Template neuronal networks in developing neocortex

When we are young our brains develop rapidly in response to experiences we encounter. This determines how it will function throughout our lives. One example is that young children are able to learn languages easily compared to adults; young minds are very adaptable. My research is geared towards understanding the processes going on in the young brain that make it adaptable.

Nerve cells, or neurons, form the circuits that do the computation that underlies brain function. Early in our lives, nature and nurture combine to influence the way the neurons become connected together into circuits in the brain. Nature's role works through the genetically-encoded processes that build basic brain structure. This basic structure acts as a template for the nurture part, as the experiences we encounter cause changes in the basic template structure. These changes allow the brain to work properly. Surprisingly, we know very little about the basic structure of template circuits that develop before sensory experiences then adjust them. However, it is very important to understand these templates because their properties will determine how much our experiences can influence brain function. In one sense, the properties of this basic structure define just how big the differences between individual brains can be. This study is specifically designed to investigate how and when the earliest template circuits form in the young brain and how they influence the nurture-dependent phase of brain circuit development.

Nerve cells communicate through structures called synapses. When a circuit changes, such as when we learn a language, it is largely because its synapses change. Likewise, when a circuit is wired up incorrectly, as in certain neurological disorders like autism, it is likely that the synapses are at fault. Therefore, to understand early template circuits, we must measure the synapses that connect it all together. Also, there are likely to be changes in those synapses that are important for development of the template circuit.

Measurement of changes in circuit structure is not easy because there are millions of synapses that are all mixed together. So, it is difficult to find which circuit they belong to. I have developed a new technique to locate which nerve cells are connected and to analyse the synapses that connect them. This techniques uses a special type of microscopy that can see deep inside brain tissue with very fine detail. This approach will be used to measure the properties of synapses and neurons within template circuits as they develop early in life.

Functional brain circuitry is generated early in life as experience-dependent plasticity shapes pre-existing template neuronal networks. The characteristics of these template networks inevitably constrain subsequent experience-dependent plasticity, yet very little is known about their structure, synaptic properties or development.
In developing neuronal circuits of the neonatal cortex, NMDA receptor (NMDAR)-dependent synaptic and structural plasticity is crucial for experience-dependent circuit maturation. Therefore NMDAR-based synaptic connectivity is likely to underlie template networks that are the basis for experience-dependent plasticity.
I previously showed that, early in neonatal life, the recurrent excitatory microcircuit in layer 4 of the barrel cortex becomes functionally connected through experience-dependent addition of AMPA receptors (AMPARs) to NMDAR-containing synapses, resulting in a highly inter-connected circuit. Preliminary data suggests that, before the emergence of AMPAR-based connectivity, there is substantial NMDAR-mediated synaptic connectivity that represents the template network. This proposal aims to define how and when the NMDAR-based neuronal template network emerges and relate its properties to the experience-dependent plasticity that subsequently acts upon it.
2-photon optical stimulation and patch clamp electrophysiology will be used to map NMDAR- and AMPAR-based synaptic connectivity in layer 4 of neonatal barrel cortex slices. Day-by-day analysis of postnatal template network development will provide information on connectivity levels and synaptic properties. Network analysis will measure the relationship between template and functional network architecture. In vivo imaging of neuronal structural dynamics will describe the link between anatomical and synaptic development.
Defining the properties of template neuronal networks will reveal the basis of experience-dependent plasticity that underlies healthy brain development.

Who will benefit from this research?
In addition to contributing to the development of the neuroscience research field, the work proposed here has the potential to have impact on a wide group of other interested parties, such as:
1. scientific industry,
2. neonatal clinicians,
3. educationalists,
4. parents.

How will they benefit from this research?
1. scientific industry
Treatment of neurological disease is a major target for many pharmaceutical companies. There are a significant number of diseases, such as autism and schizophrenia, which are thought to result from pathological neuro-development. The work proposed here will provide a basis for developing models of how such diseases are caused and influence the way in which the pharmaceutical industry approaches the development of therapies for neuro-developmental disease.
The technical advances in utilisation of 2-photon microscopy that will result from this proposal will be of benefit to manufacturers of microscopy equipment. Indeed, I have already received interest in our ideas from multiple UK-based manufacturing companies.

2. neonatal clinicians
There are clear correlations between the brain development of humans and rodents. In particular, several electrophysiological and morphological markers, which are used by clinicians to assess brain development in young children, are also present in mice. This provides an opportunity to relate information from basic research about synaptic, neuronal and network development to the growth of human babies. Cross-fertilization of experimental ideas between basic and clinical researchers will bring about more specific research strategies to relate clinical assessment of brain development to it underlying cellular processes.

3. educationalists
Research on early brain development has been used previously to influence educational policy and teaching practice relating to the education of young children. As basic research into brain development further evolves, it results should be further taken into account when making educational decisions. The work proposed here can be related to human brain development through the fact that many developmental processes are conserved across mammalian species. Our work parallels the thought processes of educationalists by asking how early life experiences can influence brain development. The outcomes of this research will further our understanding of how and at what point sensory experiences can influence brain development. In that way, this research will add to the body of evidence that will be taken into account when strategies are produced for managing the cognitive development of young children.

4. parents
Every parent is concerned about how their newborn baby is developing. Indeed there are massive medical, psychological and manufacturing industries that are based on parents' belief that intervention in their child's early cognitive development can have positive long-lasting effects on the function of their brain. But can playing Mozart, using flashcards, buying specially-textured toys really impact brain development? Now is a time when biological data can provide understanding of neuronal circuit development that can influence the decision-making of parents with regard to their child's development. The work proposed here may seem esoteric to some parents but it will generate understanding of how sensory experiences can shape brain maturation. Careful dissemination of this and related information can make the results of basic research meaningful to the parents within the lay public, enabling them to make informed choices.