With approximately 2.5 million DKK each, the four researchers have optimal opportunities to realize specific projects aimed at strengthening Denmark's position in brain research.

The four young investigators are:

• Francisca Pinheiro, postdoc in Magnus Kjærgaard Lab
• Kristoffer Højgaard, postdoc in Tomonori Takeuchi Lab
• Silvia Turchetto, postdoc in Chao Sun Lab
• Audrey Andersen-Civil in Gilles Vanwalleghem Lab

Kristoffer Højgaard:
Developing a new toolkit for finding memory-proteins

When the brain needs to convert short-term memories into long-term memories, it relies on assistance from a specific group of proteins called plasticity-related proteins (PRPs). You can think of these proteins as “glue” for memories.

However, researchers still don't know enough about which protein is activated and how it precisely works concerning memory.

That's what Kristoffer aims to change during the next three years.

By using light and chemical-based methods, Kristoffer wants to create a new innovative toolkit that can help identify these specific proteins.

Unlike current methods, this combination allows for both high precision and speed in identifying and characterizing these specific proteins using freely moving rats undergoing memory tasks.

Moreover, using light and chemicals as a trigger the tools can relocate a particular type of protein from its usual active site within the cell to other locations in the cell.

Relocating the protein allows researchers to manipulate its activity in a controlled manner. By moving it away from its usual site of action, it can disrupt its normal function and observe the effects on memory formation. This manipulation is essential for understanding the protein's role and potential therapeutic targets for memory-related disorders.

To test the toolkit and its abilities, Kristoffer will start focusing on a specific protein called ARC, known to be one of the most important proteins in memory formation.

If Kristoffer succeeds in identifying the protein that plays a crucial role, it will not only shed light on the elusive mechanisms of memory consolidation but also potentially reveal new pharmacological targets to improve memory retention.

Moreover, the flexible and modular nature of these genetically encoded tools also opens the door for their use in broader biological applications beyond memory research.
 

Silvia Turchetto: 
Identifying new therapeutic opportunities for restoring synaptic health

Our brains are like small factories, and just like factories, there are different roles and functions needed to make processes work optimally and normally.

In the brain, this is called homeostasis.

Key players that help ensure that our brain develops, and functions well are the synapses – the connection and communications system between the cells.

Synapses function well due to a process called “ubiquitin signaling”. Ubiquitin's role in synapses is akin to that of a cellular cleanup crew, ensuring that proteins are managed properly so that our cells can function smoothly.

Thus, dysfunction in ubiquitin signaling can have detrimental consequences for the development and function of synapses, and can, in the worst case, cause disease.

One brain disease thought to be particularly related to dysregulated ubiquitin signaling is schizophrenia. This disease is associated with symptoms like hallucinations, delusions, and disorganized thinking and behaviour.

However, researchers do not yet know how faulty ubiquitin signaling affects the connections between brain cells, and importantly, how it is connected to the development of schizophrenia.

This is a problem because enzymes that regulate ubiquitin signaling are promising targets for rebalancing synaptic homeostasis and correcting synaptic pathology in schizophrenia.

Silvia's goal is to close this knowledge gap and potentially identify new therapeutic opportunities for restoring synaptic health in schizophrenia.

More specifically, she will investigate how ubiquitin signals affect the connections between brain cells and which specific tools in the brain are involved in these signals.

By targeting these tools, she hopes to fix the problems in the connections between brain cells that occur in schizophrenia. This research could lead to new treatments that specifically target these problems in the brain, helping people with schizophrenia feel better.

Francisca Pinheiro:
New method to target the hyperactive parts of the brain

Whenever we turn on the light, a TV, or our hairdryer, we depend on electricity. Electricity is like a flow of tiny particles called electrons moving through wires, providing power to our machines.

The brain works in the same way, though the processes are much more complex.

In our brain, excitatory synapses are responsible for transmitting or "exciting" a receiving neuron, making it more likely to send an electrical signal. They do this by releasing a chemical messenger called "glutamate."

When an excitatory synapse is activated, it stimulates the receiving neuron, making it more likely to generate an electrical impulse and pass on the signal to other neurons. This process is fundamental for many brain functions, including learning, memory, and sensory perception.

Just like an electrical system can become overloaded with too much current, excitatory synapses can become overstimulated, leading to excessive signalling between neurons.

Scientists have found that when an excitatory synapse gets overactive, it can lead to various brain diseases, making this component an attractive drug target for researchers through the years. However, there's a catch. Developing medicines that calm down these over-excited synapses includes the risk of affecting normal brain function.

This is what Francisca wants to delve more into by creating a specific mechanism that can directly target the hyperactive parts of the brain.

Specifically, she will design a so-called coiled-coil that will change shape when exposed to activated CAMKII, a biochemical feature of strong excitatory synapses. By testing this in primary neurons, she will be able to confirm if this change also occurs in a more physiological environment and hopefully open a new avenue for studying the pathogenic mechanisms underlying neurological disorders and, especially, for the development of drugs that target specific activity states of synapses.

Audrey Andersen-Civil:
Studying the gut-brain link in neurological disorders

Neurological conditions such as Alzheimer’s, Parkinson’s and autism have been linked to disruptions of intestinal homeostasis. However, the causal mechanisms and interactions between the gut and the brain are still largely unknown.

In this project, Audrey hypothesize that early-life imbalances in immune function and the gut microbiota may affect the development of the enteric nervous system (ENS) in models of neurodevelopmental disorders. The ENS, known as the “second brain”, plays a fundamental role in maintaining intestinal health, while impairments of the ENS may explain the high prevalence of gastrointestinal disorders observed in neurological conditions.

Studying the activity of the ENS and gut mucosal immune cells in vivo is challenged by its anatomical location within the intestinal tissues. However, using transparent zebrafish we are able to monitor immune cells and thousands of neuronal cells in vivo through e.g. fluorescence microscopy and calcium imaging. Experiments will be conducted using transgenic zebrafish lines and drug-induced models of ASD, which will be exposed to inflammatory stimuli with/without an established gut microbiota by deriving germ-free zebrafish larvae maintained in a sterile environment.

This will enable us to find causal mechanisms that will indicate a clear directional effect of a given treatment in our ASD models. In collaboration with a research group at the Karolinska Institute in Sweden, Audrey aims to unravel the cellular mechanisms and inter-relationships that will explain how the development of the ENS is regulated by the immune system and the gut microbiota within the context of neurological disorders.
 

Each postdoc has recieved an amount of up to 2,5 mio. DKK, which covers a three-year postdoc salary, equipment and project-related costs. 
 

• Read more about Lundbeck Foundation Postdoc Grant