neuroprotection against NMDA-induced neuronal death in cultured neurons and ischemic stroke-induced brain damage in mice.
Our study has uncovered the molecular basis of NMDAR-dependent glutamate neurotoxicity. The new findings not only discovered why extrasynaptic NMDARs could promote cell death in the nervous system but also developed NMDAT/TRPM4 interface inhibitors, which could hold great potential as a novel therapeutic strategy to current untreatable neurodegenerative disease.

2020

Jakob Wasserthal (Maier-Hein lab)

On a simplified level the human brain is made up of two parts: The gray matter containing all the neurons and the white matter containing the axons which connect the neurons. Using a special kind of MRI sequence called diffusion-weighted MRI it is possible to measure the orientation of these axonal pathways which are connecting the different brain areas. Those pathways are organized in different groups, with each of them having a specific function. One pathway for example is called the corticospinal tract. It is responsible for connecting the neurons which control your fingers, hands and arms with the spinal cord. If this pathway is damaged the patient will have impairments in controlling his hands for example.
When looking at a diffusion-weighted MRI image we want to know where those different pathways are located in the image. This can be done manually by a doctor, but it is quite time consuming. If you want to analyze the pathways of a few thousand patients doing it manually is not really feasible anymore. Therefore, people have started to develop automatic approaches to find those pathways in the MRI image. However, the accuracy of these approaches is often insufficient, they take very long to run and it is time consuming to correctly setup those algorithms.
In his dissertation Jakob Wasserthal developed a novel method which solves these problems. By taking a novel approach which has not been considered in this field before and by using the latest innovations from deep learning his algorithm manages to find major pathways in the human brain with high accuracy. Moreover, the method is fast to run and very easy to use. This makes it a lot easier for researchers and doctors around the world to analyze their MRI images. Jakob Wasserthal made his method publicly available as a software library and is already seeing a major impact of his work: His software is already being used by over 50 research institutions from all over the world, including several of the leading research labs in the field of neuroimaging (University of Oxford, Harvard University, MIT, Charité, …).