Personal profile

Research interests

Neurons are specialised cells in our body that have long extensions allowing them to form connections (called synapses) with other neurons, leading to the establishment of neural circuits. The main function of neural circuits is to conduct signals that coordinate our bodily functions, thoughts, sensations, and perceptions of the world. Overall, neural circuit function and ultimately behaviour depend on the precise formation of synaptic connections. Hence, changes in the way neurons are wired during development can lead to neurodevelopmental disorders such as autism spectrum disorder, intellectual disability, and Schizophrenia. Moreover, failure to properly maintain synapses throughout life often results in neurodegenerative conditions such as Alzheimer’s and motor neuron disease.

The human brain contains approximately 86 billion neurons and a 1,000 trillion synapses. This indicates the staggering complexity in the way neuron wiring is established during development. To understand the development of a functional nervous system, our lab uses zebrafish as a vertebrate genetic model system. We are interested in elucidating fundamental molecular and cellular mechanisms that are essential for neural circuit formation during developmental periods, how neural connections are maintained throughout life, and how such processes are mis-regulated in certain neurological disease conditions. Current rojects available in our group include:

(i) Linking neuronal structure with function.

(ii) regulation of local RNA processing in neurons.

(ii) generating zebrafish models for neurological diseases.

Linking neuronal structure with function:

Neural circuit function and ultimately animal behaviour depend on the precise formation of synaptic connections in the brain. One of the main aims of research in our group is focused on understanding how neuronal structure relates to neuronal function. Previous findings have shown that the laminar organisation of synaptic connections in the optic tectum (which are affected in a zebrafish robo2 null allele) is indispensable for the correct wiring of visual circuits, however it is essential for the rapid assembly of neural networks (Nikolaou et. al., 2015). This suggests that neuronal structure is key to brain function. Several single-cell RNA sequencing results published by other groups revealed several genes that are uniquely expressed by neuronal subtypes. We are currently using this knowledge and through molecular genetic approaches widely used in my lab (e.g., transgenesis, CRISPR/Cas9 knock-in) we label identifiable classes of neurons and determine their structure, connectivity patterns, neurotransmitter phenotype, functional resposne properties, and contribution to behaviour. 

Regulation of local RNA processing in neurons:

In neurons, RNAs localise to axons, dendrites and synapses (collectively known as neurites), where they facilitate rapid responses to local needs, such as axon growth/extension, branching, synapse formation, and synaptic plasticity. Recent studies have uncovered a diverse range of coding and non-coding RNAs localised within neuronal projections and shown that alterations in their abundance can exert an influence in local decisions. RNA binding proteins (RBPs) mediate the vast majority of RNA trafficking and processing both in the nucleus and the cytoplasm. Whereas the protein-protein and RNA-protein Interactions of RBPs in the nucleus are well-characterised, the function of analogous interactions in neurites remains elusive. We have recently shown that U1-70K/SNRNP70, a major RNA splicing regulator, localises to ribonucleoprotein complexes inside axons and regulates the establishment of neuromuscular synaptogenesis (Nikolaou et al., 2022). We are hypothesising that the cytoplasmic/axonal pool of SNRNP70 modulates the axonal transcriptome through one or more of the following mechanisms: RNA trafficking, stability and degradation, translational repression, and local processing. Using imaging and molecular genetic techniques in zebrafish, my group has recently established knock-in and transgenic lines, which are enabling us to image the intricate relations between SNRNP70 and its axonal RNA targets in vivo. We currently have funding from the Academy of Medical Sciences to determine the protein-protein interactions mediating the axonal functions of SNRNP70. Moreover, we recently obtain a BBSRC grant (starts in autumn 2024) to explore the molecular mechanisms by which SNRNP70 regulates the axonal transcriptome. 

Many RBPs, including RNA splicing regulators, have been shown to form insoluble cytoplasmic aggregates, which interfere with the function of the neuron eventually leading to synapse loss and degeneration. We and other groups have shown that many splicing regulators localise to the nucleus and neurites in a bimodal fashion and many of these have been found to aggregate in neurodegenerative diseases e.g., Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS). Another line of research in our lab focuses on understanding how these disease-causing aggregates interfere with the function of these proteins not only in the nucleus but also locally within neurites, and what role they play in the breakdown of neurons.

Understanding and treating neurological diseases:

Many genes linked to neurological diseases such as neurodevelopmental disorders and neurodegeneration have been shown to be important for neuronal development. As a first step in understanding human disease, we determine the physiological function of disease-related genes in the nervous system. Subsequent studies are focused on known candidate risk human mutant variants. Our group has expertise in generating transgenic animals as well as CRISPR/Cas9 knock-out and knock-in lines. Phenotypic characterisations include assessments of mRNA and/or protein levels and distribution of proteins within tissues at cellular and subcellular level. Genetically encoded calcium reporters and light-sheet microscopy are used to record neuronal activity in the entire larval brain and generate network activity maps to compare with control neural networks. In parallel, animal behaviour is investigated to examine the functional outputs of the nervous system.

We currently have funding from the Bath Alumni Fund and Royal Society to generate zebrafish epilepsy genetic models. It is estimated that more than half of childhood epilepsies are due to genetic aetiologies. Seizures are difficult to control, and medications e.g. anticonvulsant drugs are mostly focused on reducing their effect. This project aims to identify better treatments for childhood epilepsies. Currently, only few in vivo models for epilepsy are available and most of these are mouse genetic models, which are not suitable for high-throughput drug screening. We are using zebrafish (the least sentient vertebrate animal model with high level of conservation of anatomical and physiological brain connectivity that is translatable to humans) to establish genetic models of mutations known to cause childhood epilepsies. A major advantage of using zebrafish is that the system is amenable to large-scale small molecule screening, once a disease model is established. 

Broad technical expertise in our lab:

- Genetic alterations using CRISPR/Cas9 and transgenesis techniques

- Grafting/transplantation of cells or tissues

- Transcriptome profiling of cells

- Live imaging of cell behaviour and function in vivo

- Behaviour analysis to study circuit function

- Primary neuron cultures  

Willing to supervise doctoral students

We are always open to students interested in neuronal development and connectivity. PhD funded projects in the lab will appear here when become available. Postdocs interested in joining our lab are also welcomed. If interested, please contact me well in advance for an informal discussion.

Teaching interests

Nikolas Nikolaou's education role spans across undergraduate (UG) and postgraduate (PG) degrees. He delivers lectures on Developmental Genetics, Developmental Biology, Molecular and Celluar Neuroscience, and Developmental Neurobiology to UG students in Biomedical Sciences, Biochemistry, Biology, and Natural Science course programmes. He also teaches Neuroscience to PG students in the department. He supervises final year UG and offers MSc lab projects. He supervises on average 2 PhD students working in his lab. He is also a personal tutor, supporting directly 20-30 students each year.

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Education/Academic qualification

Fellow of the Higher Education Academy

Award Date: 20 Jul 2022

Developmental Neurobiology, Postdoctoral research associate, King's College London

20092019

Anatomy and Developmental Biology, Doctor of Philosophy, University College London

20042008

Biology, Bachelor of Science, University of Crete

19992003

Keywords

  • Zebrafish
  • Neurobiology
  • Axon guidance
  • Neural circuit formation
  • Synapse formation
  • Neural network activity
  • Local RNA processing
  • Brain development
  • Neurodevelopmental disorders
  • Neurodegeneration

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