Genius, madness and the origin of the brain/ Génie, folie et origine du cerveau

Séjour d’étude de Seth Grant, du 23 mai au 4 juin 2022.

Summary

A schematic tree of the brain, behaviour and evolution. The tree is drawn with nerve cells organised into the shape of the brain and superimposed on this tree are organisms arranged from the simplest unicellular organisms near the trunk and the most complex organisms near the branch tips. The organisms include those made from a single cell (bacteria, algae, choanoflagellates), simple multicellular organisms with very few nerve cells (hydra), invertebrates with complex brains (snails, bees) and mammals (mice, humans) with the most highly complex nervous systems. The mice and humans are shown performing the same complex cognitive tasks using touch- screens. All these organisms share a common set of proteins which evolved billions of years ago and control their instinctive and learned behaviours.

Seth Grant is Professor of Molecular Neuroscience at the Centre for Clinical Brain Sciences, Edinburgh University, UK, is affiliated with Simons Initiative for the Developing Brain and UK Dementia Research Institute, and is a Fellow of the Royal Society of Edinburgh and UK Academy of Medical Science. He established and leads the interdisciplinary Genes to Cognition Programme. His pioneering work on the genetics of cognition and on the complexity of the synapse proteome has made seminal contributions to our understanding of the neuroscience underlying learning, memory and behaviour. These studies have revealed how synapse protein dysfunction contributes to a wide range of developmental, neurodegenerative and psychiatric brain disorders of great social and economic importance, including schizophrenia, autism, depression, addiction and intellectual disability. These studies have encompassed all scales, from molecular proteomics and transcriptomics to whole-brain networks and whole-animal behaviour. His current ‘synaptomics’ research, which delivers molecular analysis of the brain at single-synapse resolution and whole-brain scale (Neuron 99, 781-799), has uncovered a remarkable architecture of synapse molecular diversity in the mouse and human brain. Probing the dynamics and plasticity of the brain synaptome is providing groundbreaking insights into the mechanisms of memory and learning throughout the lifecourse and the impacts of natural aging and neurological disorders (Science 369, 270-275; doi.org/10.1016/j.neuron.2022.09.009). This seminal body of work has been recognised in prestigious national and international awards, most recently the 2019 IBANGS Distinguished Investigator Award and 2020 FENS EJN Award.

Résumé

Seth Grant est professeur de neurosciences moléculaires au Centre for Clinical Brain Sciences de l’Université d’Édimbourg, au Royaume-Uni. Il est affilié à l’Initiative Simons pour le Développement du Cerveau et à l’Institut Britannique de Recherche sur la Démence, est membre de la “Royal Society of Edinburgh” et de l’Académie des Sciences Médicales du Royaume-Uni. Il a créé et dirige désormais le programme interdisciplinaire “des gènes à la cognition”. Ses travaux précurseurs sur la génétique de la cognition et sur la complexité du protéome synaptique ont apporté des contributions fondamentales à notre compréhension des neurosciences sous-jacentes à l’apprentissage, à la mémoire et au comportement. Ces études ont révélé comment le dysfonctionnement des protéines synaptiques contribue à un large éventail de troubles du développement, neurodégénératifs et psychiatriques du cerveau d’une grande importance sociale et économique, notamment la schizophrénie, l’autisme, la dépression, la toxicomanie et la déficience intellectuelle. Ces études ont englobé toutes les échelles, de la protéomique moléculaire et de la transcriptomique à la totalité des réseaux cérébraux et au comportement de l’animal dans son ensemble. Ses recherches actuelles sur la synaptomie, qui fournissent une analyse moléculaire du cerveau à une résolution synaptique unique et à l’échelle du cerveau entier (Neuron 99, 781-799), ont mis à jour une architecture remarquable de la diversité moléculaire synaptique chez la souris et le cerveau humain. Sonder la dynamique et la plasticité du synaptome cérébral fournit des informations révolutionnaires sur les mécanismes de la mémoire et de l’apprentissage tout au long de la vie et sur les impacts du vieillissement naturel et des troubles neurologiques (Science 369, 270-275; doi.org/10.1016/j.neuron.2022.09.009). Ce travail fondateur a été reconnu par des prix nationaux et internationaux prestigieux, le plus récent étant le prix “IBANGS Distinguished Investigator 2019” et le prix “FENS EJN 2020”.

Abstract

Scientific endeavour has provided answers to profound questions that have radically changed the way we think. We now understand how the universe came into being, how matter arose, how life began, and how inheritance works. At the core of these and many other great scientific advances is a general theory that has broad explanatory power and far-reaching implications. A major quest of the scientific community is to find a general theory of behaviour that can explain how all organisms, from the simplest bacteria to humans, can adapt and respond to their environments, generate a repertoire of behaviours including complex behavioural sequences, and learn and remember. Such a theory needs to embrace all levels of biology from genes to cognition and thereby link the molecular mechanisms of inheritance to the behaviour of the whole animal. In addition to explaining the features of normal behaviour this theory should seamlessly explain how the abnormal behaviours that characterise psychiatric and neurological disorders arise. The goal of “Genius, madness and the origin of the brain” is to expound a general theory of behaviour based on the latest discoveries from the world of neuroscience and explain how this theory can impact on medicine and on our daily life.

Report

The Rosetta stone for a general theory of behaviour is the set of proteins found inside synapses. Synapses connect the nerve cells in our brain, and their constituent proteins ultimately control our thoughts, perceptions, innate and learned behaviours. In humans, alterations in these proteins cause more than 100 brain diseases, which manifest with a range of impairments in cognition, mood and movement. Among these are common disorders of significant societal impact, including autism, schizophrenia, depression and addictions.

Synapse proteins are a Rosetta stone because they link many different areas of scientific investigation. From studying these proteins in different species it has been possible to uncover how the mechanisms that control human behaviour first arose almost 4 billion years ago in simple bacteria, and how during the intervening millennia the proteins evolved modifications and enhancements that have made the human brain into the highly sophisticated and complex, but also vulnerable, machine that it is.

The human brain is extraordinary in that it contains a vast number of synapses – around a million billion – and a remarkable recent discovery is that these synapses are highly diverse with respect to their protein composition. Furthermore, this synapse diversity is highly organised into what are termed synaptome maps. The synaptome map of the brain changes from birth to old age, and this transition may explain how the behavioural repertoire expands during childhood, stabilises in middle age and then progressively deteriorates during old age. Synaptome maps constitute a major conceptual advance as they provide a way of storing and recalling behavioural programs and, crucially, can explain how DNA mutations can lead to altered behaviours.

The impact of contemporary molecular neuroscience on our society is starting to be felt. Numerous diseases that used to be explained by “bad parenting” or various other environmental factors are now known to be caused by gene mutations. However, there is a danger in the pendulum swinging too far from nurture to nature or in the underlying causes being oversimplified. Synapse proteins have become centre stage in the nature-nurture debate as they are modified both through the action of genes and by the activity in the brain that occurs with experience.

The science of synapse proteins is now telling us a considerable amount about why people have different social skills, including those individuals with autism. These are not just simple stories of broken genes but are, in fact, far more nuanced explanations because of the recognition that diversity in the architecture of the brain underscores behavioural diversity, producing complexity and vulnerability or resilience in a group or organisation.

One of the most striking phenomena in recent years has been that social media can powerfully induce and propagate irrational beliefs. At the heart of understanding how brainwashing occurs is the question of how information is stored in the brain and how it is forgotten. While the prospect of manipulating memories through synapse proteins may be useful for erasing traumatic experiences, technology that is capable of doing this could be misused for thought control.

How to maintain our synapses and synaptome maps in a healthy state and thereby maintain good mental health is of great interest to the public. The prospect of manipulating synapse proteins and synaptome maps offers hope to those with mental disorders, including age-related cognitive decline and dementia.