The development of the hippocampal representation of place

How is the adult brain shaped during infancy and childhood? To what extent are brains 'hard-wired', and to what extent are they sculpted by the experience of the environments in which their owners are raised? We plan to investigate this problem for the first time in a part of the brain known as the hippocampus. The hippocampus has a critical function in long-term memory, in particular for episodic memory: memories of particular events, and when and where they happened. Damage to the hippocampus leaves people amnesic, unable to form new memories. The hippocampus has another important related function: it allows us to remember the layout of our environment and navigate around it. Hippocampal damage leaves people not just amnesic, but also unable to orient themselves. We know from previous research that the hippocampus contains different sets of neurons which each respond to specific spatial variables: there are place cells, which encode the current location one occupies in space, directional cells, which act like a compass, indicating the direction in which an organism is facing, and grid cells, which we think convey information about how far it has travelled. These neurons were first discovered in rats, but more recently both place and grid cell activity has been described in humans. What are the processes that give rise to such a sophisticated navigational machinery, during development? How are the different kinds of sensory features (visual, olfactory, etc) integrated in order to generate these neural maps? Which kind of spatial experience is required to develop a sense of space? We will concentrate on the development of place cells, and plan to test a specific hypothesis that these neurons can tell where the animal is by integrating information regarding where conspicuous barriers to movement are located (walls, drops, etc.). In mammals olfaction matures first during development, while vision is the last sense to develop. We will therefore test the possibility that young animals use scents to localize themselves, and that only as they grow they will use visual information to orient in space. We will also manipulate the environment in which the rats grow up, and will investigate how these manipulations affect the development of spatial cells. The results produced by this study will allow us to better understand hippocampal development in humans. Episodic memory develops relatively late in human infants, probably reflecting the slow maturation of the hippocampal formation. Adults cannot recall memories from before 3.5 years of age, a phenomenon referred to as 'childhood amnesia'. Children cannot navigate as well as adults even at 7-8 years of age. Studying the development of the hippocampus at neuronal level in the rat will give us a good handle on understanding these developmental processes in humans. By looking at how the development of this system depends on experience, we can hope to understand whether memory or navigation abilities are affected by early-life experiences. This issue is particularly important given the susceptibility of the hippocampus to damage during perinatal deprivation of oxygen. We don't yet know why only some of the children who suffer lack of oxygen at birth will go on to develop amnesia and disorientation. This is unfortunately compounded by the fact that currently these problems go undetected until children reach school age, so that potential therapeutic strategies cannot be put in place during the early years, when brain plasticity is thought to be maximal. Understanding the processes involved in the development of the hippocampus will be important to enable accurate and early diagnoses in children which suffered lack of oxygen at birth and knowing how experience affects the development of the hippocampal system may allow compensatory behavioural therapies to be developed.

The proposed research will investigate the development of the neural representation of space in the hippocampus, focusing on the development of place cells. In the adult, place cells only fire when the rat visits a restricted portion of the environment, and have been proposed to encode a neural 'cognitive map' of the animal's surroundings. In recent work, we have charted the time-course of place cell development, finding place-specific firing in hippocampal neurons as early as postnatal day 16 (P16), but with a quality of spatial tuning that is reduced compared to adult levels. Spatial signalling gradually matures until adult levels are reached around P45. In this proposal, we seek to investigate how sensory information is integrated and processed in order to give rise to place-specific responses during development and which features of experience are capable of shaping the development of hippocampal circuits. We will first address the question of which sensory cues contribute to place cell firing during development, and how they are integrated to form a coherent representation of space. Place cells in the adult respond to multimodal configurations of different cues: we will determine when this configural integration of sensory information emerges during development. We will then test the specific hypothesis that spatially responsive cells tuned to the position of environmental boundaries may represent the main inputs to place cells in young rats, and may thus be the fundamental 'building blocks' of spatially localised firing during development. The proposal will also address a fundamental question in developmental neuroscience: what is the role of experience in shaping the development of neural circuits? We will test whether visual sensory experience is necessary during development, in order for visual cues to form a functional input to place cell firing in adulthood.

The proposed research will advance our understanding of the development of the hippocampus and its role in spatial cognition and memory. As such, it will provide potential long-term benefit in the assessment and therapy of human developmental neurological disease, lead to better knowledge of human spatial cognition, have potential economic benefit and inform the public understanding of science. Long-term health benefits in developmental neurological disease: Perinatal asphyxia occurs in 1-6 per 1000 full-term births, and the hippocampus is particularly vulnerable to ischemic damage. Our research can potentially provide the missing link between hippocampal network and cognitive functions, promising to 1) address why only a subset of those affected by hypoxia will later develop memory problems, and 2) provide sensitive diagnostic tools to detect hippocampal dysfunction early during life. We are developing parallel tests of spatial cognition in young rats and children, with the aim of developing a battery of tests for hippocampal dysfunction. Early diagnosis could then translate into early intervention. Our work aims to find critical periods during which experience impacts hippocampal development, knowing when such heightened plasticity occurs will help determine the optimal timing of potential therapeutic interventions. Spatial cognition and the built environment: Understanding spatial cognition can influence thinking about the architectural design of the spaces we live in. The workshop 'Spatial thinking', recently held at the Bartlett School of Architecture, UCL, was an example of such cross disciplinary interface. One project discussed was the design of facilities for Alzheimer's Disease patients: such considerations will also apply to designing environments for young children, whose spatial cognition is not yet adult-like. Relevance to robotics and Artificial Intelligence (AI): A central problem in AI is the integration of information from different types of sensor, known as 'sensor fusion', and analogous to the neurobiological problem of integrating sensory information from across modalities. The core focus of our proposal, the integration of sensory cues to form a neural map of the environment during development, is a classic example of sensor fusion. Our research will potentially extend biologically inspired robotic design and enhance the design of AI navigating agents. Technology-transfer: FC pioneered the application of electrophysiological recording in freely moving animals to genetically modified mice, creating new uses for this technology in both basic research and the pharmaceutical industry. The same miniaturised version of the technology is also used to study development. Axona Ltd, based in Hertfordshire UK, is now industrialising the manufacture of this miniature recording technology, which it sells to customers around the world. Further refinements in miniature recording technologies resulting from this proposal will also feed into this two-way technology-transfer between the lab and the company. Collaboration with industry: Alzheimer's disease (AD) and other dementias typically involve the degeneration of the hippocampal formation. FC was the first to test the place cells in a mouse model of AD, in collaboration with Dr Paul Chapman at GSK. We believe that our approach of combining in vivo recording, behavioural and biochemical testing will become standard in screening animal models of dementias. Looking for parallels between ageing and development processes in the hippocampus will further our understanding of animal models of neurodegenerative disease. Public engagement in Science: We will convey our results directly to the public via a variety of media channels. For example, the publication of our recent work (Wills, Cacucci et al, 2010) led to features (including interviews) on New York Public Radio, New Scientist, Scientific American and the London Metro newspaper.