Wednesday, March 9, 2016

The Evolution of the Human Brain

The evolution of the human brain was one of the most significant developments in the history of life on this planet. It was one of the unintended, unpredictable consequences of the evolution of sentience in the animal kingdom perhaps 600-650 million years earlier. The evolution of the human brain, by inserting advanced consciousness into the rest of the natural world, caused a new set of randomly expressible variables to come into being. By giving a particular animal—one that walked upright and possessed true hands—an advanced level of self-awareness in conjunction with powerful cognitive abilities, the evolution of the human brain drastically altered the “balance of power” on this planet. The evolution of a brain from which consciousness could emerge in this upright animal laid the basis for the advanced cultures and complex societies humans have constructed, and all the myriad, incalculable consequences that have flowed from them.

Moreover, the evolution of a brain in which advanced cognitive processes interact with, and have a reciprocal relationship with, autonomic regulatory functions and emotional responses, has created a psychology of vast complexity. The psychological complexity generated by the physiology of the human brain is such that it is virtually impossible to trace all the origins of specific human behaviors in particular situations. There are general responses that can be predicted, of course, but a detailed analysis of human motivation is still beyond our grasp. The brain holds memories, processes and reacts to sensory stimuli, formulates judgments about the world, imagines possibilities, stores knowledge and skills, creates a life narrative, controls crucial physical movementsand weaves all of these traits into a complex whole, an individual’s personal identity or “personality”. The brain, therefore, allows for the emergence, in every human, of a self, but it is a self which may be forever beyond our full understanding.

It is the possession of a highly complex brain, therefore, that came to define those fully upright primates whose story started so long ago (from our perspective) somewhere in the great arc between southern and eastern Africa. This complex brain has retained features common to many of the more “primitive” animals in the history of life. It has evolved in a piecemeal fashion, an odd combination of the ancient, the more recent, and the strikingly modern. We need to remember that it is, after all, flesh and blood, a collection of neurons, glial cells, blood vessels, neurotransmitters, and cerebrospinal fluid, a gelatinous mass that averages 1350cc in volume and about one and a third kilograms in weight. A brain of this type creates the human frame of reference. From a brain of this type emerges the human animal’s only connection with the “real” reality. From the interactions of brains of this type have emerged the contours of human life. And from such a brain has emerged our ability to conduct an inquiry into the nature of ourselves as beings, a project which may never be finished.

We should therefore begin by noting that the evolution of the human brain has not been completely elucidated, by any means. There are still major areas in which our knowledge is scanty. This discussion, therefore, is based on the evidence we have now, with the understanding that new findings may very well supersede this evidence.

Sentience as an Emergent Property of Energy-Matter

In Volume One I stated that the emergence of the conscious from the unconscious was perhaps the most remarkable thing that had ever occurred. But how can the ability to sense the environment, the necessary precursor to the evolution of consciousness, arise out of a world completely dominated by insensate energy-matter? At the most basic level, the distinction between sentient and insentient is a subtle one. Simple exchanges of energy, small shifts of physical conditions from one state to another, are all we would see if we could examine sentience’s deep origins. And as is the case with all aspects of reality, sentience is an emergent phenomenon, made possible by the tendency of energy-matter to self-organize and bring about the emergence of higher-levels of organization. Self-organization is facilitated by the existence of electrical charge, one of the physical   features of most energy-matter. (Electromagnetism is, after all, one of the four fundamental forces of nature.) It is electricity that makes possible “signaling” or “messaging” between and within units of energy-matter. It is the ability to transmit “signals” that lies at the base of the evolution of nervous systems. As we have already seen, this ability can begin with something as basic as a simple change in the electric potential of a charged particle. (See below.)

As life evolved out of primitive metabolic processes and simple forms of replication, units of energy-matter within some living things were able to send basic signals to each other, governed by the characteristics of electricity. The Law of Whatever Works then came into play. Synergistic tendencies made possible the growth and increasing frequency of such signaling, as feedback loops and reciprocating processes were reinforced. Since this signaling facilitated reproductive success, it became more and more common. The evolution of a full-blown nervous system out of these basic processes required a whole series of emergences, involving the co-evolution of many different components.

As we saw in Volume One, tens of millions of years elapsed between the evolution of the earliest animals and the emergence of chordates. There were no doubt many dead ends in the unfolding of the story of nervous system evolution. But there was no inherent barrier that prevented the larger course of this unfolding. That it ultimately produced human consciousness was the end result of the interaction of both random chance and physical possibility.

Again: The Function of a Nervous System

So nervous systems emerged out of the fabric of physical reality on a small planet with locally favorable conditions. Why were they useful? In the previous volume, I said that plants simply respond to the world, whereas animals, to varying degrees, experience the world and then respond to it. Perhaps I should now modify that statement. The simpler an animal’s nervous system, the more we might say that it simply responds to the world rather than experiences it. The more “primitive” animals lack the capacity to do anything except respond, and the most “primitive” animals have no nervous system at all. (We might well ask here where the line between mere response and the higher-order phenomenon of experience lies, or even if such a line actually exists.)

But regardless of this, the vast majority of animals possess nervous systems, which come in many, many varieties and levels of complexity. These animals can detect and react to a greater range of energies, individual elements, and chemical compounds than plants or one-celled organisms. In Volume One (pp. 246-248), we briefly examined the reasons why the possession of a nervous system is selectively beneficial to animals, beings which are heterotrophic and in the vast majority of cases, mobile.  

The function of a nervous system is to detect the presence, near or within an animal, of energies, individual elements, and chemical compounds, especially changes in the intensity, duration, and quality of such energies, individual elements, and compounds. The “purpose” of this information is to allow for the modification and adjustment of an animal’s behavior, if need be, or to simply facilitate those functions which allow an animal to survive. Such functions would include, among many, the processing of oxygen for use by the animal, the acquisition of food (sometimes by engaging in predation),  and movement (in the vast majority of animals) to avoid injury, resist predators, or to engage in mating activity. Nervous systems are therefore networks for the communication of this information. This communication is effected by the rapid transmission of electrochemical energy along natural circuits. So where do we begin our search for the development of such systems of circuitry? How can we trace the development of the complex human brain out of the matrix of broader nervous system evolution?

Approaches to the Study of Brain Evolution

In seeking to elucidate the evolution of the human brain, we will focus on the following areas:

1.   The general nature and function of molecules that act as neurotransmitters or biomediators, and the presence in the biosphere of the requisite chemical compounds that comprise them. We will also examine some hypotheses about the origins of neurotransmitters. Further, we will look into the origin and functions of neuromodulators and neurohormones, substances which can affect the action of neurotransmitters.

2.  The stimulus-response mechanisms of one-celled organisms and how these mechanisms became the deep origins of nerve cells in animal life.

3.  The evolution of the synapse, the active gap between nerve cells over which electrochemical signals are transmitted, the development of which transformed certain kinds of cells into neurons. The nerve cell is the essential feature of nervous systems. We will look for the steps by which such cells emerged.

4.   The evolution of rudimentary nervous systems. It is, after all, the action of neurons in conjunction with each other that marks the operation of nervous systems. The animal kingdom contains a handful of members with either no nervous systems or very fundamental ones. We will see how these simple animals helped lay the foundations for the more complex nervous systems that evolved later.

5.   The evolution of the more complex nervous systems of chordates and vertebrates (in general).

6.   The evolution of the mammalian brain, and the ways it built on the vertebrate brain.

7.  The evolution of the primate brain, with an emphasis on features conserved across the primate line. We will also briefly examine the principles that appear to govern brain evolution.

8.   The emergence of the human brain, with an emphasis on the genetic changes which allowed for the expansion of the brain in what ultimately became the hominids. It now appears that the crucial changes happened in the period between three and a half million and two million years before the present.

9.   The increase in encephalization within the hominid line, and the concomitant increases in brain complexity and neuronal interconnectivity. We will recapitulate the paleontological evidence that shows the development of the brain from the animals that stand at the borderline of humanity (such as the habilines) through the emergence of Homo sapiens sapiens

The Evolution of Neurotransmitters, or Biomediators, and Their Presence in the Biosphere

It would, perhaps, be useful at this point, to reiterate that about 99% of the chemical composition of living things is simply various arrangements of carbon, hydrogen, oxygen, and nitrogen. It is these very simple and very common elements that comprise the "stuff" of life. All organic compounds are therefore basically arrangements of these ordinary atoms, occasionally augmented by other elements, and held together by chemical bonds that rely on electrons being taken or shared. So we see first that the existence of molecules capable of mediating electrical charges and sending "messages" is yet another example of an emergent phenomenon.

To electrochemically transmit “messages” within them, nervous systems use chemical entities known as neurotransmitters. In animals, neurotransmitters are found in neurons. (More specifically, neurotransmitters are contained within small sac-like structures known as endosomes.) Nerve cells do not physically touch each other. Their signals are transmitted, as I indicated above, across a gap known as a synapse. The neuron sending a signal is called the presynaptic neuron. The neuron receiving the signal is called the postsynaptic neuron. Neurotransmitters are molecules with highly specific characteristics. A substance is considered a neurotransmitter when (A) the chemical precursors necessary to synthesize it are in the presynaptic neuron, (B) the substance is released by electrical stimulation from the presynaptic neuron (activity which involves the action of calcium ions), and (C) there must be areas on the postsynaptic neuron present to receive the substance, areas known as receptors. (Not all substances believed to be neurotransmitters have been definitively proven to be so.)1 We will examine the action of neurotransmitters more closely in the next chapter. What is their origin?

Neurotransmitter-like substances and their constituent proteins existed prior to the evolution of nervous systems. Moreover, the processes by which neurotransmitters and their related proteins operate are intimately related to the rise of multicellularity itself, and these fundamental processes were already in place when animal life began to develop. While it is true that neurotransmitters have become greatly elaborated and modified by the evolution of animal life in general and nervous systems in particular, the fact remains that they were not novel features of the biosphere at the time neural networks began to develop. Neural networks used them and repurposed them in ways which were reproductively advantageous, thereby reinforcing them in a synergistic way. Interestingly, in a group of single-celled organisms known as choanoflagellates, we can see evidence that this has happened.

Choanoflagellates are the closest non-animal relative animals have. Choanoflagellates, of  course, have no nervous systems. And yet they possess proteins which in animals are essential to neural processes. A particular superfamily of proteins is indispensable in the process of signal transmission between neurons. Known as soluble N-ethylmaleimide-sensitive-factor attachment protein receptor or SNARE proteins, they operate in what is known as a SNARE complex. A particular protein, Munc18-1, appears to coordinate a SNARE complex. It does so in apparent conjunction with a protein known as Syntaxin 1. At one time, it was thought that the structure and function of this complex were unique to neurons, but in recent years a Munc18-1/Syntaxin 1 complex of similar structure and function has been found in the choanoflagellate Monosiga brevicollis. In other words, the origin of modern SNARE complexes may be very ancient, and such complexes may have been present in the common ancestor of both choanoflagellates and animals.2 (We should perhaps remind ourselves that as a general rule, the more widespread a phenomenon is in the living world, the older it is.)

Another protein essential for neuronal signaling has been found in the choanoflagellate Salpingoeca rosetta, where it interacts with a protein typically found in the cell membrane. This protein, known as Homer, is crucial to postsynaptic functions, among other tasks. The scientists researching this protein have tentatively concluded that its origin is very ancient, and like the Munc18-1/Syntaxin complex, it may have existed in the common ancestor of both animals and choanoflagellates. In their words, it may have been co-opted to perform its role in neurons.3

Neurotransmitters function by the processes of secretion. The development of the mechanisms of secretion was the crucial factor in the rise of this form of communication, and the evolution of multicellularity was deeply affected by the evolution of secretory mechanisms. It now appears that SNARE proteins played a significant role in the growth and diversification of secretory processes. SNARE proteins appear to be conserved across enormous stretches of time and a huge range of life forms. Some researchers now believe there were two major changes in the functions of SNAREs in multicellular beings such as animals. First, as animal life became more widespread and diverse the number of SNAREs found in endosomes appears to have increased significantly. Second, the increase in the number of SNAREs involved in secretory processes may have allowed secretory processes with a greater range of functions to evolve.4 In short, the method of chemical transport that would later be used in nervous systems was already beginning to develop before nervous systems themselves evolved.

Other research has confirmed the fact that the chemicals being secreted already existed by the time nervous systems first began to emerge. In a major research paper in 1988, J. C. Venter (who did pioneering work in sequencing the human genome) and a group of his colleagues pointed out that the components of intercellular communication, such as neurotransmitters, hormones, and enzymes, and the proteins we associate with neurotransmission, have been conserved over hundreds of millions of years. Venter, et al., further explained that while certain of these molecules existed in single-celled organisms, adrenergic and cholinergic receptors didn't emerge until multicellular life forms evolved. [Adrenergic receptors secrete or are activated by epinephrine or similar chemicals. Cholinergic receptors are activated by acetylcholine.] In general, what changed over millions of years was not so much the specific chemical entities themselves but rather the uses to which they were put, and the patterns of reaction and interaction into which they fell.5

The two important neurotransmitters GABA (gamma aminobutyric acid) and glutamate are found in a wide range of animal life other than Homo sapiens sapiens. They have been detected in insects, varieties of worm, and non-human mammals. (GABA acts as an inhibitory neurotransmitter, glutamate as an excitatory one.) GABA and glutamate regulate each other.  Further, the genes involved in the action of glutamate in vertebrates are found in humans, fish, mice, prototheria ("primitive", egg-laying mammals), amphibians, and all the existing reptiles and birds. The genes are found in different numbers in different life forms because of such events as the whole genome duplication in vertebrates (one of two such duplications) which apparently took place some 500 million years before the present. Some individual genes seem to have been lost after this event.6

Serotonin is also found widely among the animals, so much so that some researchers believe the mechanisms of the serotonergic system may stretch back hundreds of millions of years. As one team has put it,

Serotonin is an ancient neurotransmitter found throughout the animal kingdom, indicating an early origin of a nervous system using this neurotransmitter. More specifically, it suggests that the basic organization of the central part of the vertebrate serotonergic nervous system may already have been established in the line of invertebrate ancestors leading up to vertebrates.7

Intriguingly, the molecules we usually refer to as neurotransmitters have been found in the plant world as well. A Russian researcher has put it this way:

Today we have more and more evidence that neurotransmitters, which participate in synaptic neurotransmission, are multifunctional substances participating in developmental processes of microorganisms, plants, and animals. Moreover, their universal roles as signal and regulatory compounds are supported by studies that examine their role in and across biological kingdoms.

This researcher suggests that since what we commonly call neurotransmitters are ubiquitous throughout nature,  they should perhaps be called biomediators, the universal means by which electrochemical signals are transmitted.8

Another researcher, writing about the presence of neurotransmitters in plants, has pointed out that no fewer than 11 different neurotransmitters have been found in them so far, including melatonin (involved in the regulation of Circadian rhythms), acetylcholine, GABA, serotonin, and dopamine. Melatonin, for example, may affect such processes in plants as flowering and root formation. This same researcher, in conjunction with two others, has identified certain neuroregulators in plants, (substances such as caffeine and hyperforin that help regulate mood) and some of the neurotoxins (substances that do damage to neurons) that plants can sometimes contain, such as beta methylamino-L-alanine or BMAA. 9 , 10

Catecholamines (epinephrine, norepinephrine, and dopamine) are crucially important neurotransmitters. The amino acid tyrosine is necessary for the synthesis of catecholamines. Chemical pathways necessary for catecholamine synthesis have, in recent years, been found in plants. The functions of catecholamines in plants are not yet fully understood, but they may be implicated in protection against insects, in wound healing, and in protection against fungal invaders.11

Plants also contain endosomes, and these structures appear to perform crucial functions within them, such as helping the movement of material into plant cells (endocytosis), hormone regulation, and the physiology of roots.12 Some researchers now hypothesize that the potential for the evolution of endosomes existed in the common ancestors of animals, plants, and fungi, and that these structures evolved in parallel.13

What are some of the current hypotheses regarding the evolution of these biomediators? One group of researchers has hypothesized that acetylcholine and GABA were originally involved in cellular metabolic processes. These metabolic processes, the researchers postulate, caused the flow of these particular molecules out of cells, a flow that acted as a kind of signal. This signal may have evolved into a paracrine signal. Paracrine signals cause changes in neighboring cells, changes that can alter their functions.14 Nervous systems are driven by complex patterns of paracrine signaling.

Another researcher has hypothesized that neurotransmitters evolved by two separate and  parallel routes. In this conjecture, the first method was through chemical reactions that produced amines, purines, and amino acids, the second through the conversion of neuropeptides. (This researcher also points out that known neurotransmitters have been detected in prokaryotes, as well.) In the case of neurotransmitters based on amino acids, purines, and amines, the molecules for them either already exist or their synthesis is based on simple and well-understood reactions. The neuropeptide-based neurotransmitters seem to be genetically produced and modified after they have been chemically translated. 15  

Key roles in neurotransmission also belong to neuromodulators and neurohormones. Neuromodulators (such as somatostatin) can increase or lessen the effects of neurotransmitters, and are not necessarily released at synapses. Both neuromodulators and neurohormones can exert significant effects at points distant from their release.16  Recent research has confirmed that the molecules that control neurotransmitters, neuromodulators, and neurohormones existed prior to the evolution of nervous systems themselves, and that their evolution was facilitated by the repurposing of gene function, gene duplication (see below), and the loss of certain genes. More specifically, a major role in neurotransmission is played by what are known as G-protein-coupled receptors (GPCRs). GPCRs are receptors that exist on the surface of the cells of eukaryotes. They perform a huge number of tasks in the human body. They appear to have arisen early in the history of animal life, and neuromodulation depends on them. Both invertebrates and vertebrates inherited the signaling mechanisms used by neuromodulators from a common bilaterian ancestor. Nonetheless, certain neuromodulators affecting animal behavior appear to have evolved in parallel to each other.17, 18

So, the chemical agents involved in neurotransmission and the proteins necessary to their functions have been found throughout the world of living things, and they have existed for a very long time, although their use in nervous systems has modified them. The biological “machinery” that allowed for the basic function of neurotransmitters existed before nervous system-based neurotransmitters themselves came into being. The chemical prerequisites were already in place. As is so often the case in the living world, unconscious evolutionary processes used existing physical entities in a variety of ways.

Stimulus-Response Behavior in Single-Celled Organisms

As I pointed out in Volume One, Steven Rose, in his 1976 study of the brain, addressed the question of nervous system origins. He discussed the tendency of even one-celled organisms to exhibit “behaviors”. In explaining the response of bacteria to the presence of nutrients in their immediate environment, he pointed out how the structures on the surfaces of bacteria known as chemoreceptors must sense in some way the location of the nutrient in relation to the bacterium and cause it to move toward the food source. This action, he pointed out, could be effected by a change in the electric potential of the cells.19 The evolutionary advantage of such a property is obvious, and in the operation of this simple electrochemical system of “communication” we see, perhaps, the deep origin of the electrochemical operation of our own highly advanced nervous systems.

Since the 1970s, research on this subject has greatly expanded our understanding. We know that both prokaryotic and eukaryotic cells exhibit chemotaxis, the ability to move toward a favorable environment (or away from a noxious one) in response to some sort of chemical stimulus.  John Morgan Allman points to the example of Escherichia coli in this regard:

E. coli has more than a dozen different types of receptors on its surface. Some are specialized for the detection of different nutrients, such as particular types of sugar, which provide energy, or amino acids, which are the building blocks of proteins; other receptors are responsive to toxins, such as heavy-metal ions.20

Recent research on chemotaxis has determined that there are three primary mechanisms that control such movement. Among these mechanisms is intracellular biochemical signaling that enables the cell to respond to stimuli in its environment. Since organisms like bacteria move through the use of flagella, these biochemical signals control the function of these appendages. Most strains of motile bacteria have chemosensory processes that seem to be governed by similar types of proteins, suggesting a phylogenetic relationship among them.21

In the chapter on single-celled organisms in Volume One we briefly examined the phenomenon of ion channels, complexes of proteins on a membrane surface that make it possible for charged particles to cross through the membrane. The phospholipid bilayers (which form the structure of the cell membrane) themselves are evolved to form a barrier to water-friendly, charged molecules. Ion channels, in effect, are a kind of insulation for charged particles, giving them a pathway through otherwise hostile territory. Not everything about their structure is yet understood, but five different kinds of them have been identified.22 (Ion channels also frequently interact with GPCRs, and are often modulated by them.)23 In 2005 a team of researchers contended that the evolution of simple kinds of ion channels that could carry out complex functions may have occurred early in the history of cellular life, and that there are proteins associated with the construction of ion channels common to all three domains of living things. They argue that the different kinds of ion channels have enough “universal” features that they could have readily adapted themselves to a number of different functions during the course of evolution.24  

A researcher at the University of California has presented evidence that voltage-gated sodium (Na) permeable ion channels, or Nav, existed before the evolution of neurons themselves. (Such ion channels are what allow electrical stimulation in both animals and a wide variety of one-celled eukaryotes.) He has concluded that these channels existed in the common ancestor of choanoflagellates and animals, and later played a major role in the evolution of advanced electrically-based signal transmission in animal life.25

Single-celled organisms therefore developed receptors, areas on the surface of their membranes that chemically detected their external environment, and along with this they possessed the ability to transmit signals within themselves. It was their ion channels that facilitated electrical signal conduction. Some researchers caution us here, reminding us that there is not necessarily a straight, linear progression from chemosensory abilities to neurotransmission. But the fact remains that single-celled organisms can indeed "sense" the world and "communicate" information about it. These features are the sine qua non of nervous system function. Neurons in the human nervous system are covered with ion channels for sodium and potassium, as we will see. It is through the polarization and depolarization of these channels that neurons convey "messages". Modern human neurons are the descendants of those first cells that had the ability to use electricity to "communicate".

The Evolution of the Synapse and the Neuron  

Cells, as we saw in Volume One of this work, have existed in some form for at least 3.4 billion years. Cells have an inherent ability to use electricity to "communicate" both within themselves and with other cells, and possess ion channels which facilitate this purpose. And, as we saw above, the proteins and biomediators required for neurotransmission existed in the biosphere long before there were any nervous systems whatsoever.

Then, somewhere between 650 million and 600 million years ago, the ability of cells to transmit "information" to each other yielded, as we will see below, the first neural networks and the first true nervous systems. This epic emergent phenomenon was made possible by the evolution of the synapse. A true synapse requires the proper chemical environment and that environment's corresponding neural structures. Neurons communicate both by chemical signal and electrical signal, but these means are so intimately related to each other that we can safely call such communication electrochemical. It was the evolution of the synapse that transformed certain kinds of cells into true neurons, although the earliest synapses and neurons were far less elaborate than those possessed by humans.

As we have already seen, the protein structures necessary for neurotransmission have been found in choanoflagellates, and recent research has confirmed the strong likelihood that these proteins were in the common ancestors of both these single-celled beings and the animals.26 The search for the evolution of these proteins has led scientists to investigate their presence in simple animals. Some researchers working on this issue have focused on animals from the phylum Porifera, the sponges. As you will recall, sponges are the oldest animals for which we have any fossils, and they quite possibly lie at the very foundation of the animal kingdom itself. (Many scientists, however, contend that the animals at the base of Kingdom Animalia were either the placozoans, the jellyfish, or the ctenophores, not necessarily Porifera.) As we noted in Volume One, sponges have no nerve cells. But research has revealed that they possess the protein structures from which synapses are constructed. Further, these proteins display chemical bonding abilities strikingly similar to those proteins found in more “advanced” animals. As the authors of one study state, “A relatively small number of crucial innovations to this pre-existing structure may represent the founding changes that led to a post-synaptic element.” More specifically, this study focuses on what are known as scaffold proteins. Scaffold proteins bind and organize other proteins, and are crucially important in efficient cell signaling. The researchers found, in their words,

The data presented here support the presence of a proto-post-synaptic scaffold in the last common ancestor to all living animals. [The presence of the necessary genes, mitochondrial RNA, and binding structures in common between the sponge Amphimedon and animals with neurons] suggest the proto-post-synaptic scaffold existed as an assembled functional structure very early in animal evolution.27

Other researchers working with the sponge Amphimedon have reached a similar conclusion. They note with interest that this animal has virtually all of the genes necessary to build synapses of the type found in mammals. The evidence these researchers gathered led them to conclude that it was a "reorganization of gene expression, most likely through the modification of transcriptional regulation" that allowed for the evolution of true synapses in the early history of the animal kingdom.28

Two British researchers have also done important work in this area, focusing on the development of the complex, deeply interrelated and interacting sets of proteins that enabled the rise of synapses. Their research centers on analyzing  synapse proteomes. (As you may recall, a proteome is the complete set of proteins in a living entity.) And these researchers emphasize an important point: In a very real sense, the evolution of neural nets/nervous systems represents the shift from direct to mediated sensing of the exterior environment.

In the case of the unicellular prokaryote, the sensing is initiated at the cell's surface, where it is in direct contact with the environment. In the case of the brain, the environment of the outside world is detected by sensory organs (e.g., eyes, ears) which convert information into patterns of action potentials that are transmitted by nerve conduction to the synapses in the brain. These action potentials stimulate releases of pulses of neurotransmitters into the local extracellular environment where the receptors and signaling systems in the PSP [post-synaptic proteome] are activated. The sets of synapse proteins comprising receptors and their signaling and biosynthetic pathways arose in prokaryotes, and their role in enabling the prokaryotic organisms to respond and adapt to changing environments appears to be broadly the same role they perform in the brain.

The proteomes of pre- and post-synaptic structures originated from the single-celled life forms in different ways. Pre-synaptic release is governed by the same kind of mechanisms used by single-celled organisms to release chemicals or send "messages". Postsynaptic mechanisms involve a dense structure of receptors on cell surfaces themselves. Almost 30% of the genes that encode post-synaptic proteins in humans are found in all three of the superkingdoms (eukaryota, archaea, and bacteria). The basic structures necessary for the evolution of synapses existed in prokaryotes. It was the evolution of eukaryotes that carried these structures to a new level. It was the evolution of the protosynapse, which in all likelihood predated the emergence of axons and dendrites in neurons, that laid the foundation for the evolution of higher-level nervous systems. The ion channels possessed by the early metazoans interacted with proteins that already existed, and as the number of receptors on cell membranes grew, so did the rapidity and complexity of the signals mediated by these early synapses.29

Many researchers are now gravitating to the hypothesis that neurons arose out of the epithelium (in this instance the external covering) of members of the phylum Cnidaria (the jellyfish and related animals). One team of researchers has found that members of Cnidaria possess genes crucial for the development of nervous systems in bilaterians, indicating that these genes are very ancient in origin.30

Another group of researchers hypothesizes that the evolutionary sequence that led to the emergence of nerve cells began with the split between the choanoflagellates and the evolution of the poriferans and placozoans, each thought to contain cells that had sensory-like abilities. Then the first eumetazoans, represented by the ctenophores (comb jellies, marine animals that have some resemblances to Cnidaria but use a different method of locomotion) and cnidarians, evolved. It was these phyla, the researchers believe, that first exhibited true nerve cells, synapses, and neuromuscular transmission. Then, in this scenario, came the split between the cnidarians and the bilaterians. It was the bilaterians that evolved true central nervous systems. This research team also points out that many of the regulatory genes that govern such processes as neurogenesis (the formation of neurons) have been conserved across not only the bilaterians in general, but the cnidarians as well (although the cnidarians lack some key genes). Some regulatory genes of the same type have even been identified in the choanoflagellates. The researchers point out, however, that the processes that drove nerve cell evolution in the cnidarians, and why there are differences between their nervous systems and those of the basic bilaterians, have not been fully elucidated. They explain that understanding the patterns of gene expression in the two subkingdoms of animal life is crucial in the matter of neurogenesis.31

Other researchers are delving into the genomes of ctenophores. These researchers consider the members of phylum Ctenophora to be the possible basal animals of the animal kingdom rather than the placozoans or sponges, although they caution that the evidence is not conclusive. They note that ctenophores also have a set of genes consistent with postsynaptic function. Intriguingly, certain ctenophores have been found to contain GABA, acetylcholine, and glutamate. Whether ctenophores have presynaptic proteins comparable to animals with advanced nervous systems is an open question, but if they possess them (as sponges do not) it would strongly suggest that ctenophores were the link between the insensate and the sensate worlds.32

One team of researchers has hypothesized that the growth of nervous system sophistication was not driven simply by an increase in the number of synapses in animal brains. It was also driven by the proliferation of many different synaptic proteins (at least 600 varieties in mammals) which allowed for the more efficient processing of nerve signals, and with that, the development of more complex behaviors. According to these researchers' findings, the evolution of the synapse seems to have been driven by two distinct periods of acceleration. The first was an "explosion" of proteins about one billion years ago, when the first multicellular animals may have evolved. The second period of acceleration seems to have occurred about 500 million ybp, as the vertebrates began to emerge. The key finding:

Most important for understanding of human thought, they found the expansion in proteins that occurred in vertebrates provided a pool of proteins that were used for making different parts of the brain into the specialised regions such as cortex, cerebellum and spinal cord.

More numerous and diverse proteins, therefore, may have made more complex brains possible.33

As synapses evolved, more complex and communicative neurons evolved along with them. But the original neurons probably lacked the complexity of later versions. As neurologist R. Joseph has put it:

The first neurons were not well developed. Indeed, it is likely that these first neural cells were without axons,[long, thread-like structures that transmit signals] and were probably without dendrites [tree branch-like structures that receive signals]. Instead, these first primitive neurons simply secreted electrical and chemical substances which acted on other cells in a generalized manner. Later, neurons developed the ability to grow a single, long, thin axonal transmission fiber through which these same electrochemicals could be selectively secreted to a second neuron. The dendrite of this second neuron in turn would absorb these chemicals molecule by molecule via a selective receptor surface located along its terminal junctions.34

There is the possibility that the neuron evolved more than once. Some recent research at this writing claims that, based on genomic studies, the comb jellies indeed lie at the base of the animal kingdom [as some other scientists contend] and that their neurons have evolved in a distinctive way, indicating that the neurons that led to the nervous systems of the cnidarians and bilaterians evolved separately. But other scientists contend that the studies that place Ctenophora in the basal position are flawed and the much more "primitive" sponges are the first true animals. Another researcher points out that ctenophores and bilaterians could have had common neuronal ancestry but then evolved along separate, accelerated lines.35, 36

Animals can move in one of two ways: through muscular action or movement by means of cilia. One researcher has hypothesized that neurons arose to coordinate the action of cilia. This scientist has focused on a large animal group known as the spiralians, which contains various worms and mollusks, noting the concentration of their sensory-motor neurons.  He hypothesizes that although improved circuitry may have made the swimming of ciliated animals more efficient, the major reason that the motors controlling cilia became more concentrated is that this concentration condensed the length of the circuitry, and reduced the number of cells and synapses involved in facilitating movement.37

In sum, the early forms of animal life, even though lacking true nervous systems, nonetheless possessed sensory cells. These cells possessed the ability to respond to chemicals, light, and/or gravity.  Certain arrangements of proteins and simple elements in the external environment of these animals, coupled with genetic regulatory changes within them, led to the early evolution of synapses by means of exaptation. It was these synapses that allowed certain cells to electrochemically "communicate" with others. It was the evolution of increasingly sophisticated synaptic structures that allowed these sensory cell types to evolve into genuine neurons. We are not certain in which phylum this momentous event occurred.

It bears repeating that it is not just the set of genes that matters in looking for the evolution of the synapse and the neuron. It is the pattern of gene expression that is of paramount importance. This expression was controlled by complexes of regulatory genes that used existing structures in new ways. In fact, regulatory sequences that change in their function may lie at the root of many evolutionary changes. The outcome of these genetic changes, as we will see in greater detail below, was sensory transduction, the conversion of sensory information into an electrochemical signal.

It is my supposition that neurons and synapses developed in a synergistic fashion, facilitated by increasingly complex arrangements of proteins that in turn allowed for more rapid and advanced forms of electrochemical signaling, which allowed for more complex proteomes to evolve. The evolution of the synapse, in one respect, is an example of natural selection being "opportunistic", unconsciously using whatever means and materials were at hand to "encourage" reproductive success.

From Neurons to the Simplest Brains

At what point does a brain emerge from a mass of nerve cells connected by synapses? It is likely that neurons scattered across the surface of ancient, jelly-like animals were connected to each other in a nerve net. But this may not have been the true precursor to a brain. So we must look to the origin of the bilaterians.

All bilaterally symmetrical animals are descended, most scientists now believe, from a single bilaterian, an animal called simply Urbilateria. It is now thought that this animal evolved approximately 600 million ybp. The physical traits of the first true bilaterian are not definitely known yet. However, two researchers who have carefully analyzed both the morphological and genetic evidence have come to the conclusion that Urbilateria was a segmented, worm-like animal with very basic eyes, basic appendages, and most significantly, in their words, "a centralized nervous system with a regionalized brain and ventral nerve cord"38.

In the view of many researchers, there seem to be sufficient conserved features in all the nervous systems of the members of Subkingdom Bilateria to warrant the view that there is a single, original type of nervous system in the subkingdom from which all others are derived. (Others believe vertebrates and invertebrates trace the evolution of their central nervous systems to separate lineages.) There is evidence that the molecular mechanisms that control the development of nervous systems in beings as widely separated as worms and chordates are very similar.39 One particular researcher points out that the genetic array that produces a dorsal-ventral (back to front) orientation of the nervous system is conserved in both superphylum Protostomia [the arthropods, segmented worms, mollusks, etc.] and superphylum Deuterostomia [the other animals that possess a coelom]. It is his overall view that all the basic circuitry was in place in Urbilateria, circuitry that would be prove to be useful in a variety of nervous system functions.40

Further support for the view that Urbilateria bequeathed all bilaterians with their basic nervous system structure comes from research on control genes in invertebrates and vertebrates. One researcher, focusing on genes that regulate neural stem cells and embryonic development, has concluded:

Comparative studies of different aspects of brain development in vertebrates and invertebrates reveal remarkable similarities in expression and function of key developmental control genes. Indeed, vertebrates and invertebrates share a complex set of control genes and molecular genetic interactions that are responsible for neural induction, regionalized patterning, progenitor proliferation and circuit formation in the developing brain. This suggests that many of the molecular mechanisms involved in building the brains of extant bilaterians may already have been present in their common urbilaterian ancestor.41

In general, genes are expressed or not expressed in the developing neural tube in ways that are similar across the bilaterian subkingdom.

The first true brains seem to have evolved out of bundles of nerves known as ganglia. Specifically, the first brains may have been examples of cerebral ganglia, a phenomenon associated with cephalization, the acquisition by a line of organisms of a distinct head. But how to define the term "brain"? Two researchers introduce their study on the subject with a very convincing definition: a brain governs the whole of the animal, not just a part of it, it has distinct sections that carry out specialized tasks, it has two lobes, its surface is comprised of connected bundles of nerve tissue and nerve cells and its core by axons, neurons that communicate directly within distinct areas of the brain are more numerous than neurons involved in motor or sensory tasks, and the circuitry within a brain tends to have multiple synapses rather than single ones.42

Brains are biologically "expensive", which is to say they take a lot of finite physical resources to build and maintain. Brains may have appeared and disappeared several times in the early course of central nervous system evolution. Some researchers, examining the evidence of the Ediacaran fauna, believe this may have happened as many as four times, while other specialists, analyzing genetic data, are convinced Urbilateria's brain became the template for all others.43

The utility of possessing a brain of some sort—a place where electrochemical sensory signals can be received, coordinated, transduced, and acted upon—is so great that the possession of a brain has come to be a major feature of the vast majority of bilaterians. Research in the early years of the 21st century has revealed that about 90% of all known animal species possess a brain. As one of the major researchers in the field of brain evolution has put it, "Clearly, the evolution of a brain as part of an adaptive suite has been under heavy selective pressure."44 Put another way, we can say this: Brains facilitate survival. They confer reproductive advantage. They have been doing so for about six million centuries. The more sophisticated and capable the brain, the greater the advantage to that brain's possessor.

Vertebrates have more sophisticated brains than invertebrates, and thus greater advantages. In the individual development of invertebrates such as worms, arthropods, and certain mollusks, the brain develops out of a cerebral ganglion. In modern vertebrates brains form from the embryo's neural tube rather than from cerebral ganglia. How did the chordates and the vertebrates come to have more advanced brain structures, and a deeper perception of the exterior world?

The Evolution of the Chordate and Vertebrate Nervous Systems

As we saw in Volume One, the earliest chordates yet described have been discovered in the Kunming region of southern China, dating from about 515 million to perhaps as early as 530 million ybp. As we also saw, two of the chordates discovered there appear to be primitive vertebrates. What evidence do we have about the brains of the earliest chordates? Many researchers have focused on the amphioxus, commonly known as the lancelet, a marine invertebrate. (See the discussion in Volume One, pp. 253-254.) A researcher looking for clues in amphioxus has concluded that major elements of what he calls the ancestral brain of the chordate were located near the mouth, and assisted in the acquisition of food.45 Other researchers examining amphioxus, the closest invertebrate relative to the vertebrates, have concluded that its original version was the last common ancestor of both vertebrates and invertebrates. Their research also confirms that there were two whole genome duplications that brought about the rise of the vertebrates.46 (As you may recall, whole genome duplications are when multiple copies of parental genes are inherited in reproduction.) Such duplications are often harmful, but on occasion their outcomes are advantageous enough to be "chosen" by natural selection. These duplications provided large numbers of genes that could be blindly repurposed for other uses. For example, as we saw in the previous volume, the four clusters of Hox genes possessed by vertebrates (as opposed to the single cluster in amphioxus) are the basis of the backbones that define a vertebrate.

Along with the rise of vertebrates came a more elaborate brain, a brain which had roots going back to Urbilateria but which showed a new level of organizational sophistication. Vertebrates possess a tripartite brain. This means that vertebrate brains all possess a forebrain (which develops from the embryonic prosencephalon), the midbrain (which develops from the embryonic mesencephalon) and the hindbrain (which develops from the rhombencephalon, and is divided into the metencephalon and myelencephalon).

Interestingly, all vertebrates, with one minor exception (the agnathans), possess the same number of brain divisions within this tripartite scheme. Each of these vertebrate brains possesses an olfactory bulb, an accessory olfactory bulb, a cerebellum, cerebral hemispheres, a medulla oblongata, an optic tectum, and a pituitary gland. These structures vary greatly in size and complexity across species, but the fact that similar structures exist in (virtually all) fish, reptiles, amphibians, birds, and mammals gives us strong evidence of the evolutionary ties between the vertebrate classes of the animal kingdom. It also demonstrates how powerful a principle the conservation of brain structures actually is.47 (We will touch on the functions of these divisions in the next chapter.)

A pair of European scientists has studied gene expression in the zebrafish to gain insights 2about vertebrate tripartite brain evolution. Their research indicates that the tripartite zebrafish brain reflects different periods of evolutionary history. One part of its brain reflects the earliest form of nervous system. Another major region reflects the emergence of chordates, and the third major region reflects what they call "a genuine vertebrate innovation", an advanced region of the cerebrum--the upper and largest part of the brain of vertebrates--known as the pallium.48 The pallium is the outer layer of tissue of the cerebrum. But other scientists place the deep origins of the pallium within the invertebrate line. Researchers examining a type of marine worm have found structures in the worms' brains similar to the vertebrate pallium. Since the vertebrates and these earthworm-like creatures last shared an ancestor 600 million years ago, that pushes the pallium's origins far deeper into the past than we had suspected.49 In vertebrates, the pallium became the basis of what ultimately came to be known as the cerebral cortex (although the terms pallium and cortex are not synonymous). The full evolution of the cortex in our genus ultimately brought about the dominance of humans in the living world.

The genes that govern neuronal development and diversity are known as clustered protocadherins. Only discovered in the late 1990s, these genes encode protocadherin proteins. Recent research has found that these genes are conserved throughout all vertebrates, and hence are very, very old.50 Other recent research has discovered protocadherins in cephalopods (such as the octopus and the squid) as well, the first invertebrates in which they have been discovered, which would indicate such gene clusters are even more ancient than supposed.51

Some researchers looking into the evolution of the vertebrate brain have concluded that certain clusters of protocadherin genes evolved through gene conversion, which is when genetic material is replaced by highly similar DNA from another section of it. These researchers also found that gene duplication and other factors played a role as well.52 Other researchers investigating the role of protocadherin genes have found, in their words, "The majority of vertebrate protocadherin (Pcdh) genes are clustered in a single genomic locus, and this remarkable genomic organization is highly conserved from teleosts [ray-finned fish] to humans." Protocadherin genes appear to play a role in many neural processes.53

Not only do almost all vertebrates have the same number of brain divisions, but vertebrate brain size has grown, albeit at variable and independent rates within the major vertebrate radiations. These increases in brain size have in turn often brought about increases in the number and variety of neurons, and, in all likelihood, more complex behaviors. Since basic vertebrate brain structures have been conserved across the major vertebrate lines, it is probable that this arrangement arose early in vertebrate history, but fossil support for this contention is limited.54

Vertebrate brain size is related to general body size. As body size increases, so does brain size, but it does so in an allometric way. [This is to say, generally, that brains do not grow proportionally to bodies in vertebrates. They tend rather, to grow disproportionally large.]

Different types of vertebrates have seen different rates of brain expansion. As one of the foremost experts in vertebrate brain evolution has put it,

Both birds and mammals have brains that are 6–10 times larger than the brains of reptiles of the same body size. Among birds, the largest brains for body size are seen in perching birds, woodpeckers, and parrots, while the relatively smallest brains are found in pigeons and chicken-like birds. Similarly, mammals have brain sizes that are 10 times larger than those in reptiles of the same body size. Primates and cetaceans have the largest brains for their body size, while non-placental mammals, marsupials, insectivores, and rodents have the relatively smallest brains.55

The development of the brain in vertebrates was facilitated (in part) by the neural crest, a feature of the embryo we first encountered in Volume One (page 253) in connection with the vertebrate skeleton and other structures. Two French scientists investigating the neural crest's role point out that the NC "played a crucial role in the protection of the developing brain by encasing it within the skull and generating the face." The NC also plays a role in generating neurons, especially in those areas of the brain that are most recent from an evolutionary standpoint.56

Neurons in vertebrates are characterized by (A) the body of the cell itself (the soma), (B) a long, thin signal-transmitting thread known as an axon that ends in branch-like structures (C) other branch-like structures known as dendrites that receive signals, and (D) various substructures, such as dendritic spines, which we will examine in the next chapter. A striking feature of vertebrate axons is that they are myelinated.  The myelin sheath is a fatty membrane surrounding the axon. In the central nervous system myelin sheaths are generated by a particular variety of glial cell. (Glial cells may broadly be thought of as structural support cells.) In the peripheral nervous system these coverings are generated by Schwann cells. It is an oversimplification, but myelin sheaths can be thought of as electrical insulation. They facilitate the flow of energy through the axon. There are small gaps in the myelin sheath known as nodes of Ranvier, where sodium channels are found. These nodes are crucially important, as we will see in more detail in the next chapter.57

Myelin sheaths are not exclusive to vertebrates. Such sheaths are also found in worm-like animals and arthropods, for example. Many scientists are now convinced that the myelin found in chordates, annelids, and arthropods has separate and independent evolutionary roots.58,59. But other research points to the fact the myelin found in vertebrates is more efficient, more like a "true" myelin sheath than the coverings found in invertebrates. Vertebrate myelin allows for a much higher conduction speed of action potentials. It can be argued that the widespread acquisition of these efficient myelin sheaths and axons in vertebrates was a crucial advantage for the members of this subphylum, allowing for the generally larger body sizes of vertebrates.60

So vertebrate brains represented an evolutionary leap, so to speak. Their tripartite structure reflected the various evolutionary stages that had brought them into being. These brains had largely uniform divisions, a tendency toward large size in relation to the body, a distinctive and ancient genetic basis, increased physical protection, and myelinated axons. They set the stage, so to speak, for the even larger breakthroughs to come.

The Evolution of the Mammalian Brain

As you may recall, the earliest true mammals, which emerged between 200 million and 225 million ybp, were unimpressive animals. Their brains  were, at first, small, and in the first mammals the sense of smell was probably the chief way by which they explored the world. How do we trace the evolution of the mammalian brain from such humble beginnings? Phylogenetic analysis has revealed to us the genetic relationships between mammalian clades, and has, in conjunction with fossil analysis, given us crucial insight into brain evolution in our class.

Among the most significant features of the mammalian brain has been its expansion (as we will see below). Intensive research has begun to reveal the genetic structure that facilitated this expansion. One particular brain researcher has first explained that all cells are involved in four crucial processes—division, differentiation, migration, and planned cell death, [or apoptosis]. In the specific case of the brain: (A) Division generates neural cells in the developing embryo. (B) Differentiation separates these newly generated neural cells into specialized types. In the human brain there may be more than 100,000 different neuronal specializations. (C) Migration is the movement of neural cells from their point of generation to that part of the developing brain where they will function. (We will examine migration more closely below.) (D) Planned cell death, or apoptosis, [to which we referred in Volume One] helps shape the developing brain. He then explains that gene expression controls all of these processes.61 There are genes that have been conserved since the time of the earliest vertebrates, and genes that seem to be conserved more specifically across the various mammalian species, as we will see below.

The proteins and genes that control gene expression are being identified, as are genes and proteins from the early vertebrate line that play a crucial role in mammals. For example, the protein FGF8 in rodents controls a gene called Emx2. Emx2 controls the balance in size between the hippocampus and the frontal cortex. [We will examine these structures in more detail elsewhere.] More broadly, it appears that many of the genes that are involved in embryonic brain development have roles to play in other regions of the body. The Pax6 protein, which appears to be very ancient, encoded by the Pax6 gene, plays a crucial role in the formation of the eye, as well as having other functions. Otx2 governs the size relationship of the midbrain and the hindbrain. There are, it seems, thousands of genes implicated in the brain's development.62 (You may recall that there are such things as control proteins which govern genes, and control genes that encode specific proteins, all of which are implicated in gene expression.)

The key evolutionary development in mammals was the emergence of the neocortex—the dominant part of the brain in humans. The neocortex appears to be exclusively a mammalian trait.63 The neocortex in humans is the gray matter that covers the cerebral hemispheres. The possession of a complex neocortex gives mammals a crucial survival edge: the ability to adapt quickly to unexpected changes in the environment around them. The mammal with the greatest ability to do this is Homo sapiens sapiens. It is in the neocortex that the higher functions of human consciousness lie.  It is the possession of the most advanced neocortex in the animal kingdom that has made humans the most powerful multicellular life form on the planet.

The mammalian neocortex evolved a six layer structure. [The layers are labeled I to VI, with I being the outermost and VI the innermost.] Each layer has distinct functions. Sensory information is communicated layer to layer, from one set of neurons to another. As one of the foremost researchers in this area has put it, "This innovation allows serial steps in cortical processing of sensory information, so that very complex computations are possible." It is not yet clear how this layer-like organization evolved, but the neocortex in general has given the mammals a decisive advantage over the reptiles. 64

Different kinds of mammals evolved neocortices of different complexity. Since (A) brain tissue is metabolically very "expensive", (B) complex brains take time to develop, and (C) the offspring of animals with complex brains require more time to mature, the growth of the brain in general and the neocortex in particular require a large "reward" in the form of survival benefits conferred. The analysis of contemporary mammal species has been useful in elucidating how these different types of neocortex emerged. In addition to a strong emphasis on olfaction,  the first mammals may have possessed an acute sense of hearing, chiefly the capacity for hearing very high frequency sound waves. The evidence also indicates that early mammals had cortices divided into 15-20 sections, with each section having a distinctive structure and function.65

In order to understand the evolution and function of the neocortex, it is necessary to understand the role of interneurons. Interneurons function entirely within a particular region of the central nervous system, chiefly in specific areas of the brain. They act as relay neurons, helping to establish connections between sensory and motor neurons. In a developing embryo, interneurons migrate from their point of origin to the region that will become the neocortex. In the early evolutionary history of mammals, changes in the migratory abilities of interneurons containing the inhibitory neurotransmitter GABA may have helped bring about the evolution of the neocortex.66 In other words, the distribution pattern of those neurons that help establish neural circuitry may have changed in such a way as to become self-reinforcing.

The evolution of the neocortex may also have been facilitated by variations in the number of neural progenitor cells. Progenitor cells are a type of cell similar to stem cells but they produce more limited and specific types of cells. Large populations of neural progenitor cells in a region of the embryonic brain called the subventricular zone (SVZ) can contribute to neocortices of large size and complexity. According to one team of researchers, the outer SVZ or OSVZ affects both the number of neurons and the direction in which migrating neurons travel upon being generated. (The SVZ in adults is one of the sites in the brain implicated in neurogenesis.) In the evolutionary history of the mammals, but especially the primates, the OSVZ was, quite possibly, of key significance in bringing about the enlargement of the neocortex.67  

The abilities of the neocortex do not depend solely on the density and variety of neurons. They are also the product of the folding that is characteristic of advanced mammalian brains. [This folding gives advanced neocortices a wrinkled appearance. The grooves that cause this wrinkled appearance are called sulci, singular sulcus. The ridges between these grooves are called gyri, singular gyrus.] An advanced neocortex is folded in on itself, creating a substantially increased surface area. This increased surface area in turn creates dense masses of interacting neurons, facilitating the advanced functions of the neocortex.  Research has revealed that during mammalian evolution the neocortex has undergone numerous episodes of expansion. The processes of neurogenesis may be implicated in these episodes, as we have noted. It is important to bear in mind that this neocortical growth has happened in the context of specific selection pressures that interact with genetic predisposition. One team of researchers offers a hypothesis that explains how different neocortical sizes among mammalian species arose:

Differential growth across the neocortex and between species, however, may tell us how variation in neocortical size is achieved, even if it will not necessarily inform us of the environmental selection pressures effecting that variation. Here, we have taken a reductionist approach by claiming that a gross neuroanatomical feature (neocortical folding) may signify differences in neurogenic programming both within an individual and across species. We have made this claim based on evidence that neocortical size is determined before any neuronal connections are established and on the assumption that the formation of neocortical gyri is the result of an interaction between selection pressures in cognitive or sensory behavior and the cell-biological properties of neural progenitors throughout neurogenesis.68

In short, certain types of mammalian behaviors and sensory experiences were made possible by the neocortical expansion that may have been brought about by changes in how neurons are generated within the subventricular zone. Different environments "rewarded" or "discouraged" different behaviors and sensory capacities, accounting for variations in neocortical features across the various orders and species within Class Mammalia. There is also evidence that during mammalian evolution there were changes in patterns of gene expression in the regions of the brain involved in neurogenesis, changes that contributed to the folding of the neocortex.69 (This folding  is a phenomenon known, by the way, as gyrencephaly.) More broadly, genes with a variety of functions or which acted in similar ways in a variety of bodily regions had a profound impact on brain evolution.

Within the neocortex itself different tasks are carried out by different regions. The process by which functions are subdivided is known as arealization. Two French researchers investigating this phenomenon have also looked to those regions of the embryonic brain involved in neurogenesis in order to understand how arealization occurs. They emphasize that while the neocortical structure shows a great deal of conservation across species, indicating strong genetic similarities in what they call neocortical patterning, the plasticity of the neocortex, its ability to rewire its structures and establish new connections in the face of sensory impairments tells us that there may be other factors at work. [Plasticity can also have broader definitions, as we will see below.] After considering a number of the major hypotheses concerning the wiring, shaping, and location of different neocortical areas, and noting the fact that there is not always a direct correlation between the presence or absence of certain genes and the presence or absence of certain sensory areas, the authors make the following observation: "is it reasonable to consider cortical areas as emergent properties of a complex system...? In this case different mechanisms may concur, either independently or synergistically, in creating the specific cytoarchitecture and connectivity of a given neocortical area." The authors emphasize that this may account for the plasticity of the cerebral cortex both in the embryonic and post-embryonic stages.70

So the emergence of the advanced neocortex may have been brought about by a complex, synergistic interaction between those regions of the developing brain that generate neurons, the expression patterns of genes within the various mammalian species, and particular selection pressures in the environments in which these mammals evolved. This interaction "rewarded" neocortices that exhibited pronounced folding, folding which facilitated the division of the neocortex into areas with distinct functions. Perhaps these functions may have helped bring about the six layered structure of the neocortex, which in turn would have been aided by this structure.

The Evolution of the Primate Brain

As we saw, the first primates probably emerged about 65 million ybp, although an earlier emergence, perhaps at 85-90 million ybp, is certainly a possibility. Primates are distinguished in part by their well-developed brains. While the primates are certainly not alone in Class Mammalia in the possession of advanced brains—the cetaceans are also impressive in this respect—it is the combination of the prehensibility of primate extremities, the acuteness of primate vision, and the physical agility of primates in conjunction with their unusual mental abilities that has proven so advantageous to the members of Order Primates. Those primates that developed first, facultative bipedalism (the ability to use bipedalism for specific tasks) and then, ultimately, obligate bipedalism (the habitual use of upright postures and walking) were especially well-served by these advanced brains. How did the primates acquire such brains?

One approach is to first note the differences between the sensory apparatuses of primates and those of the rest of the mammals, and the genetic factors that account for them, then to investigate the broader genetic factors affecting primate brain evolution. Primates generally have a poor sense of smell. Primates generally have excellent vision, with the more "advanced" primates possessing vision that is both stereoscopic (which means that images from both eyes are resolved into a single image, which allows for superior depth perception) and trichromatic (which simply means these primates perceive a wide range of colors). A researcher looking into these phenomena first focuses on gene expression affecting primate olfaction:

Mammalian olfactory receptors, a gene superfamily consisting of more than one thousand genes, form a significant portion of the mammalian genome. This extensive diversity is likely the result of olfactory receptors specific binding to odorant molecules. But this specificity that leads to such variety overall also leads to significant losses when a given organism is not exposed to the odorant. In rodents and dogs, only 20% of the olfactory receptor genes are nonfunctional and yet in humans fully 60% of olfactory receptors have undergone pseudogenization...[Pseudogenization means the gene has lost its ability to code a protein.] While initially focused on the human genome, this finding has also held up across other non-human primate species, correlating well with the relative roles of visual and olfactory perception.71

Pronounced differences between primates and other mammals in genes affecting the sense of taste have also been noted, and the genetic basis of trichromatic vision in the Old World monkeys, apes, and humans has been determined as well.72 The researcher examining these phenomena believes that the broader picture of brain evolution is also amenable to the methods of genomics, but, so far, only to an extent.

Generally speaking, mutations in DNA that don't alter the making of amino acids, and consequently the encoding of proteins, are called synonymous mutations. Mutations that alter amino acids, and typically change the encoding of a protein, are called nonsynonymous mutations. Algorithms have been developed that measure the rate of change caused by non-neutral mutations. The rates of synonymous as opposed to nonsynonymous mutation can be stated as a ratio (expressed as a decimal) which tells us something about the selection pressures being exerted on a given species. In the case of primates, this ratio seems to be low. However, although this method of tracking changes in primate brains has its uses, it is limited in certain respects. Selection pressures affecting the brain can be very complex. Individual genes can even be under multiple selection pressures. And there is a somewhat surprising result we have seen from genomic analysis: "...there simply are not a tremendous number of species-unique genes. The gene complement of each of the primate species is largely the same enough so the exceptions warrant significant attention even in the absence of any functional understanding."73

The most obvious feature of primate brain evolution been the growth of the brain's size. Each branching of primates has brought with it changes in encephalization (again, the ratio of expected brain size to body size). But not only has there been an increase in size, there has been an increase in complexity, an increase in neuronal interconnectivity and interaction. Locating the specific genetic substrates of these changes has been a challenge. What have we been able to ascertain?

First, it must be understood that although many genes influencing the primate brain have been identified, their specific functions are not always clear. But some progress has been made. Genes connected with certain disorders such as microcephaly (which is apparently linked to the genes ASPM and microcephalin) and speech disorders (apparently linked to FOXP2) have been identified. [ASPM may also have a major role in the expansion of the cortex.] FOXP2, you may recall, was discussed in Volume One in relation to the ability of humans to speak. FOXP2 is broadly conserved across mammals, (and some birds) but the version of it inherited by humans differs from all others. Further, the whimsically named sonic hedgehog (SHH) gene seems to have been positively selected in the line that led to the evolution of the apes. SHH is a regulatory gene that is implicated in the development of a broad range of different tissues.74

Two scientists from Cambridge have been analyzing the role of a gene named NIN. NIN appears to have evolved during the period in which the anthropoids were evolving. (As you may recall, the anthropoids, the so-called "man-like" primates, are the members of suborder Haplorhini, a group which contains the vast majority of the world's primates.) NIN is involved in the functioning of what are known as radial glial cells. RGCs are involved in neurogenesis in the developing central nervous system. It appears according to this research that NIN may have made a significant contribution to anthropoid brain size.75

However, as we noted above, it is not simply the size of the primate brain that is significant in assessing its evolution, but its complexity as well. The anthropoids exhibit brains more sophisticated than any other land animal. According to recent research, in the course of 40 million years of evolution among Haplorhini, the various species within the suborder have demonstrated a significant range of neocortical development in response to different environments. The organizational sophistication of anthropoid brains seems to owe a great deal to the white matter (brain tissue below the surface of the cortex) of the prefrontal cortex. [The significance of the prefrontal cortex was touched on briefly in Volume One.] The prefrontal cortex is crucial to such functions as social interaction, goal direction, and the general synthesis of information. It is the prefrontal cortex that seems to be under particular selection pressure in the anthropoids. In apes the white matter of the prefrontal cortex seems to develop right along with increased brain sizes, and in humans the relationship is especially pronounced. In the words of two researchers examining this relationship, "enhanced connectivity in the prefrontal cortex accompanied the evolution of the human brain". It is striking, by the way, that even in primates where brain size seems to have diminished over time, the importance of prefrontal white matter remains.76

Further, brain structures associated with learning acquired by stimulus-response and habit-formation, and structures associated with cognitive memory, appear to be emphasized in the great apes. In smaller primates, brain structures associated with spatial memory, necessary for movement in a variety of settings, may be under strong selective pressure. The great apes and the monkeys also appear to have parted ways in their  different emphases on the development of the cortex and the cerebellum. The apes have "invested" their brain development in these areas, whereas the small primates have developed a greater emphasis on parts of the brain involved in physical agility. It now appears that it was the more advanced organization of the higher primates' brains in conjunction with the growth of their brain sizes that allowed the great apes and humans to stand out among the primates. Varied selection pressures on different species of primates produced what the researchers investigating primate brain evolution call a "mosaic", one in which different brain structures grew and developed in a variety of ways. The development of differences between the brains of apes and Old World monkeys may have begun 20 to 30 million years before the present.77

Additionally, an embryonic structure known as the cortical subplate, found beneath an embryo's developing neocortex, is also thought by some researchers to have been a key element in the evolution of the primate brain. Although it appears that the subplate has long existed in the history of animal life, it is very pronounced in primates. The evidence shows that the subplate is involved in the organization of axons and general neuronal interconnectivity, linking with various other structures as it pushes its connections outward, and adding a great many neurons in the developmental process.78

So, primate sensory abilities were shaped by the interaction of primate species with the various environments in which they lived. Perhaps, as early primates ascended higher into the forests of the world, they left the rich world of smells farther and farther behind, leaving it to their ground-dwelling mammalian relatives such as the carnivores to live in and adapt to this richness, while their own olfactory powers atrophied. The perilous environment in which the primates lived rewarded brains with a pronounced shift toward visual capacities. The genes influencing the primate brain, building on the vertebrate tripartite structural inheritance and the six-layered mammalian neocortex, began adapting different primate species' brains to different conditions, "rewarding" the prefrontal cortex, particularly in the larger anthropoids. Brain structures that permitted intense neuronal interactions, and increasingly intricate linkages between different areas of the brain, were selected more and more.

And as the primate brain evolved, especially the brains found in the larger anthropoids, a strong feedback loop between the exterior world of experience and the interior world of cerebral anatomy and physiology was established. The complexity and size of the primate brain appear to have been affected by what is called sociality, an increasingly dense web of interactions among the members of a primate population group. This sociality "rewarded" or "discouraged" different traits, in so doing shaping reproductive success or failure within a given primate group. Behaviors reflected genetic inheritances. Multiple genetic inheritances came together in complex ways in some species, giving rise to behaviors more novel, varied, and unpredictable than those which came before. Even more significantly, these genetic inheritances allowed certain primates to learn more about the exterior world than any animals prior to them ever had. Things learned that facilitated survival led, increasingly, to the perpetuation of the combinations of genes that had given rise to them. This ability to learn, and the mental agility it reflected, also came in handy in matters of self-defense. Primates could not always defeat adversaries by sheer physical strength (although many primates were and are physically formidable). But now some of them were developing the ability to outwit those attacking them, especially by joining in mutual, cooperative action to do so.

The social brain hypothesis, which postulates that the large brain size of primates is, in major part, a result of the demands placed on them by the complexity of primate social life, is now widely accepted. There are degrees of sociality among certain other mammals, but such relationships are especially intense among primates. The particular forms primate sociality takes have a decisive impact on primate group size. Very intense interaction tends to constrain the size of a primate group because of the cognitive demands such a group places on the individual. The evidence shows that the larger anthropoids also show a tendency toward pair bonding. These pair bonding tendencies appear to affect not only the reproductive process but also other types of relationships, creating alliances and loyalties between group members.79

The preponderance of evidence now leans toward the view that resisting predation was the main issue facing early primate groups, and hence the greatest stimulus toward primate brain evolution. It also appears that neocortical growth, not simply the general growth of the brain, is the major determinant of group size and interactional complexity among primate groups. Intriguingly, neocortical growth may have made a major impact both on primate mating patterns and the ability of primates to deceive other animals, as one scientist notes:

... male mating strategies are a function of relative  neocortex  size  In  this  case,  the  correlation  between  male  dominance  rank  and mating success was a negative function of neocortex ratio: In other words, in larger brained species, low-ranking males are able to subvert high-ranking males’ abilities to monopolize matings,  but  in  small-brained  species  they  are  not  (presumably  because  they  lack  the cognitive abilities to exploit loopholes such as alliances and female choice).Similarly, [researchers have found] that grooming clique size (a proxy for alliances) correlated with relative neocortex size [and it has been]reported that rates of deception (standardized by number of studies on the species) also correlated with neocortex size.80

Furthermore, primates engage in grooming behaviors as a form of bonding, and cooperate in foraging. Neocortical development seems to have a great impact on such behaviors, but the exact mechanisms by which this occurs have yet to be elucidated.81 But what is most significant is this: behaviors such as mutual defense, pair bonding, deceiving external enemies, forming alliances, grooming, and group foraging reinforced group cohesion and group survival. The factors that gave rise to these behaviors were selected, and they became self-reinforcing. Later, tool making would establish a similar pattern of self-reinforcing feedback.

Scientists looking at all these processes have attempted to formulate some general principles that seem to govern the evolutionary growth we have been examining. Comparative neuroanatomist George Striedter has offered several of them. Striedter emphasizes that these principles do not exist in isolation. Rather, as he puts it, they "coexist and interact". He begins as follows:
The most important principle of brain evolution is that many aspects of brain structure and function are conserved across species, with closely related species tending to have brains that are more similar than those of distant relatives. Generally speaking, the degree of conservation is highest at the lowest levels of organization (genes and other molecules), and embryonic brains tend to be far more similar than adult brains.82

Striedter then emphasizes that "brains tend to change in internal organization as they vary in size." He points out that the largest vertebrate brains are 100,000 times the size of the smallest ones, and the increases in size are correlated with changes in structure, numbers of neurons, neuronal density, neuronal interconnectivity, and the size of various brain regions. These increases in size and complexity almost certainly have an effect on animal behavior. Striedter also explains the principle of "late equals large". Research has revealed that in brain development, the longer it takes a particular region of the brain to   fully mature, the larger it tends to be.83

A Dutch neuroscientist has pointed out, as have others, that the most obvious development in primate brain evolution has been the dramatic growth of the cerebral cortex, [of which the neocortex is the greatest part in humans]. Such development is the best indicator of general intelligence, such as the ability of a primate to predict the behavior of other animals. Specifically, the dominance of gray matter in advanced brains is striking. In humans, gray matter comprises 50% of the brain as opposed to 25% of the brains of insectivores. The total area of the cerebral cortex, white and gray matter together, is 80% of the brain in humans as opposed to 40% in mice.84

But in regard to general brain growth, the cerebellum appears to occupy the same percentage of the brain's mass across many mammalian groups, including primates, approximately 10% to 15%. It now appears that the cerebellum and the cerebral cortex grew (roughly) in tandem during the evolutionary history of mammals. Many researchers now believe the cerebellum plays a significant role in learning, and it appears to have many connections to structures in the cerebral cortex implicated in cognitive functions.85

Among the factors associated with cortical growth:

It is now well established that the cerebral cortex forms as a smooth sheet populated by neurons that proliferate at the ventricular surface and migrate outwards along radial glial fibers...Differences in the duration of neurogenesis, which increases more rapidly with brain size for the cerebral cortex than for subcortical areas...lead to a systematic increase in the ratio of the cortical to subcortical regions. Whereas in small brained species the cortical volume expands by virtue of a combined increase in surface area and cortical thickness, the increase of the cortical volume in species with a brain size of more than 3–4 cm3 is almost entirely due to a disproportionate expansion of the cortical surface area ... It is the increase of the cortical surface area beyond that expected for geometrically similar objects of different volumes which creates the need [for] cortical folding.86

Further, and of crucial significance, the evolution of the thalamus, a structure in the lower center region of the brain involved in many of the brain's most critical functions, is deeply interconnected with the evolution of the cerebral cortex. The thalamus interacts closely with the cortex. A standard neuroanatomy work calls it, "the gateway to the cerebral cortex. It is, indeed, the principal terminus of the great sensory subsystems, a forebrain structure ideally suited to serve as a central clearing house for all sensations."87 We will look at this more closely in the next chapter, but suffice it to say all sensory information (except for olfaction) passes through it, specifically through the dorsal thalamus. And of course, the thalamus has a key role in motor functions.

But scientists have now discovered that the thalamus's role is not limited to simply transmitting sensory and motor data. The thalamus actually regulates the information going to the cortex. Most significantly, the thalamus regulates the flow of data through it by means of neural inhibition. We have already noted that one of the major neurotransmitters, gamma amino butyric acid (GABA) acts as an inhibitor. Now we should mention neural inhibition's importance. In the brain there are special types of interneurons that act to check excitatory impulses. Without these restraints, in a brain with only excitatory action, it would be impossible to organize effective neuronal activity. Coordinated patterns of excitation and inhibition, countless episodes of impulse generation and impulse restraint, make it possible for clusters of neurons to act in concert with each other.88 (We will examine this phenomenon more closely in the next chapter.)

Research has found that GABA is widespread in the animal kingdom, as we have seen. But inhibitory neurons, ones sensitive to GABA, are found in higher and higher concentrations in the thalami of the more "advanced" animals of Class Mammalia, and GABA apparently plays a more active role in these animals. The dorsal thalamus of primates appears to have the most significant number of inhibitory neurons. The primate dorsal thalamus is, in effect, the most effective "gatekeeper" and organizer of sensory-motor impulses in the animal kingdom.89

Other researchers have also confirmed that there is a greater concentration of GABA-sensitive neurons in primate thalami than those of other mammals. They stress that the cortex, dorsal thalamus, and what is known as the thalamic reticular nucleus (sometimes abbreviated as Rt or TRN) are deeply interconnected and appear to have evolved in parallel to each other.90 The TRN is a membrane that covers much of the thalamus. Most of the major axonal connections between the cortex and the thalamus pass through it, and the TRN appears to regulate communications between the two structures.91

So the advanced primate brain fell into patterns of signaling and signal inhibition, as cortex, cerebellum, and thalamus (along with the brain's "lesser" structures) acted to generate and regulate these complex, intricately interconnected and interweaving signals, signals that helped establish the reciprocal relationship between the brain's physiology and the outer world of social interaction. This reciprocal relationship acted as a selection factor, the signals shaping the interaction and the interaction in turn "rewarding" or "discouraging" the action of the signals and the clusters of neurons that generated or restrained them.

The Great Turning Point: The Human Brain Emerges

So now we stand at the juncture where a brain directly ancestral to ours has begun to evolve. As with the evolution of the genus Homo itself, the line between the non-human and the human is not clearly defined. We should perhaps begin by recapitulating some of the paleoanthropological evidence we looked at in the first volume, and add to that some new data that may shine more light on a brain that is unmistakably that of the genus Homo.

As we saw, the genus of upright primates known as Australopithecus is still the likeliest ancestor genus to the human race, although not all researchers agree. And as we noted in Volume One, there are still many gaps in the fossil record. But in 2015, two important finds, one in Ethiopia and the other in South Africa, added significantly to our knowledge. The find in Ethiopia, a mandible and some teeth, was in the Afar region, where so many striking discoveries have been made. Designated (temporarily) as LD 350-1, the specimens appear to be a mixture of australopithecine and Homo characteristics. They may be as old as 2.75 to 2.8 million ybp. The specimens are younger than the examples of Australopithecus afarensis found in the Hadar region of Ethiopia, and older than the examples of Australopithecus garhi.  Since A. garhi has been postulated as a possible human ancestor, its status in that regard may have been put into doubt. 92 We have, as yet, no evidence that bears on the cognitive abilities of the animal represented by the LD 350-1 find.

The finds in South Africa are unusually abundant. They number some 1,400 bones and 140 teeth from at least 15 individuals. The type of animal to which they belong has been designated by its discoverers as Homo naledi. This proposed species of human appears to be a mosaic of features. In that respect it is similar to Australopithecus sediba, a specimen which was discovered a short distance from these finds. [We discussed sediba's importance in Volume One.] At this writing the age of the specimens has not been ascertained, but they almost surely fall between 3 million and 2 million ybp. For our purposes here, we should also note that the skulls of naledi appear to indicate a brain size less than half that of ours. There are scientists who disagree about giving these specimens the designation Homo, and some researchers point out significant differences in the forehead slope of different pieces of recovered skulls. Nonetheless, these fossils are an important addition to our knowledge. The feet of these animals appear to be strikingly like our own; the braincases, not so much. But there may be important clues to the cognitive functioning of these possible early humans:

Dean Falk at Florida State University in Tallahassee is especially excited by the fact that [Paleoanthropologist Lee]Berger’s team has produced a cast of Homo naledi‘s small brain. Images of it hint at interesting features close to one brain region associated with speech in modern humans, she says. Berger says it’s possible that for the first time, we have found another creature not that closely related to us, yet with a cognitive ability “different but essentially equal to ours”.93

The designation Homo habilis, which as we saw in Volume One, is a matter of controversy, may be strengthened by the Ethiopian finds. In any event, habilis's cognitive  abilities still bear examination. A key measure of cognitive ability is the production of tools. One researcher, examining the evidence carefully, believes that the animal known as Paranthropus boisei, along with Homo habilis, created the Oldowan tool making tradition. This researcher believes in general that australopithecine cognitive abilities have been underestimated. He believes, based on an examination of modern African primates, that Paranthropus and habilis, both of them possible off-shoots of australopithecines, possessed highly dexterous hands [and by implication brains developed enough to control these capable hands]. He maintains that the invention of stone tools, not bipedalism, was what he calls "the great adaptive invention of the savannah".94 As we noted in Volume One, the cranial capacity of habilis and that of the species that may have lived at roughly the same time, Homo rudolfensis, ranged from about 500 to 775cc. Chronologically, the earliest habilis fossils are about 2.4 million years old. (The Ethiopian finds may yet prove to be habilis.) It bears repeating that the cultural line between australopithecines and habilis/rudolfensis may not have been very distinct.

In support of the idea that non-human primates had considerable cognitive abilities, it is worth noting at this juncture that some pre-human primates appear to have indeed been tool users. Tools more than 3.3 million years in age have been discovered at a site in West Turkana, Kenya. The site has been named Lomekwi 3, and the tools discovered there pre-date the oldest Oldowan tools by about 700,000 years.95

In comparison to the pre-human primates and proposed human types such as habilis/rudolfensis, we know much more about the cranial capacities and cultural abilities of Homo erectus. As we noted in Volume One, the oldest example of "Upright Man" that we have may be a 1.9 million year old specimen, although we are on firmer ground in asserting that the examples we have from 1.8 million and 1.7 million ybp are indeed erectus. The cranial capacity of the specimens we have found ranges from 600 to 900cc in the earliest examples to 900 to 1200cc in later finds. This means that the estimated brain size of late erectus overlapped with the lower ranges of brain size found in modern humans. The cranial vault of erectus tended to be low compared to modern humans, and the typical erectus skull was wider than it was high, in contrast to humans like us. The shape of the braincase itself was similar in certain respects to that of modern humans.

Since cultural achievements are tied closely to cognitive abilities, we should note that erectus (and perhaps also the species quite possibly related to it known as Homo ergaster) had the ability to use fire. Erectus had the ability to manufacture tools efficiently. More crucially, it had the ability to conceptualize and plan tool manufacture. These abilities infer the possession of such capacities and skills as communication, developed working and long-term memories, spatial cognition, planning, cooperation, and effective social interaction. And erectus/ergaster was able to make a living across a huge stretch of the planet's surface, from eastern Africa through the Levant, from northern China to present day Indonesia, and perhaps even parts of Europe. There may have been erectus types in China for more than a million years. [In Volume One I used the more conservative estimate of 900,000 years.] So we are talking about a kind of human with impressive mental skills.

It is obvious, therefore, that between 3.5 million ybp and 2 million ybp there were major changes in the cognitive abilities and motor skills of the primate order's most advanced members. At the start of this period such animals as Australopithecus afarensis and Kenyanthropus platyops flourished. By 2 million ybp, recognizable (possible) humans such as habilis roamed the African landscape and the definite humans known as erectus may already have begun to emerge. What hypotheses have been put forward to explain these monumental changes, and what evidence have researchers gathered?

We have discussed a few of the genetic changes that appear to have been associated with the rise of the primate brain in general. Now we will zero in on those changes which seem to have facilitated the development of a distinctly human brain. We turn first to research that shows certain genes that are crucial in regulating brain size during development, ASPM [which we noted above] and MCPH1, must have been particularly important in the line leading to humans. FOXP2 [which we have noted for its role in the human ability to use spoken language], and GLUD2 also appear to have had a major impact on human brain evolution as well. All of these genes and the proteins they encode underwent strongly positive selection.96

Other research has emphasized the role of such genes as ADCYAP1 (adenylate-cyclase-activating polypeptide 1). As the embryonic brain develops, neurons are first proliferated, the proliferative state of development. The transition into the state where neurons are differentiated (which is to say when they begin to take on the traits typical of neurons) is in part regulated by ADCYAP1. From the time the proto-hominid line and the chimpanzee line began to diverge from each other, ADCYAP1 appears to have been one of the most strongly selected genes in humans.97

Other genes that appear to have played an important role in human brain development include: AHI1 (Abelson helper integration site 1), which is involved in linking axons from the brain to the spinal cord and which has shown strong divergence from the chimpanzee line; SHH (Sonic hedgehog), already mentioned, which plays an important role in signaling; MAOA (monoamine oxidase A), which encodes an enzyme that chemically breaks down a variety of neurotransmitters, and which also shows strong divergence from the chimpanzee line; and a large number of others, the functions of which are not always clear but which seem to be selected in humans. One study found no less than 214 genes that appear to have had accelerated development in the line leading to humans. Other research has revealed genes that have been lost and patterns of gene expression which have changed.98

But the researchers involved in this study make a particularly cogent point:

The view that the human brain is the result of a trend also affecting other primates is consistent with many studies. Both large-scale surveys of evolutionary changes in brain-related genes, in addition to studies of many single genes such as ASPM, microcephalin, SHH and GLUD2, have shown that these genes experienced adaptive evolution in various time periods along the lineage leading to humans, often affecting humans and other related primates rather than being specific to humans only. Thus, available data point away from the anthropocentric notion of human brain evolution to a more nuanced view, which sees the human brain as resulting from a trend of increasing size and complexity that also affected other living primates, although the impact on humans is undoubtedly most profound. More plainly stated, the salient features of the human brain did not all come about in the terminal human branch after divergence from chimpanzees. Rather, many changes have occurred in much earlier stages of the human lineage. Given this new view, genetic studies of human brain evolution should focus on comparisons across many primates and even non-primate species instead of being limited to only comparing humans and chimpanzees.99

But the most significant genetic factor in the evolution of the human brain may be the role of a gene known as SRGAP2. Research has proven that SRGAP2 has had a definite role in human brain development. It has been ascertained that the human genome has three additional copies of this gene, located at various places on chromosome 1, the only primate genome that does. The four copies are not identical to each other, and are designated SRGAP2 A through D. By comparing the different copies of this gene with those possessed by orangutans and chimpanzees, scientists have discovered that the original SRGAP2 gene duplication occurred in the line of primates leading to humans about 3.4 million ybp, yielding the A and B variants. The C variant seems to have appeared in the human lineage about 2.4 million ybp, and the D variant is about 1 million years old. Researchers have zeroed in on the C variant, which may have played a major role in the emergence of the genus Homo between 2 million and 3 million ybp. Specifically, SRGAP2C seems to facilitate the growth of what are known as dendritic spines. These very small structures jut out from the dendrites of neurons. They are exceedingly important in nerve impulse transmission. Humans have more dendritic spines, and greater concentrations of them, than any other type of primate. This characteristic may have contributed to the rapid growth of the cortex in the line leading to humans. This growth in turn would have allowed our ancestors' brains to function at a higher level than those of other primates. It would have increased the ability of their brains to make new neuronal connections in response to novel experiences. In short, it would have strengthened the nexus between the exterior world in which an animal found itself and the interior world of the brain. But it may have had another impact as well. Many researchers now think a larger and more complex brain is inherently more vulnerable to neurological disorders.100 The very abilities that made us the most powerful multicellular life form made possible the mental torments and problems that plague us.

How might this crucial change have occurred? Research on this question has revealed that the original gene duplication approximately 3.4 million ybp may have been incomplete. This incomplete duplication may have ultimately triggered the duplication that resulted in the C variant at about 2.4 million ybp. The incomplete duplication that produced the C variant may have contributed to its importance and its functions. SRGAP2C appears to be universal in the human race, and it has been detected in Neanderthal and Denisovan DNA as well. (The B and D variants of the gene appear to have little or no impact on the human phenotype.) The SRGAP2C variant is the dominant one.101 Other research has confirmed SRGAP2C's significance. The authors of this research emphasize that SRGAP2C interferes with the action of the ancestral variant of the gene and in so doing changes the physical structure of dendritic spines and their density. The study also suggests that it was the incomplete duplication process itself that permitted the C variant to have this effect.102

In conjunction with these genetic data, it is intriguing to recall the possible role of sialic acid in brain evolution. We touched on this in Volume One. To recapitulate what I said there: In humans, sialic acid, specifically N-acetylneuraminic acid (abbreviated as Neu5Ac), is found in the greatest concentrations in the brain, where it plays a significant role in building synapses and facilitating “signaling” between neurons. But humans are the only mammals unable to synthesize a different kind of sialic acid known as N-glycolylneuraminic acid (abbreviated as Neu5Gc). The gene responsible for Neu5Gc synthesis, the CMAH gene, became inactive in humans. This pseudogenization occurred, according to various estimates, between 3 million and 2.7 million ybp. Studies of Neanderthal specimens have detected Neu5Ac but not Neu5Gc. This means the mutation that blocks the synthesis of the latter acid must have happened before the emergence of the common ancestor of Neanderthals and us. In fact, this change occurred just before the great increase in encephalization among certain hominins. A definite relationship has not been established between the two events, but it is suggestive to some researchers. (The absence of Neu5Gc in humans appears, by the way, to have a significant effect on how humans react to the presence of various pathogens.)103, 104, 105

Another factor  associated with the development of a modern human brain may have been a change in the diet of early humans. Human brains have very high metabolic demands. For a human to survive, these demands must be met by food with a high energy content. Protein derived from the flesh of other animals is the most abundant source of this energy. There seems to have been a great expansion in African savanna land between 2 million and 1.8 million ybp, and a concomitant growth of grazing animal populations. This larger number of herbivores may have afforded erectus an opportunity to engage in basic hunting activities. The making of hunting weapons would have arisen, as well as manifestations of sociality such as cooperative effort, food sharing, and increased interpersonal communication. The musculature of the human would have become slimmer, while the fat storage capacity grew. Many researchers are convinced that the consumption of high quality animal protein by early humans was crucial in maintaining their expanding brains.106 There would have been a feedback loop established between the activities involved in procuring meat and brain development. These activities facilitated the survival of the brains that conceived of them, thus making it likely that such brainpower would be reproduced.

So between around 3.5 million and 2 million ybp a confluence of events created a self-reinforcing synergy. A series of fortuitous genetic changes made early humans more capable of social interaction and cooperation, and these capacities proved reproductively useful. The making of tools, already underway in pre-human primates, was encouraged by the growth of these capacities, and tool-making became a factor in human survival strategies. The increased capacity for socialization and communication strengthened the unseen mental bonds that kept early human tribes together, reinforcing the tendencies that had encouraged these behaviors. General intelligence, the ability to learn new information, and, crucially, the ability to apply this information in novel situations, grew significantly. And the natural environment in eastern and southern Africa provided opportunities for the acquisition of high-quality protein, which in turn both facilitated the development of large brains and the cooperation necessary for the hunting of large animals. All of these developments made it possible for knowledge to be shared and communicated across boundaries of both space and time. Several primates possess the capacity to teach simple things to their offspring. But now the human primates could teach increasingly complex and subtle lessons, and interact in ways which had hitherto been impossible. The genetic, social, and environmental factors that facilitated the growth of the human brain and contributed to the complexity of its wiring made possible the basis of all complex human social life—advanced culture.

The Emergence of the Modern Human Brain

When we speak of encephalization, we are analyzing the size of the brain relative to the rest of the body based on the expected ratio for an animal of a particular size. An encephalization quotient of 1 would indicate the brain was of the exact size expected for the particular type of animal. At an encephalization quotient  of  6 (and other sources say as high as 7.8)107, modern humans have the highest EQ of any primate, or any large mammal of any kind, for that matter. We have noted the brain size of Homo habilis and Homo erectus above. Starting from around 500cc (a figure thought by some to be too low to define a genuine human brain) to around 1200cc in the latter erectus types and in Homo heidelbergensis, there was a dramatic expansion of size. The brains of anatomically modern humans (AMH) now average around 1350cc. Neanderthal brain size even reached 1750cc in one example. So the growth in size of the brain is obvious.

But as we have noted, size is not the only significant factor. Intelligence and true consciousness seem to arise out of a combination of absolute brain size, brain size relative to body size, encephalization, and most significantly, density and complexity of neuronal organization, particularly in the cortex. Broadly speaking, the structural traits of a cortical region are affected by the number of neurons in that region, neuronal size, and how those neurons are distributed in the region. In the neocortex, pyramidal neurons, which are excitatory, comprise 70% to 85% of all cortical neurons. As the authors of one general survey put it,

In all primates examined to date, pyramidal neurons are characterized by extensive morphological changes during post-natal maturation and remodeling throughout life, potentially underlying flexible behavioral responses typical of all primates. Pyramidal neurons in the human neocortex display a prolonged period of development compared to other primates...especially in the cortical areas characterized by expansion during human evolution, including selected areas in the prefrontal cortex (PFC).108

It was the evolution of an advanced prefrontal cortex that chiefly distinguished Homo sapiens from its ancestors. A recent study confirms there is a heavier-than-expected concentration of glial cells in the human prefrontal cortex compared to other anthropoids. [Glial cells may broadly be thought of as structural support cells, and there are several major varieties of them.] A high ratio of glial cells to neurons seems to be necessary for the human brain's metabolic support.109 Other research indicates that the prefrontal cortex is more likely to exhibit folds (gyrification) than the prefrontal cortices of non-human primates, and this appears to be a crucial factor in the advanced behavioral abilities of humans. Further, the growth of white matter in the frontal lobes (noted in a different context, above) appears to be especially significant in humans, outpacing the white matter found in the frontal lobes of all other primate species. This may help account for the advanced cognitive functions found in the prefrontal cortex, such as an understanding of cause and effect, language, time perception and time-related information, and the control of other conscious functions, or the "executive function".110 The executive function allows humans to plan, organize, and do other tasks connected with the accomplishment of specific goals.

The human prefrontal cortex is three times larger in absolute size than that of any of the great apes, but the importance of this fact is still debated by some researchers.  The key areas of the prefrontal cortex do not appear to be disproportionate in size relative to those of other advanced primates. The crucial differences appear to be in organization and what is called microstructure. In this case microstructure refers to what the authors of one study refer to as "complex dendritic arborizations" in some of the PFC's substructures. The PFC is one of the last parts of the brain to mature, and the reorganization of its neuronal network may have been comparatively recent in human evolution. Additionally, it appears that certain disorders within the PFC's circuitry give rise to neurological conditions such as autism.111

In addition to the prefrontal cortex, the evolution of the human cerebellum has been of great significance. We have examined briefly the importance of the cerebellum in the ability of primates to learn and utilize information. Some researchers believe the cerebellum's role in human brain evolution has been more significant than generally believed, pointing out that the human cerebellum has four times as many neurons as the neocortex. These researchers note that the cerebellum is of indispensable importance in the human capacity for developing tools, inasmuch as it is involved in sensory-motor functions and the learning of step-by-step procedures. Research has shown that in the evolutionary history of the cerebellum, its expansion relative to neocortical growth was as much as six times faster among the great apes than in non-ape-like primates. (Some researchers hypothesize that this difference was the result of the challenges large primates had to meet in moving their bodies through an arboreal environment.)  The cerebellum's rapid development may also have helped facilitate the human acquisition of language.112

As we have noted already in a different context, the human brain's development was also intimately tied to feedback loops and synergies associated with complete obligate bipedalism and the use of the hands to allow for fine (in the sense of small) motor skills. Upright posture freed the hands for the task of manipulating objects. There is evidence that truly agile hands preceded obligate bipedalism,113 but once these features began to act in combination, they created a synergy that reinforced human technological efforts by rewarding the brains that conceived of better, more effective tools. The brain's development may also have been profoundly affected by climatic conditions, competition between and among early humans, and general ecological factors (such as the presence of parasites in a given area). Two researchers have found that while there were multiple factors that influenced the growth of brain size, "the core selective force was social competition". Those humans that were most effective at finding or constructing shelter, devising weapons, hunting, and using other critical survival strategies were the ones that natural selection tended to favor.114

Vertebrate brains conserve a great many distinct structures across many species. The human variation of the vertebrate brain in turn became an arena of increasing specialization. But why has this specialization come about? One researcher has made this argument:

If adaptations in the brain resemble other organismal adaptations—e.g., tissue types, limbs, organs, and the molecular machinery of cells—they are likely to be both heterogeneous and hierarchical. Heterogeneity arises from the fact of form-function fit: adaptations have different histories and have evolved to do different things, so they are likely to have diverse properties rather than coming in just two kinds. Hierarchical organization, in turn, is characteristic of systems that evolve via descent with modification. Because new structures evolve from older structures, adaptations frequently share a mix of ancestral and derived features, with relatively ancient features (e.g., properties of neurons in general) shared more widely across organismal structures, and relatively recent ones (e.g., properties of specialized brain regions) more narrowly distributed, in a hierarchically organized fashion.115

The human brain, in this view, is a mixture of structures inherited over millions upon millions of years of development, with the more specialized functions being most recent. The human brain, in short, often uses ancient features in novel ways, and incorporates a startling range of adaptations into its key functions. The way I think of it is this: the evolution of the human brain was not a matter of constructing a brain “from the ground up”. It was the modification of/and addition to existing structures, and with it a concomitant elaboration of brain functions, that created its distinctive features.

David Geary, one of the chief figures in brain evolution research, maintains that the functions of what we call mind are a mixture of genetic limitations acting in combination with experiences, especially experience acquired early in life. The brain must operate within the boundaries genes have set for it, boundaries which facilitated reproductive success, but experience can modify the brain within these boundaries, and give to it a considerable degree of plasticity.116 By plasticity in this context Geary means "the ability to adapt brain and cognitive systems and processes to socially and ecologically salient information." The debate among neuroscientists and scientists studying cognition in general is the degree to which these factors affect the composition of the mind, with some scientists emphasizing genetic constraints while others give major weight to culturally-determined experiences to which an individual is exposed.117

The human brain seems to have reached the limit of its average size approximately 100,000 ybp. There are a number of hypotheses that attempt to explain this. Striedter has pointed out that the size of the birth canal in Homo sapiens females appears to have reached its evolutionary limit. Indeed, this limit may have been reached in the era of erectus. The brain size of sapiens may have grown greater than that of erectus because natural selection favored increased postnatal brain growth.118

The end result of all these processes has been a brain that is evolved, in Geary's view, to seek control over the variables surrounding the individual. These variables can include physical resources and social relationships. It appears to be a general tendency among humans to arrange these variables to their own (perceived) advantage as much as possible. Humans tend to seek advantage. They are evolved to do so. [In my view, humans who do not seek any advantage or control are highly anomalous.]119 In the statement "humans tend to seek advantage" perhaps lies the source of human ambition, the human desire to acquire survival skills, human attempts to manipulate other humans, human competition, human striving for success in a given social setting, and human ethical unscrupulousness (in some cases).

The end result of human brain evolution has also been, in the view of neuroscientist Sebastian Seung, the emergence of what he calls a connectome. Seung defines a connectome as "the totality of connections between the neurons in a nervous system...It is all of them." He adds, "Minds differ because connectomes differ."  He sums up the definition by saying, "You are the activity of your neurons."120 Seung stresses the fact that a neuron's function is mostly the result of its connections to a whole host of other neurons, either directly or indirectly. These neurons form electrochemical relationships with each other. As he explains,

If two neurons are repeatedly activated simultaneously, then the connections between them are strengthened in both directions...If two neurons are repeatedly activated sequentially, the connection from the first to the second is strengthened.121

In other words, every one of the estimated 100,000,000,000 members of the genus Homo that has lived has been neurologically unique. Yet, these humans have shared enough in common neurologically with those with whom they lived that they were capable (in most cases) of establishing working relationships and effecting some level of communication with them. These relationships in turn altered their connectomes in ways that cannot be readily comprehended, ways that could not have been predicted or explained. The evolution of the brain produced such complexity, such a subtle and multivariate interaction between genetic inheritance and culturally-experienced reality, that humans were, in many ways, strangers to themselves—and to each other.

So let us now step back and sum up the very brief and very inadequate examination I have made of this momentous subject.

An Overview of Brain Evolution

One of the giants of the study of human brain evolution is Ralph Holloway. Early in the 21st century Holloway proposed the following overview of hominin brain evolution. In the initial stage, 7-8 million ybp, in the period of the last common ancestor of hominins and chimpanzees, the typical brain of an advanced primate was ape-like in organization with an approximate  brain size of 350-450cc. In the australopithecine era, around 3.5 million ybp, brain reorganization was taking place perhaps before there were any major increases in brain size. Careful examination of endocranial casts reveals a reduction in the visual cortex, an increase in the posterior association cortex, and the possibility of increased memory and foresight. By the early Homo era, around 1.9 million ybp, an increase in brain size and encephalization was evident. The region of the skull above Broca's area (which is associated with language) was prominent. By inference, humans were now more adept at social interaction, tool-making, and spoken communication. In the era of Homo heidelbergensis, Homo neanderthalensis, and Homo sapiens, the period 500,000 ybp to now,  systems of symbolic communication arose, the brain's hemispheres became asymmetric, the feedback loop between tool making and brain development was well established, and brain size and encephalization reached their current maximums.122

A Summary of the Evidence

We noted first that humans have not yet, by any means, fully elucidated the evolution of the human brain. We started the process of trying to trace the brain's origins with the existence of sentience. Sentience, as we saw, is an inherently possible condition of energy-matter, emerging from its processes, specifically those associated with life. Sentience utilizes one of the four basic physical forces, electromagnetism. The possession of sentience provided crucial advantages to those beings possessing it, advantages that were reproduced in increasing extent and diversity. The chemical precursors of neurotransmitters were found throughout the world of living things. In the line of living things that were heterotrophic and in which sexual reproduction was the rule, these precursors were repurposed and utilized in ways that made electrical communication between and within cells possible. Single-celled organisms evolved response mechanisms to chemicals in their environments. Ion channels facilitated these responses. Structures on certain cells allowed for the transmission of "information" between certain kinds of other cells, and the synapse began to evolve. With the rise of the synapse came the evolution of the neuron, the basic unit of the nervous system. These neurons may have first manifested themselves on the exteriors of simple invertebrates. They were extremely basic versions of the modern neuron. Synaptic proteins proliferated, enhancing the ability of cells to "communicate" with each other. The earliest animals had the capability to evolve nervous systems, but did not themselves possess them.

With the coming of the bilaterians came the evolution, perhaps from ganglia, of the first genuine brains. Complex sets of genes helped control this process, genes that were expressed or not expressed in varying patterns. With the evolution of the vertebrates came a more elaborate brain, one possessing a tripartite structure, and possessing a set of substructures found throughout the vertebrate line. The cerebrum and the pallium emerged. Clustered protocadherin genes governed neuronal development in the vertebrates. Vertebrate brains expanded at greatly varying rates. The neural crest began to provide protection for the expanded brains. The vertebrate axon became myelinated, enhancing its function. With the mammals came increasingly large brain sizes, expansion facilitated by genetic changes in embryonic cell generation. From these processes evolved the six-layered neocortex, the crucial turning point in brain evolution. Neocortical tissue developed folds and ridges, allowing for a great expansion of its surface area. Different areas of the neocortex began to handle specialized tasks. Selection pressures grew sharper, driving the neocortex's evolution. A synergy between the neocortex's structure and its increased reproductive usefulness was established.

Tree-living mammals, the primates, began to evolve throughout certain forest areas. Their brains increasingly emphasized visual acuity and de-emphasized olfactory ability. A complex set of selection pressures began shaping primate evolution. Within the anthropoids, critically important genes enabled major increases in brain size. White matter expanded in anthropoid brains. Brain structures associated with learning and memory expanded. The cortical subplate, an embryonic structure, may have been of critical importance in the evolution of a highly interconnected network of neurons in the primate brain. Social interaction played an increasing part in primate brain development. The primate thalamus emerged as the great "gatekeeper" of neural signals, organizing effective neuronal activity in coordinated patterns of excitation and inhibition.

In the great arc somewhere between eastern and southern Africa, certain terrestrial primates, already in possession of excellent hands, began to evolve fully upright posture and more sophisticated brains. The first primitive tools were made, enhancing the survival of the genes that had helped conceive them. A copying error in a particular gene may have made a crucial difference in the evolution of increasingly powerful brains. Handy Man and then Upright Man began to exhibit these more capable brains, produce better tools, and develop more useful social relationships. The prefrontal cortex and the highly neuron-dense cerebellum began to emerge, enabling the upright animals with dexterous hands to gain increasing control over their immediate surroundings. The upright animals were now the most intelligent beings that had ever lived on the tiny planet, each one possessing a unique set of neuronal connections, and almost all of them ceaselessly seeking to control those features that they could in the world around them. Their brains were adaptable, more capable of adjusting to changing circumstances than those of any other animal.

In sum, the human brain is the product of hundreds of millions of years of evolutionary development. Its principal task remains what the brain's task has always been in whatever animal possessed one: keep the organism alive long enough to pass its genes down. It is in the attempt to fulfill that task that much of human life and the human experience has been directed.

But the human brain became much more than just a tool of reproduction. It was complex enough, its anatomy and physiology sophisticated enough, to interact with and more accurately perceive the outer world than the brain of any other animal. It was  especially evolved for interaction with those animals possessing similar brains. This interaction and perception change the brain in a multitude of ways, and the brain in turn changes the outer world in some respects, setting up a reciprocal process.

But there are limits to this perception, ones which are not readily apparent. The sensory apparatus that serves the brain does not permit it to perceive The Thing in Itself. The brain perceives a version of reality, one suited to its multitudinous survival tasks. The human brain is extraordinary in its abilities, but is a highly flawed and vulnerable instrument. It is, as I pointed out at the start of this chapter, a physical object after all. The complex anatomy and physiology of the human brain allowed for the development of a very high level of consciousness. Consciousness, the awareness of one's awareness, a sense of being a self, a sense of being present in a given moment, the sum total of a brain's reactions to the sensory stimuli to which it has been exposed, is so complex and varied that its possessors do not fully grasp its nature and functions. The very thing that most defines a human, and which gives a human such extraordinary power relative to other animals, often acts as a barrier to that human, making existence itself unpredictable, unexpectedly difficult, and even mysterious.

In short, evolutionary processes produced a physical entity that was, in one perspective, an exceedingly complex mass of electrochemical signals, signals that were expressed or inhibited in a pattern that ultimately produced what for us was the ultimate emergent phenomenon: our own minds.

So let us now examine the physical object in which the mind resides.

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