By The human brain is one of the most complex systems on the planet, capable of putting men on the moon and creating sublime art. To understand how it achieves so much involves making sense of its trillions of structural and functional connections. This huge challenge of scientists requires mapping the brain on not just one but several scales, from the microscopic level of synaptic connections between neurons to the global level of connections between brain regions and between the brain and behaviour. Brain imaging, genome sequencing, genetic manipulation and huge computing power are accelerating this mapping in humans and other animals with unprecedented scope and accuracy, opening up a greater understanding of brain function in both health and disease. An international group of scientists discussed these contemporary explorations of the brain in Paris on May 5th, at the 22nd Neuroscience colloquium hosted by Fondation IPSEN.
The meeting has been organised by Henry Kennedy (Inserm U846, Bron, France), David van Essen (Washington University School of Medicine, St Louis, USA) and Yves Christen (Fondation IPSEN, Paris, France), not only surveyed the enormous progress of the past decade in delineating brain circuits and their relation to behaviour and disease but also gave a flavor of what we can expect in the coming years.
The brain depends for its computational power on the routing, integration and non-linear mapping of information about the world inside and outside the body. Its programs and its memory are embedded in the connections between its structural elements: the neurons and their support cells, the glia. Mapping these connections began over 150 years ago but was limited because the anatomical description of the components could be done only on dead tissue, so correlations with physiology and behaviour were slow and indirect. This chasm between structure and function first began to be bridged in the 1970s, with the development of tracers that could be introduced into living nerve cells, followed in the 1980s by the first imaging of the whole, living brain.
Today, the numerous technical innovations that will be a recurring theme in this meeting are producing huge amounts of data. Connections between neurons and brain areas are being traced with modified viruses and proteins that light up when activated (Karl Deisseroth, Stanford University, Palo Alto, USA; Edward Callaway, Salk Institute for Biological Studies, La Jolla, USA). The activity in neuronal networks can be manipulated and related to changes in behaviour (Deisseroth; Cori Bargmann, The Rockefeller University, New York, USA; Wim Vanduffel, Massachusetts General Hospital, Charlestown, USA). Vast improvements in the power of brain imaging are enabling finer and more accurate mapping of functional brain areas (van Essen), and crowd-sourcing is being employed to analyse huge data sets (Winfried Denk, Max Planck Institute for Medical Research, Heidelberg, Germany). The comparative approach is once again providing insights into both evolution and function, as well as for testing the accuracy of imaging methods used with humans (van Essen).
Analysing so much data depends on advanced computing methods and the development of theoretical models on scales ranging from single neurons to the whole nervous system (Olaf Sporns, Indiana University, Bloomington, USA). Large collaborations such as the Human Connectome Project (van Essen) and the ENIGMA Consortium (Paul Thompson, UCLA School of Medicine, Los Angeles, USA) have been set up to correlate human brain imaging, with genetic and behavioural information, so as to provide a basis for linking adult brain structure to development and to disease.
At one extreme, the challenge is to produce a wiring diagram that describes the information flow through the cellular components that make up the neuronal circuits (Terrence Sejnowski, Salk Institute for Biological Studies, La Jolla, USA). Reconstructing the ‘microphysiology’ of the neuronal connections in the CA1 area of the hippocampus, a structure associated with short-term memory, is revealing how synaptic geometry influences the electrical and biochemical processes involved in synaptic transmission and plasticity. The spatial distribution of different types of synapse in the mouse retina is being determined using high resolution electron microscopy (Denk), and structural and molecular details of synaptic connections are being visualised optically in post-mortem brains using rapid preservation methods (Deisseroth).
It is in the ‘dense thickets’ of the cortex (Kevan Martin, Institute of Neuroinformatics, Université de Zurich, Switzerland) that so much information is processed and integrated. The mammalian cortex is composed of repeated units, or columns, each containing a small number of interconnected neurons and with very similar wiring throughout the cortex. Outstanding puzzles are how these units do such different processing tasks and how they produce the very different behaviours of rodents and humans. A theoretical model of a cortical column could provide some answers.
The complexity of the mapping of the visual world is illustrated in the mouse visual cortex, where the visual field forms nine orderly maps, with each visual area projecting to about 30 reciprocally interconnected cortical targets (Andreas Burkhalter, Washington University School of Medicine, St Louis, USA). Neurons within conscribed areas of visual cortex show functional specialization that is reflected in their connectivity, with some patches of neurons carrying high spatial information and projecting to the object-recognition areas of the temporal cortex, while other patches terminate in object-location centres of the parietal lobe. The wiring between neighbouring cortical areas is similar and dense but as distance between areas increase, the connections are fewer and sparser, establishing a spatial continuity of function that represents neighbouring bits of visual space (Kennedy).
Anatomical and even physiological studies provides static snapshots of connectivity but functional networks are dynamic and an important question is how the static wiring generates behavioural variability. The nematode worm, Caenorhabditis elegans has a small, fixed number of neurons and connections, but when it follows chemical gradients, the timing of its turns is unpredictable. The variability arises from the level of activity in the interneuron network (Bargmann). A range of techniques has been developed to change activity levels in monkey brains during functional magnetic resonance scanning. Monitoring the impacts of specific manipulations on behaviour should provide insights into the dynamics of the network (Vanduffel). The variability in transmission of information between the two cerebral hemispheres in humans correlates with handedness, brain volume and the type of task (Nathalie Tzourio-Mazoyer, Université de Bordeaux Segalen, Bordeaux, France) but anatomical asymmetry accounts for only a fraction of functional variability.
One goal of all these studies is to enhance our understanding of normal brain function. Another is to throw light on brain diseases. One approach is the large collaborative programs such as the Human Connectome Project and the ENIGMA Consortium (van Essen; Thompson), each involving thousands of participants, which are examining genetic variation, behaviour and life history alongside brain imaging. The ENIGMA program is focusing on how disease risk genes, such as those recently discovered for Alzheimer’s disease, TREM2 and ApoJ, disrupt and alter brain wiring and on identifying causative factors that may be treatable (Thompson). The effect of asymmetries in inter-hemispheric connections on psychological health is being examined in 450 healthy adults (Tzourio-Mazoyer). On the micro-scale, the use of specially designed opsin proteins, which can be stimulated by light to activate or deactivate neurons in freely moving animals, are being used to investigate in detail the circuits involved in anxiety, depression and motivation (Deisseroth).
About the Fondation Ipsen
Founded in 1983 under the aegis of the Fondation de France, the Fondation Ipsen is dedicated to contributing to the development and dissemination of scientific knowledge. During this time, the Fondation Ipsen aims to promote the interaction between researchers and clinicians, essential exchanges because of the extreme specialization of these professions. The Fondation Ipsen’s goal is to incite contemplation of the great scientific challenges for years to come. The Fondation has developed a significant international network of scientific experts, who meet regularly at Medicine and Research Conferences, dedicated to five main themes: Alzheimer's disease, neuroscience, longevity, endocrinology and cancer. Furthermore, since 2007 the Fondation Ipsen has introduced several series of meetings in partnership with the Salk Institute, the Karolinska Institutet, Massachusetts General Hospital, the DMMGF Foundation, as well as with the journals Nature, Cell and Science. The Fondation Ipsen has published over one hundred books and has awarded more than 250 prizes and grants.
