Defining the genetic and activity-dependent instructions for striatal circuit development

Newly born nerve cells, or neurons in the brain, contain a set of instructions written in their genes, which together with messages they receive from neighbouring neurons, guides their development. These factors will determine the type of neuron it will become and determine which other neurons it will make contacts with and form a neural circuit. Errors in the development of neural circuits at these early stages can lead to problems later in life. For instance, schizophrenia, Tourette's syndrome and autism are disorders where abnormal developmental events have been proposed to underlie aberrant communication in the adult brain. This programme of research will investigate the contribution of both intrinsic genetic instructions and extrinsic activity patterns to the development of the correct wiring of neurons in the striatum, a part of the brain essential for the planning and execution of movements. It has been observed that the striatum consists of two segregated pathways of information flow and that these pathways need to communicate with each other at a precise level for normal function. The experiments outlined in this proposal will investigate how much crosstalk exists between these two pathways and how genetic instructions and early life extrinsic inputs instruct the degree of crosstalk. Findings from this work will advance our understanding of foetal and neonatal brain development, with follow-on implications for our understanding of cellular changes that occur in common disorders of the nervous system.

The aim of the proposed study is to dissect out the role of genetic and activity-dependent factors in coordinating the development of recurrent inhibitory connectivity between striatal medium spiny projection neurons (MSNs), which is shown to be disrupted in a variety of basal ganglia disorders. I will employ in vitro and in vivo electrophysiology in mice to define the development of synaptic connectivity between MSNs under baseline conditions and after disruption of early activity patterns. Furthermore, I will genetically label different types of MSN with fluorescent probes to investigate the role of genes in coordinating striatal recurrent connectivity. These complementary experiments will define critical factors and processes in the development of the striatum and can guide new rationales and identify targets for intervention in a range of basal ganglia disorders.

This work will directly advance our knowledge of the development of neural circuits and circuit connectivity and lead to conceptual advancements in our understanding of the brain. A detailed mechanistic understanding of neural circuit formation and connectivity will guide new rationales and identify targets for intervention in a range of neurological disorders and will be relevant for clinicians, the pharmaceutical industry and smaller biotech companies contributing to the development of new treatments. For example, an understanding of the fine scale connectivity of the striatum can guide improved targeting and stimulation paradigms for deep brain stimulation. Furthermore, knowing the roles for intrinsic genetic factors and extrinsic activity-dependent instructions in the development of connectivity between neurons will provide insight into novel strategies for improved integration of neural precursors in stem cell-based treatments. The pharmaceutical industry has en masse reduced or terminated their neuroscience R&D for which a lack of understanding of many basic aspects of brain function is to blame. Therefore, an increased understanding of basic mechanistic processes is tantamount for the return of this vital industry to spur discovery of new treatments and drugs for neurological disorders. Secondly, the ability of clinicians and the pharmaceutical industry to transform basic biomedical advancements into direct treatments for patients in clinics will improve the health and wellbeing of humans although this process is slow and can take many years, as discoveries in non-humans have to be validated in both healthy participants and patients. I intend to impact patients and patients groups more directly through meetings in which I can share new findings and concepts. Thirdly, it is important for policy makers to be aware of the possibilities and limitations of basic biomedical research. This necessitates a dialogue with policy makers and puts responsibility with scientists to both engage with policy makers and promote research. This will impact the thinking and decision-making on scientific subjects and will improve evidence-based policy and understanding of the processes underlying scientific discovery. An correct understanding of the opportunities and limitations is crucial as policy makers have the power to fund large projects as recently showcased by the US government (The Brain Iniative; http://www.nih.gov/science/brain/) and European governments (Human Brain Project; https://www.humanbrainproject.eu/en_GB) and need to base their decision making on as good an understanding as possible. Fourthly, it is important that general public is aware of what scientists do and how they do it as science constantly pushes boundaries and their needs to be a dialogue with the public what is and isn't acceptable (e.g. cloning issues). Lastly, the research will directly impact the health and wealth of the United Kingdom by increasing its prestige and will attract international scientists and other skilled people to the workforce.