The human brain is an enormously complex organ, made up of billions of neurons connected by trillions of synapses into vast networks. Even the human genome, which consists of approximately 3 billion base pairs and 30,000 genes, is dwarfed by the intricacy of this three-pound bulk of tissue.
“But as you know, we still continue in the scientific community to grapple with understanding the human genome – in fact, I don’t think we understand it at all,” said Thomas C. Südhof during his Lindau lecture. “So you can imagine that understanding the brain will be a much bigger challenge.”
Südhof along with two other Nobel Laureates – Michael M. Rosbash and Edvard I. Moser – discussed the evolutionary wonder that is the human brain on Thursday at the 70th Lindau Nobel Laureate Meeting. In their Agora Talk, Rosbash summarized his work on circadian rhythms, while Moser spoke about the grid cells that constitute a positioning system for the brain. During his lecture, Südhof described the state of the art in neuroscience research regarding synapse and circuit formation.
Neuroscience Research in the 21st Century
In 2013, Südhof received the Nobel Prize in Physiology or Medicine for discoveries of machinery regulating vesicle traffic, a major transport system in our cells. Specifically, he demonstrated how vesicles are held in place, ready to release signal-bearing molecules at the right moment. By studying brain cells of mice, his work identified how an increase in calcium ions in a nerve cell triggered the release of neurotransmitters within a few hundred microseconds.
His lecture focused on a different aspect of neuroscience – namely, how nerve cells in the brain form synapses.
“How to approach this challenge has been a bone of contention so to speak for a number of decades,” he said. “But in recent years, the concept of the neural circuit has emerged as a unifying basis among neuroscientists to discuss how the brain works.”
Populations of neurons are organized into circuits interconnected by synapses that process specific kinds of information. For example, two excitatory neurons are connected by a synapse, and one is also connected to an interneuron that is in turn connected to the other neuron.
“Synapses are the fundamental computational unit of the brain that exhibit an amazing speed, precision, and plasticity,” said Südhof. “A key question in neuroscience is how synaptic connections are formed.”
Synapses also exhibit specific properties that can greatly differ between neurons. However, in general, three initial steps are required to establish specific synaptic connections. After neurons have migrated, they extend axons that can travel long distances. They must be guided towards those targets through a process called axon guidance. The targets are selected and only then, synapse formation may occur.
Time and Localisation
Earlier that same day, a session consisting of two fascinating Agora Talks explored fundamental questions of space and time. Instead of delving into physics, however, the Nobel Laureates spoke about these topics from the perspective of the human brain. How do we inherently know where we are and what time of day it is?
Rosbash, who received the 2017 Nobel Prize in Physiology or Medicine for discoveries of molecular mechanisms controlling the circadian rhythm, first discussed the basics of how our body clock works.
“Intrinsic in the function of circadian rhythm is the fact that tomorrow is really a carbon copy of today, which is a carbon copy of yesterday,” he said. “We have this inexorable repeat in which every day is the same as the day before with only one small difference, namely perhaps a two-minute change in photoperiod in the temperate regions.”
The sun rises and sets on a 24-hour schedule, and it’s this environmental change that has given rise to the time mechanism we all have and live by. However, the inner workings of our internal clock remained a long-unsolved mystery for centuries. Scientists wondered whether such a timing system actually existed or was simply driven by the light-dark cycle.
In 1984, Rosbash and fellow Nobel Laureate Jeffrey C. Hall isolated and sequenced the period gene in fruit flies, a gene discovered a decade earlier to play a role in the regulation of the flies’ circadian rhythm. In the 1990s, they found that the protein encoded by the period gene accumulates in cell nuclei during the night and degrades during the day. These fluctuations persist in constant darkness.
“The cracking of this problem is really a homage to genetics, in particular fruit fly genetics,” he said. “I might add that our Nobel Prize was the fifth Nobel Prize for the fruit fly and its contribution to basic science.”
Moser took on the question of space and localization by giving an overview of his work on the positioning system of the mammalian brain. He received the Nobel Prize in Physiology or Medicine in 2014 for the discovery of grid cells, a type of nerve cell that generates a coordinate system for spatial navigation.
Along with his wife at the time, fellow Nobel Laureate May-Britt Moser, he performed experiments that mapped the connections to the hippocampus of rats moving around in a room. In a nearby part of the brain called the entorhinal cortex, they found that certain cells were activated when the rat passed multiple locations arranged in a hexagonal grid.
“Together, these grid patterns can very precisely in combination define the current location, and these differ from the place cells discovered much earlier in that the place cells are more related to specific places, specific context, specific memories,” said Moser. “For example, if your house has five rooms, there would be different configurations of active place cells in each of those five rooms. However, for grid cells, it is one general map that is played out wherever you are.”
Each individual cell would be active only in certain spots in that room, and those spots formed a very regular hexagonal pattern of activity, like a grid. For that reason, they chose to call them grid cells.