Early Cerebral Cortical Development and Evolution
The brain is an incredibly complex organ that offers a variety of rewarding challenges for every kind of investigator (i.e. developmental neurobiologist, electrophysiologist, neuropathologist, neonatologists and psychologist). A functional nervous system relies on precise spatial and temporal orchestration of gene expression, billions of proper electrical and chemical connections between millions of cells, and an exact balance of cell types that navigate and integrate over great distances.
As connections form between nerve cells and their electrical properties emerge, the brain begins to process information and mediate behaviours even during embryonic life. Some circuitry is built into the nervous system during embryogenesis; however, interactions with the world continuously update and adapt the brain's functional architecture throughout life. The mechanisms by which these plastic changes occur appear to be a continuation of the process that sculpts the brain during development. To understand the brain and its devastating diseases, we need to reveal the mechanisms that produce it and the ways in which it can constantly change.
Our research focus is on the cerebral cortical development. It seeks to decipher how cerebral cortical neural cell fates are determined (with special attention in the earliest generated cells in the subplate and in the large pyramidal cells of layer 5), and how development of cortical functional specialisation (arealization) is determined by genetic and environmental factors. We study the development of the cortical connectivity in this context with special attention to the thalamocortical connectivity.
Greater understanding of these systems could solve numerous questions relating to cortical development as well as to the prevention and treatment of many neurological and psychiatric disorders (e.g. childhood epilepsy, schizophrenia, attention deficit disorder, autism) that affect millions of people of all ages at tremendous cost to the national economy.
The embryonic rodent and human telencephali are useful models for our studies. Corresponding regions share several basic features and their development is governed by related systems of genes. In recent years, the molecular and cellular processes underlying fundamental aspects of cortical development have begun to be elucidated in transgenic mouse models. Mouse genetics will continue to be in central stage of cortical research, but the insights we can gain from studying other species are limited, therefore comparative studies are needed. The enormous size of the human forebrain, the vast number of functionally specialized cortical areas and the richness of human cognitive capacity, all demand explanations.
Current Research Programme
Cerebral Cortical Cell fate determination
The principal neuronal types of the cerebral cortex are the excitatory pyramidal cells, which project to distant targets, and the inhibitory nonpyramidal cells, which are the cortical interneurons. Pyramidal neurons are generated in the cortical neuroepithelium and migrate radially to reach the cortex following an inside-outside gradient. In rodent, only a few nonpyramidal cells are generated in the cortical ventricular zone. We examine the cerebral cortical cell generation and early differentiation. We study two particular systems: subplate cells and layer 5 projection neurons.
Recently, several transcription factors, including Mash1, Ngn1/2, Pax6, Emx1/2, Er81, Otx1, Fezl and Tbr1/2 have emerged as important players in cell fate specification in rodents. The combinatorial expressions of these factors determine the different cortical cell fates and set up the basic coordinates for cortical arealization and basic connectivity. We propose composite analyses of gene expression patterns that will allow us to identify molecularly distinct progenitor domains in the telencephalon and to elucidate genetic interactions underlying the generation of unique cellular phenotypes and regionalization of the cerebral cortex.
Migration of cortical neurons and migration disorders
It was recently established that cells of the pallidum also contribute to the formation of the cerebral cortex with interneurons. These cells migrate tangentially through the striatocortical junction to reach the cortex. Cell determination (commitment of progenitor cells to a particular fate) is an essential early step in the development of cell lineages, and current evidence indicates that common mechanisms operate in different tissues to regulate this step.
We are interested in the molecular and cellular mechanisms of cortical cell migration. We compare and contrast the radial versus tangential migration patterns and investigate the possible links with human migration disorders. We are particularly interested in the comparative aspects of interneuron generation and migration in reptiles and in examining the differences between primates and rodents.
Cortical arealisation and thalamocortical connectivity
Cortical areas do not appear to be fully pre-programmed and some of the differences arise by interactions with afferent neuronal projections. We are studying the signalling mechanisms that set the coordinates for the further establishment of cortical areas. Thalamic axons, which later will mediate most sensory information from the environment, reach the cortex at a very early stage, before the majority of cortical neurons have even been born.
Recent work points to the crucial role of the early-developing thalamocortical projections and their interactions with the developing cortical circuitry in establishing some aspects of the functional and structural organization of the cortex. Nevertheless some aspects of cortical specialisation do not require thalamic input. We are particularly interested in the cellular and molecular mechanisms involved in the cortico-cortical and thalamocortical connectivity.
To understand the function of early neuronal activity patterns we have been investigating mutants with disrupted synaptic vesicle release machinery due to lack of SNAP25, MUNC18 or MUNC13). These tools help us to dissect the various forms of early activity patterns based on regulated and spontaneous neurotransmitter release. Understanding the role of Snap25 (a presumed susceptibility genes in schizophrenia) could have general clinical implications. Combinations of genetic susceptibility and environmental perturbations are thought to be responsible for the diseases of: schizophrenia, autism, dyslexia, and attention deficit disorders. This field faces difficulties because no single gene or factor is responsible for driving a highly complex biological process.
Evolution of cortical development
The cerebral cortex provides the biological substrate for human cognitive capacity and is, arguably, the part of the brain that distinguishes us from other species. Understanding the evolution and development of this complex structure is therefore central to our understanding of human intelligence and creativity, as well as of disorders of cognitive functions. Evolutionary expansion in size and complexity of the human cerebral cortex is probably a result of changes in the molecular mechanisms of cell proliferation and phenotypic differentiation. Although the basic principles are similar in all mammalian species, the modulation of developmental mechanisms leads to the emergence of new neuronal subclasses and the addition of specialised cortical areas in human and non-human primates.
Interest in History of Neuroscience
Knowledge of the history of neuroscience can enrich our current research and teaching. I am very interested in the history of neuroscience at Oxford with special attention to Thomas Willis, Sir Charles Sherrington and Sir Wilfrid Le Gros Clark. Together with Dr Richard Boyd in 2010 I established the “Oxford History of Science Seminar Series” and together with Dr Damion Young and Professor Richard Brown (Halifax) we created a historic repository for the University of Oxford Medical Division: https://learntech.imsu.ox.ac.uk/historyofmedsci/.