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Neuroscientist Prof. UrtÄ— NeniÅ¡kytÄ— from ÃÛ¶¹ÊÓƵ Life Sciences Center (VU LSC) has secured the full €2 million available through the European Research Council (ERC) Consolidator Grant scheme for her research project ‘Sugars Maketh the Brain: Investigating the Role of Neuronal Glycocalyx in Shaping the Architecture of Emerging Circuits (GlycoCirc)’. The project will explore how sugar structures known as glycocalyx, which are found on the surface of brain cells, contribute to the formation of neural networks, influence brain development, and may help explain what makes the human brain unique.

The overlooked sugar coating the brain

‘The GlycoCirc project looks at the sugary surface molecules, trying to understand how they guide synapse formation between neurons and how they mediate interaction between neurons and other brain cells, such as microglia or astrocytes. These molecules, known as glycocalyx, form a sugar-rich layer on the cell surface. They were largely neglected in neuroscience for decades,’ says Prof. Neniškytė.

According to her, these molecules resemble tiny ‘sugar trees’ covering the surface of brain cells. On neurons, the glycocalyx can span up to a micrometre in thickness, forming a barrier and acting as the first point of contact between a neuron and its surroundings, whether that’s another neuron or a nearby glial cell.

The Professor believes this layer plays a vital role in early brain development: ‘I strongly believe that the glycocalyx-mediated interactions are critical when new synapses are being established or when unnecessary synapses are being pruned in the developing brain, and I would like to look at this in more detail.’

A human signature written in sugar

She points out that the glycocalyx might hold clues to what makes human brains special: ‘If we look at the composition of our glycocalyx, it is important to note that it is unique to humans. We can detect differences even when compared with the closest of our relatives, bonobo chimps. Interestingly, the emergence of these human-specific genetic modifications coincides with the time when we see the accelerated development of the human brain, which indicates that these processes can be related to each other.’

Now, with the ERC funding, Prof. Neniškytė’s team will be able to pursue further research on these ideas using a wide array of advanced methods.

‘I’m really excited now to take an in-depth look into these glycocalyx effects on neuronal networks, combining the techniques that span from neurophysiology-focused methods, such as recording and imaging neuronal activity, and combining it with biochemical approaches – understanding the composition of the glycocalyx and how it changes during the development, as well as how it differs between species. I believe that these insights can reveal the distinct features of the human brain and, overall, help us understand the uniqueness of humans as a species,’ states the neuroscientist.

Stem cells and the brain

To understand what makes the human brain unique, Prof. Neniškytė’s team uses a comparative approach based on induced pluripotent stem cells (iPSCs) derived from humans and non-human primates.

The researcher explains that while conducting this type of research on living humans or non-human primates would be ethically unacceptable, iPSCs offer a powerful and sustainable alternative. These cells can be derived from minimally invasive sources such as skin biopsies or blood samples and then developed into various types of brain cells, including neurons, microglia, and astrocytes. This approach enables researchers to model complex cellular interactions in the lab, essentially creating miniature, brain-like systems from cells that regain the capacity to become any cell type in the body.

Furthermore, iPSC technology could be used in the future to explore how the deficits in glycocalyx pathways contribute to neurological disorders. Prof. Neniškytė emphasises that most conditions related to disturbed glycocalyx turnover present with a pronounced neurological phenotype.

‘Sometimes patients have only mild peripheral symptoms, but they show severe neurodegeneration and neuroinflammation. My lab has already observed specific changes in the glycocalyx and its modulating enzymes in human epilepsy tissue. It seems that the composition of the glycocalyx defines neuronal excitability in both ways. For example, with some changes, you get epileptic bursts, while others don’t allow neurons to transmit signals effectively,’ says the neuroscientist.

Advancing neurobiology through global collaboration and local excellence

In addition to enabling new technologies, the ERC funding allows Prof. Neniškytė’s team to expand their expertise and attract top researchers from around the world. While it was not the case that these technologies were entirely out of reach in Lithuania, the primary limitations concerned access to advanced equipment and the availability of specialised knowledge.

‘The major qualitative impact on the research my group performs comes from the added value of the ERC grant. I hope it will help us to attract competent researchers who are the hands and the brains of the projects implemented in the lab,’ observes the ERC grantee.

She is now working on attracting two strong postdoctoral fellows – one with experience in induced pluripotent stem cells biology and another with a strong background in multi-electrode arrays; this will enable her team to investigate the activity of neurons by conducting highly detailed analysis.

The Professor sees long-term benefits in bringing such expertise to Vilnius: ‘Attracting early career researchers who were trained in the best centres in Europe or beyond, and harnessing their expertise effectively, will definitely be very important for the implementation of the project. In addition, it introduces new competences into the lab that can support other ongoing projects and further strengthen ÃÛ¶¹ÊÓƵ Life Sciences Center as a whole.’