Neural Development, Plasticity and Repair

Our work

Glial cell development and plasticity

Principal Investigator: Professor William D. Richardson, FLS, FMedSci FRS
ORCID iD: 0000-0001-7261-2485

Oligodendrocyte plasticity and its role in learning and memory. Pools of precursor/ stem cells persist in the adult CNS. 

Some inhabit the subventricular zones (SVZ) of the forebrain where they produce new neurons for the olfactory bulb throughout life. Others reside in the hippocampus and continuously generate new hippocampal interneurons in the adult. 

Another population of neural precursor cells - adult oligodendrocyte precursors (OLPs, also known as OPCs or NG2 glia) - is scattered uniformly throughout the adult brain and spinal cord. 

We showed that NG2 glia continue to divide and generate new myelin-forming oligodendrocytes throughout adulthood in mice. 

What is the physiological role of these late-born oligodendrocytes and the myelin they produce?

One important function of adult-born oligodendrocytes is to repair demyelinating damage following CNS injury or disease.

Our lab has shown that they also play a critical role in learning and memory formation in normal healthy mice. For example, production of new OLs is necessary for adult mice to learn new motor skills (e.g. running on a wheel with unevenly spaced rungs), or to improve their cognitive performance in a radial maze task that taxes working memory.

Working memory is a short-term, low-capacity memory system that is important for all sorts of mental tasks such as decision-making or problem solving. In humans, working memory is tightly correlated with measures of general or “fluid” intelligence. Thus, plasticity of OL lineage cells and myelin is central to learning, memory and cognitive performance.

Neuro-glia development and disease

Principal Investigator: Professor Nicoletta Kessaris
ORCiD ID: 0000-0003-1191-6009

Brain development commences in the embryo and continues well into postnatal stages as neurons and glia assume their final positions, before undergoing maturation, apoptosis, or maintaining a stem-cell-like state.

Disruptions to these developmental processes can give rise to brain disturbances and neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), which initiate early in life but become apparent during childhood.

Our laboratory is committed to unravelling the genetic underpinnings of forebrain neuron and glia development to understand how developmental abnormalities may contribute to NDDs.

We explore the impact of genetic mutations on the generation, specification, and maturation of neurons and glia in the forebrain, as well as the formation of cortical neuronal networks and behaviours associated with NDDs.

Employing model organisms, our research utilizes a diverse set of approaches, including in vivo loss- and gain-of-function genetic approaches, -omic technologies, electrophysiology, and behavioural analysis.

Our overarching goal is to decipher how genetics and the environment influence brain formation, ultimately shedding light on the origins and behavioural manifestations of ASD and NDDs.

Cellular and molecular neuroscience

Principal Investigator: Professor Huiliang Li
ORCiD ID: 0000-0002-8274-3785

The Central Nervous System (CNS) is made up of diverse types of neurons and glial cells. Glia (literally ‘glue’) have proven to be much more than a passive support matrix for neurons. In fact, mounting evidence indicates that glia are highly complex cells engaged in a plethora of brain activities.

Employing transgenic approaches, we aim to find answers to the following questions:

• How do Neural Stem Cells (NSCs) choose glial versus neuronal fate? 
• What are the molecular mechanisms behind gliogenesis?
• What are the causes and consequences of glial dysfunction?

We are also investigating the impact of cholesterol metabolism in both healthy and diseased brains. The brain is known to have a higher cholesterol concentration (15–20 mg/g tissue) than other tissues (2 mg/g tissue on average). Cholesterol is unable to cross intact blood brain barrier (BBB) and has its metabolic machinery to regulate homeostasis.

Our research interests include:

• The effects of disturbances in brain cholesterol homeostasis on autism spectrum disorder (ASD), Alzheimer’s disease (AD) and aged brains.
• The regulation of the gut-microbiota-brain axis on cholesterol metabolism in ASD, AD, and aged brains.
• The regulation of the liver-brain axis on cholesterol metabolism in ASD, AD, and aged brains.

Glial cells in neural circuits

Principal Investigator: Dr Matthew Swire
ORCiD ID: 0000-0003-4294-4926

In the vertebrate brain and spinal cord, cells called “oligodendrocytes” construct an insulating layer around “axons” - long filamentous extensions of “neurons”, the electrically excitable cells. This insulation, “myelin”, greatly speeds up the electrical signals sent by neurons as well as providing energetic support to neurons and their axons.

Recently it has been demonstrated that oligodendrocytes and the myelin that they make also help the brain to adapt to new experiences, contributing to learning and memory formation. How exactly myelin influences learning is still not well understood.

One hypothesis is that oligodendrocytes can sense the neurons that are activated by specific behaviours, resulting in the formation or remodelling of myelin on those active neurons. We predict that this process will fine-tune electrical signals and alter the connectivity of the active neurons leading to the development of new neuronal circuits responsible for new behaviours.

Using a range of transgenic mice, we aim to determine:

• How the myelin on activated neurons changes during learning
• The mechanisms that may enable oligodendrocytes to sense neuronal activity
• How changes to myelination alters neuronal connectivity.

The Neural Development, Repair and Plasticity group

Selected publications

1. Shimizu T, Nayar SG, Swire M, Jiang Y, Grist M, Kaller M, Sampaio Baptista C … Li H, Richardson WD (2023). Oligodendrocyte dynamics determine cognitive performance outcomes of working memory training in mice. Nat Commun, 14:6499.
2. Kessaris N and Denaxa M (2023). Cortical interneuron specification and diversification in the era of big data. Current Opinion in Neurobiology 80, 102703.
3. Wu S, Hu L, Fu Y, Chen Y, Hu Z, Li H, Liu Z (2023). Effects of Intestinal M Cells on Intestinal Barrier and Neuropathological Properties in an AD Mouse Model. Molecular Neurobiology.
4. Kessaris N (2022). Human cortical interneuron development unraveled. Science 375 (6579), 383-384.
5. Asgarian Z, Oliveira MG, Stryjewska A, Maragkos I, Rubin AN … Kessaris N (2022). MTG8 interacts with LHX6 to specify cortical interneuron subtype identity. Nature Communications 13 (1), 5217.
6. Magno L, Asgarian Z, Apanaviciute M, Milner Y, Bengoa-Vergniory N, Rubin AN, Kessaris N (2022). Fate mapping reveals mixed embryonic origin and unique developmental codes of mouse forebrain septal neurons. Communications Biology 5 (1), 1137.
7. Magno L, Asgarian Z, Pendolino V, Velona T, Mackintosh A … Kessaris N (2021). Transient developmental imbalance of cortical interneuron subtypes presages long-term changes in behavior. Cell Reports, 35 (11), 109249.
8. Zhang G-Y, Lv Z-M, Ma H-X, Chen Y, Yuan Y, Sun P-X … Li H, Li W (2021). Chemical approach to generating long-term self-renewing pMN progenitors from human embryonic stem cells. Journal of Molecular Cell Biology, Vol. 14, Issue 1.
9. Ju J, Yang X, Jiang J, Wang D, Zhang Y, Zhao X … Li H, Li N (2021). Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder. Frontiers in Cellular Neuroscience, 15.
10. Swire M, Assinck P, McNaughton PA, Lyons DA, Ffrench-Constant C, Livesey MR (2021). Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length. J Neurosci. 22;41(38):7954-7964.
11. An J, Zhang Y, Fudge AD, Lv H, Richardson W, Li H (2021). G protein-coupled receptor GPR37-like 1 regulates adult oligodendrocyte generation. Developmental Neurobiology 2021 Nov;81(8):975-984.
12. Asgarian Z, Magno L, Ktena N, Harris KD, Kessaris N (2019). Hippocampal CA1 somatostatin interneurons originate in the embryonic MGE/POA. Stem Cell Reports 13.
13. Swire M, Kotelevtsev Y, Webb DJ, Lyons DA, Ffrench-Constant C (2019). Endothelin signalling mediates experience-dependent myelination in the CNS. Elife 28;8:e49493.
14. Kasuga Y, Fudge AD, Zhang Y, Li H (2019). Characterization of a long noncoding RNA Pcdh17it as a novel marker for immature premyelinating oligodendrocytes. Glia. Nov;67(11):2166-2177.
15. Jolly S, Bazargani N, Quiroga AC, Pringle NP, Attwell D, Richardson WD, Li H (2018). G protein-coupled receptor 37-like 1 modulates astrocyte glutamate transporters and neuronal NMDA receptors and is neuroprotective in ischemia. Glia. Jan;66(1):47-61.
16. Xiao L, Ohayon D, McKenzie IA, Sinclair-Wilson A, Wright JL, Fudge AD, Emery B, Li H, Richardson WD (2016). Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning. Nat Neurosci, Sep;19(9):1210-1217.
17. McKenzie IA, Ohayon D, Li H, Paes de Faria J, Emery B, Tohyama K, Richardson WD (2014). Motor skill learning requires active central myelination. Science. Oct 17;346(6207): 318-22.
18. Young KM, Psachoulia K, Tripathi RB, Dunn S-J, Cossell L, Attwell D, Tohyama K, Richardson WD (2013). Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodelling. Neuron. Mar 6;77(5): 873-85.
19. Li H, de Faria JP, Andrew P, Nitarska J, Richardson WD (2011). Phosphorylation regulates OLIG2 cofactor choice and the motor neuron-oligodendrocyte fate switch. Neuron, 69(5), 918-929.
20. Kessaris N, Fogarty M, Iannarelli P, Grist M, Wegner M, Richardson WD (2006). Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat Neurosci. 9(2):173-9.

Funding and partnerships

Grants awarded:

Related programmes

Our members contribute to BSc and master’s degrees within the Faculties of Medical Sciences and Life Sciences. We also have a long and excellent track record in providing high-quality training to undergraduate, master’s and PhD students interested in the areas of neuro glia development, plasticity and disease. More than 30 PhD students have trained with us, graduated and moved on to further research positions in academia, industry and UK government positions.

Outreach

We regularly visit schools to discuss careers in academia. We also host school-age children for work experience. We are proud to say that we have inspired several next-generation scientists! Contact us if you are interested in experiencing the fascinating life of a neuroscientist!