Cellular mechanisms of developmental plasticity in mouse primary visual cortex

How we see the world depends on how visual information coming from the eyes is processed in the brain. At the first stage, the primary visual cortex integrates the images from the two eyes, which is essential for stereo vision. At the same time, neurons (nerve cells) in that part of the brain have the ability to detect the orientation of line segments and contours (horizontal, vertical, etc) which forms the basis for object recognition. This 'tuning' or sensitivity for line orientation is partly innate, and partly acquired during a so-called critical period in childhood. Even in adulthood, it can still be affected e.g. by perceptual training. Similarly, the balance between the two eyes depends on early visual experience, and if this is in some way atypical visual disorders will occur that cannot be corrected later in life. In this project, we want to investigate how the orientation tuning and binocularity of individual neurons in mouse primary visual cortex are influenced and altered by early visual experience, a phenomenon known as developmental plasticity. For this purpose, animals will be reared either in a visual environments which contains only contours of a single orientation, or with one eye closed. We will then record the responses of individual nerve cells to visual stimuli using a novel brain imaging technique of very high resolution called two-photon imaging. This technique in which active cells give off fluorescence signals can even be used to monitor the responses of the same neurons over time. We want to use it to find out more about the cellular mechanisms underlying developmental plasticity. First, by using genetically modified mice we can distinguish the two main types of neurons (excitatory and inhibitory ones) which will appear in different colours. We will assess what role these two cell types play in plasticity. Second, we know that certain genes are important for how neurons communicate with each other. We will study mice lacking two particular genes in order to see whether the proteins encoded by these genes are critical for developmental plasticity. It is becoming increasingly evident that many neurodevelopmental and neuropsychiatric diseases such as Fragile X or schizophrenia involve defects in the communication between nerve cells. Ultimately, we hope that knowing more about how plasticity works under normal circumstances will help us to better understand what goes wrong in childhood developmental disorders and in the ageing brain, and will enable us to develop treatment strategies.

The aim of this project is to elucidate at the cellular and molecular level whether plasticity for the two key features of primary visual cortex (V1) neurons, ocular dominance (OD) and orientation tuning, involves similar mechanisms. It is increasingly clear that many neurodevelopmental and neuropsychiatric disorders involve defects of synaptic transmission. Establishing a common pathway for different forms of plasticity will underscore the importance of V1 as a model system for the study of learning and memory, for illnesses impacting on these and for potential treatments. While previous work has elucidated the physiological effects of the classical paradigms for induction of plasticity, namely monocular deprivation (MD) and 'stripe-rearing', the use of transgenic mice and of two-photon microscopy to image V1 activity with single-cell resolution will enable us for the first time to dissect the contribution of inhibitory vs. excitatory neurons and the role of key players in the signalling cascades involving the main excitatory receptors. The objectives of the study will be: 1) to show whether stripe-rearing causes orientation specific depression and/or homeostatic facilitation similar to MD; 2) to ascertain whether a class of inhibitory interneurons, the parvalbumin positive (PV) basket cells, play the same role in the cortical response to stripe-rearing as they do for MD - this will be investigated by selectively labelling PV cells in transgenic mice, and comparing their responses with those of excitatory neurons; 3) to examine whether the AMPA receptor subunit GluR1 which is regulated via NMDA receptor signalling is critical for orientation plasticity just as it is for OD plasticity; 4) to compare the role of the NDMA receptor subunit NR2B, which is prevalent during the early part of the critical period, in OD vs. orientation plasticity - we will assess this indirectly via a knockout of the postsynaptic density protein SAP-102 which is associated with NR2B.

The primary visual cortex has long been one of the key areas in the brain for studies of developmental plasticity, which in turn sheds light on learning processes more generally. Despite much progress, it is not yet clear how universal the underlying synaptic mechanisms are across the brain or even within the visual cortex, for different cell types or stimuli. This project will reveal key mechanisms of how the developing brain adapts to a changing environment, and will link phenomenological plasticity with cellular mechanisms. It is becoming increasingly evident that many neurodevelopmental and neuropsychiatric diseases such as Fragile X or schizophrenia involve defects and malfunctions at the cellular and synaptic level. A better understanding of the cellular processes involved in synaptic plasticity under normal conditions will ultimately increase the chances of understanding and fighting disease processes that disrupt developmental plasticity, learning and memory. Therefore, this research will have many beneficiaries beyond the visual neuroscience community. Upon completion, this project will have identified cell types as well as molecules involved in synaptic transmission that play key parts in one model system of cortical plasticity. These results will be of interest to researchers working on other systems (e.g. other sensory cortical areas, hippocampus etc.), allowing for a wider generalisation of the findings. They will also be of interest to researchers both in the academic and commercial sector who work on conditions in which developmental plasticity is disrupted: the paradigm employed in this proposal is one that could be adapted readily for assaying plasticity in a variety of those conditions (such as e.g. Fragile X). This could in turn lead to testing of potential cures in the same paradigm. Cardiff University provides the ideal environment for exploiting the outcomes of basic neuroscience research for translational purposes. The new Neuroscience & Mental Health Research Institute has the explicit aim to bring neuroscientists from different disciplines together (Biosciences, Medicine, Psychology and Optometry & Vision Sciences) and to facilitate translating advances in neuroscience research into greater understanding, diagnosis and treatment of neurological mental illness. Furthermore, the wider public can benefit from this research through public engagement activities. Many members of the public are fascinated by neuroscience and want to know more about how the brain works. The PI is the public engagement leader at Cardiff University's new Neuroscience & Mental Health Research Institute, organising public lectures, speaking about neuroscience research on local radio and in public events, and educating young and adults during Brain Awareness Week and throughout the year, including activities in schools and the local science discovery centre, Techniquest. He is also engaged with artists collaborating with Cardiff University (e.g. Paul Evans) who will benefit from images generated by this project which they will use creatively.