Continuing from the previous part, we examine the brain's paradox in which calcium is both a signal and a poison, and the coevolution of intelligence and calcium.
86 Billion Neurons: The Trade-off Between Energy and Complexity
The figure of 86 billion neurons in the human brain is impressive, but for a more meaningful comparison we must measure it against other animals. The elephant's brain has about 250 billion neurons, nearly three times more than a human's. Yet we cannot regard the elephant as three times more intelligent than a human. The reason lies in the distribution of the neurons. Most of the neurons in the elephant's brain are concentrated in the cerebellum. The cerebellum plays an important role in motor control and balance, but it is not the center of higher cognitive function. In the human cerebral cortex, by contrast, there are about 16 billion neurons, the most among primates. The chimpanzee has about 6 billion, the gorilla about 9 billion. The cerebral cortex is the center of higher cognitive functions such as language, abstract thought, planning, and decision-making. What makes the human brain special is not simply the total number of neurons but the number of neurons concentrated in the cerebral cortex and the complex patterns of connection among them. And this complex pattern of connection demands complex calcium signaling. At each synapse calcium must be precisely controlled. Too little and the signal is not transmitted; too much and the cell is damaged. This precise regulation must occur simultaneously at trillions of synapses.
This complexity comes at a price. That price is energy. The human brain is only about 2 percent of body weight, yet at rest it accounts for about 20 percent of the energy consumed. An organ that is only one-fiftieth of body weight monopolizes one-fifth of the energy the whole body uses. Converted to a daily figure, this amounts to roughly 300 to 500 kilocalories; a single brain consumes the calories of one or two bowls of rice. A considerable portion of this energy is used to run ion pumps. The sodium-potassium pump maintains the membrane potential, and the calcium pump maintains the calcium concentration gradient. In Chapter 1 we learned that a cell uses about 5 to 10 percent of its total energy to maintain calcium homeostasis. Since neurons use calcium far more actively than other cells, this proportion is likely to be higher. Every time an action potential occurs, ions move across the membrane, and to restore the original state the pumps must expend ATP to bail those ions back out. With 86 billion neurons exchanging hundreds of billions of signals at every moment and repeating this process, energy consumption cannot but be enormous.
This is an evolutionary trade-off. More neurons, more synapses, more sophisticated calcium signaling. All of this demands more energy. Richard Wrangham, an anthropologist at Harvard University, proposed the hypothesis that the invention of cooking by human ancestors is related to the increase in brain size. When food is cooked with fire, it becomes easier to digest and more nutrients can be extracted. From the same amount of food one can obtain more calories than when eating raw food. This extra energy thus secured may have been used to maintain the energy-intensive brain. In fact, other primates spend a considerable portion of the day eating and chewing food. The chimpanzee spends about five hours a day chewing food. Humans, by contrast, thanks to cooking, spend far less time eating and can use that time for other activities. The claim is that cooking was the technological innovation that made the evolution of the human brain possible. Suzana Herculano-Houzel, a Brazilian neuroscientist, attempted to verify this idea quantitatively. According to her calculation, for a primate with as many neurons as the human brain to take in the necessary calories from raw food alone, it would have to spend more than nine hours a day just eating. This is unrealistic. Without cooking, the human brain might not have been able to evolve.
An Evolutionary Perspective: The Coevolution of Calcium and Intelligence
When and how did the nervous system emerge? Synthesizing the fossil record and molecular-phylogenetic evidence, the first nervous systems and synapses are estimated to have appeared in the late Ediacaran to the early Cambrian, around 600 million years ago. This corresponds to the period just before the Cambrian explosion examined in Chapter 2. The appearance of the synapse is closely related to the increasing complexity of multicellular animals. In multicellular animals cells must cooperate. Information sensed by one cell must be conveyed to other cells, and the activities of many cells must be coordinated. Even before the appearance of the synapse, cells exchanged signals with one another, but this was mainly a slow process that relied on the diffusion of molecules. When one cell released a signaling molecule, considerable time passed before that molecule diffused and reached another cell. The synapse dramatically accelerated this process. Calcium-dependent vesicle fusion made fast signal transmission on the scale of milliseconds possible. Fast signal transmission enables fast responses. When a predator appears, the animal that responds slowly is eaten, and the animal that responds quickly survives. When prey appears, the animal that responds slowly starves, and the animal that responds quickly catches the prey. The appearance of the synapse provided animals a great survival advantage, and the explosive diversification of complex animals in the Cambrian explosion is likely not unrelated to the appearance of the synapse.
As the brain grew larger, the calcium control system evolved along with it. One of the animals with the simplest nervous systems, the roundworm Caenorhabditis elegans, has exactly 302 neurons, and every connection among them has been decoded. Even in this small nervous system calcium is a key signaling molecule, but the number of synapses to manage is limited. When the number of neurons increases, however, the problem grows complex. Each neuron must manage thousands of synapses, and at each synapse calcium must be precisely controlled. If the wrong synapse is strengthened or the right synapse is weakened, information processing is distorted. As the vertebrate brain grew larger, the complexity of the calcium regulation system also increased. The kinds and expression levels of calcium-binding proteins increased, and the diversity of calcium channels increased as well. There are several kinds of presynaptic calcium channels, each with a different voltage sensitivity and gating speed, and they are expressed at different types of synapses. Some synapses transmit quickly and tire quickly; some transmit slowly but continuously. This kind of diversity makes complex information processing possible. In mammals, and especially in primates, as the cerebral cortex expanded the calcium signaling system became even more sophisticated. What makes the human brain special is not simply the number of calcium-related genes but the fact that in the cerebral cortex these genes are expressed in finely differentiated patterns across different cell types and layers, forming far more diverse combinations and networks than in other mammals.
How is the sophistication of calcium signaling connected to cognitive ability? Synaptic plasticity, the core of learning and memory, depends on the precise regulation of the calcium signal. As we saw earlier, a synapse is strengthened or weakened according to the calcium concentration. High calcium induces strengthening, low calcium induces weakening. This bidirectional regulation makes it possible for the brain to be reconfigured according to experience. When we learn something new, the relevant synapses are strengthened, and connections that are not used are weakened and removed. This is the plasticity of the brain, and it is the basis of our ability to learn new things and change throughout our lives. Higher cognitive functions such as working memory, attention, and decision-making also depend on precise regulation at the synaptic level. The neurons of the prefrontal cortex change their activity patterns on the scale of milliseconds, and this makes flexible thought possible. The fact that, while reading this sentence, you can at the same time ignore the background noise, remember what you read a moment ago, and anticipate what comes next, is because the neurons of the prefrontal cortex rapidly regulate their activity patterns through calcium signals. Uniquely human abilities such as language, abstract thought, and creativity are also, ultimately, built upon this material foundation. The calcium signals that occur at the 100 trillion synapses among 86 billion neurons create our thoughts, emotions, and memories, and all of this depends on a single ion called calcium.
Conclusion: The Material Foundation of Thought
In this chapter we have seen that calcium is central to brain function. In synaptic transmission calcium is the trigger for neurotransmitter release. This principle, discovered by Katz and Miledi in 1967, was later elucidated in detail at the molecular level, and today we understand the sophisticated molecular machine that runs from the calcium channel to synaptotagmin, from synaptotagmin to the SNARE complex, and from the SNARE complex to vesicle fusion. This process, which occurs within a few hundred microseconds to a few milliseconds, makes communication among 86 billion neurons possible and is repeated hundreds of billions of times at every moment. In learning and memory calcium is the signal of synaptic change. A coincidence detector called the NMDA receptor opens only when two neurons are activated together, letting calcium in, and the synapse is strengthened or weakened according to the calcium concentration. High calcium activates CaMKII to induce long-term potentiation, and low calcium activates calcineurin to induce long-term depression. And calcium activates CREB to promote gene expression and bring about structural changes in the synapse, converting experience into permanent memory.
Yet calcium is at once a signal and a poison. The paradox of calcium examined in Chapter 1 appears most dramatically in the brain. Calcium overload kills nerve cells, and this is the excitotoxicity that is the main cause of nerve damage after a stroke. In chronic neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, failure of calcium regulation also plays an important role. The evolution of the higher brain was a process of developing a more sophisticated calcium regulation system while taking on this risk. The calcium pumps of the cell membrane, the SERCA pump of the endoplasmic reticulum, the buffering action of the mitochondria, the concentration regulation of calcium-binding proteins, and even cooperation with glial cells. Multiple layers of safety devices keep the calcium concentration within a narrow range, making possible the tightrope walk between its usefulness as a signal and its danger as a poison. The 86 billion neurons and 100 trillion synapses of the human brain display the pinnacle of this calcium-control ability, and to maintain this complexity the brain, while being only 2 percent of body weight, consumes 20 percent of energy.
Of course, intelligence is not explained by calcium alone. Genes, developmental processes, the arrangement of neurons and synapses, and experience and learning have all piled up in layers to make the human brain of today. Calcium, as the key medium that exchanges signals upon that complex blueprint, is closer to the operating infrastructure that helps thought and memory be realized in real time. But without this infrastructure no blueprint works. Without calcium the synapse does not work, and if the synapse does not work learning and memory are impossible, and if learning and memory are impossible nothing worth calling intelligence can exist. With this we conclude Part 1. We have examined the evolution of calcium-control ability across four dimensions. In Chapter 1, which dealt with intracellular calcium management, we saw that the figure of 100 nanomolar is a fundamental design principle of life that has been conserved for 3.8 billion years. In Chapter 2, which dealt with the formation of extracellular calcium structures, we saw that the Cambrian explosion was a calcium revolution and that shells and skeletons were the external expression of calcium-control ability. In Chapter 3, which dealt with whole-body calcium homeostasis, we saw that with the move onto land the parathyroid hormone and vitamin D system evolved to manage the calcium bank called bone. And in this chapter we saw that the sophistication of calcium signaling became the material foundation of higher intelligence. Each stage was built upon the previous one, and calcium-control ability was a survival ability and a key element of evolutionary fitness.
In Part 2 we will look at how this sophisticated system breaks down. According to the DIAH hypothesis, deficiency, inflammation, acidosis, and hypoxia disturb calcium homeostasis, and this becomes the origin of chronic disease. The heart of Part 2 is to trace how the calcium-control system refined over 3.8 billion years slowly collapses under the modern living environment, and how, as a result, chronic diseases such as cardiovascular disease, diabetes, osteoporosis, and neurodegenerative disease arise. It is precisely when the sophisticated homeostatic apparatus surrounding this thinking ion, calcium, collapses that even the higher brain functions we call consciousness, memory, and personality come to be threatened together. But let us first make clear that this is not an established fact but a new perspective that this book proposes. Calcium has been with us from the beginning of life, has played a key role at every turning point of evolution, and even at this very moment is creating thought in your brain. Calcium is truly the thinking ion.
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