Award details

The comparative connectome

Reference	BB/N019814/1
Principal Investigator / Supervisor	Dr Rogier Mars
Co-Investigators / Co-Supervisors
Institution	University of Oxford
Department	Clinical Neurosciences
Funding type	Research
Value (£)	981,958
Status	Completed
Type	Fellowships
Start date	01/03/2017
End date	28/02/2023
Duration	72 months

Abstract

The current project aims to exploit phylogenetic diversity in primate brain organization to understand the human brain. There has recently been a rapid acceleration of our understanding of the connections between areas of the human brain, through efforts such as the Human Connectome Project, but their role can only be fully understood if we study them in a comparative context. We will collect high-resolution neuroimaging data from post-mortem samples from great and lesser apes and Old and New World monkeys, providing a large data resource to create a "comparative connectome", mapping the areas and connections in the brains of these species and providing quantitative comparisons between them. We will use this unique resource to study three particularly human specializations. First, we will investigate the phylogenetic origin of the connections between areas in temporal and frontal cortex mediating language in the human brain. By collecting both diffusion-weighted MRI data that allows the visualization of connections between brain areas and myelin maps that allow the localizing of individual brain regions we can test whether connections that seem expanded in the human brain actually invade new cortical territory or that their target areas have shifted due to cortical expansion. Second, we will investigate the neural basis of human tool use. We will map the parallel parietal-premotor pathways that mediate various types of motor behavior in primates and test whether human tool use relies on newly formed pathway in the human brain or on an elaboration of an existing primate pathway. Finally, we will investigate what is likely the most famous human specialization: our large frontal cortex. By exploiting phylogenetic diversity, we will determine whether the connectivity of the human frontal cortex is a natural result of its size or whether it forms a unique specialization.

Summary

What makes humans unique? Relative to our body size, we have the largest brain of any primate. This massive brain allows us to dominate the planet, while our closest animal cousins, the great apes, are relegated to small patches of Africa and Indonesia. However, exactly what changed in our brain when it got bigger and how this relates to our uniquely human behaviors, such as spoken language, advanced tool-making, and bipedal walking, remains a mystery. In this project, we try to solve this mystery, by comparing the architecture of our brain to that of a range of other primates. If we want to understand what makes our brain different, it is not enough to compare it to that of just one other ape or monkey. We differ in many respects from other primates and thus any differences we find might find can be related to many behaviors. If we want to understand how different behaviors are related to particular changes in our brain, we have to compare our brain to that of a range of other primates, each with different behaviors. Therefore, in this project we aim to map the connections and brain regions of a range of different primates. We will use new developments in neuroimaging to scan the brain of primates post-mortem. We will obtain the brains from animals that have lived in zoos and that have died through causes completely unrelated to our research. This will allow us to study more species than ever before without any ethical constraints. By using neuroimaging we can obtain different types of information from each brain, such as how big specific brain regions are, where they are located, and how they are connected. This project will be based at the University of Oxford's FMRIB centre. The Fellow and a post-doctoral research assistant will conduct the majority of the work, in collaboration with the MRI Physics Group at FMRIB. We will investigate differences in brains related to three types of behavior that we believe are particularly well developed in humans: language,tool use, and general decision-making. Human language has been suggested to be possible due to a series of new connections between the temporal and frontal cortex of the human brain. However, it has recently been suggested that some of these connections are already present in great apes, such as gorillas, which mean they might not be exclusively related to language. By comparing these connections between monkeys, apes, and humans we can test this idea, and see which connections are special to which group of animals. Human tool-making has been essential in our conquest of the world. It is thought that we integrate much more complex conceptual information into our tool use than other animals do. This can have happened in two ways, by the formation of a new pathway in the brain specifically for using tools or by elaborating on existing pathways for reaching and grasping in the parietal and premotor cortex of monkeys. We will compare the pathways connecting parietal and premotor cortex in humans and monkeys and see whether there is a new pathway in humans that might mediate tool behavior. The most distinctive part of our human brain is the prefrontal cortex, which is very large in the human brain and has been related to our decision-making abilities However, whether this size is the reason that our brain is capable of complex behavior or whether it is due to the extended connections with the rest of the brain that bring our frontal cortex more information than in the monkey is unknown. We can only study this by comparing both the size and the connections of the frontal cortex across species. This way, we can see whether in our brain the relationship between size and connections of the frontal cortex is as predicated based on other primates or whether there is something special about our case. Together, this work will help us understand not only what makes us different from other animals, but also what makes these animals different from one another.

Impact Summary

ACADEMIC BENEFICIARIES The scope of the project is such that it will be of interest to researchers in a wide variety of fields. Indeed, the project provides a new type of data that can be used by researchers. These benefits are described separately in the 'Academic beneficiaries section'. SOCIETY BENEFICIARIES Research on animals, whether fundamental or medically related, evokes strong opinions in society. These days research on animals is widely viewed within the ethical framework of the '3Rs'. These three Rs reflect Replacement, Reduction, and Refinement of animal research. The current project addresses all three categories. The project focuses on the use of diffusion MRI to study the connections between areas of the brain. Given that the study of connectivity still mostly employs invasive and often terminal research in animals, this method has tremendous potential in the Replacement and Reduction of animal research. With regard to the Refinement, because this project focuses on diffusion MRI in post-mortem brain samples, it allows us to study a much wider range of primates than has even been possible without resulting in animal suffering. Public engagement is of vital importance for science. Especially in these times of austerity it is important that scientists ensure that the general public understands the goal of their work. The work in this project focuses on understanding the differences between different primates. By extension, this work contributes to the understanding of our place in nature. This topic is ideally suited to public engagement. Books on the relationship between humans and other animals and on the working of the human brain are consistently found on the best-seller lists, such as Frans de Waal's books on human-like behaviour in non-human primates and Dick Swaab's book "We are our brain". Changes in climate and the destruction of the habits of many animal and plant species routinely make the headlines. Changing public opinion has, fortunately, created a lot of attention for the conservation of the habitats of the species studied in this project. By developing a better understanding of the adaptations of primates to their environment, this project is able to inform this work and to provide a link between fundamental neuroscience and behavioural science and applied conservation science. HEALTH Disorders of brain function, both in psychiatry and neurology, represent an important and increasing proportion of health problems in the Western world. Although the proposal is aimed at comparative and evolutionary neuroscience, the methods that are developed in the context of the project have the potential to be applied to our understanding of impairments in the human brain. The applicant has in the past assisted researchers in clinical fields in adopting his approach to their work (e.g., Brazil et al., 2009, Biol Psychiatry; Brazil et al., 2013, Front Psychol; Johnen et al., 2015, eLife). The methods developed for this project to compare the brains of different species can be used to study differences between individuals of the same species, such as human brains in health and disease. The applicant has had repeated discussions with Prof Masud Husain of the University of Oxford to attempt such an application of the analysis toolbox he is developing (see Pathways to Impact) and currently is engaged in a pilot project to test whether his methods can be used to detect the impact of small strokes on the communication between brain areas. If successful, this pilot is expected to lead to a grant applicant in which the applicant is a collaborator for the autumn 2016 grant cycle. ECONOMIC BENEFICIARIES Education and research are thriving export sectors for the UK. By basing the fellowship in a university environment in which the fellow is actively involved in teaching, he will contribute to this economic benefit.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	Fellowship - David Phillips Fellowship (DF) [1995-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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