Evolution of the Somatosensory System – Clues from Specialized Species

3.15 Evolution of the Somatosensory System – Clues from Specialized Species K C Catania, Vanderbilt University, Nashville, TN, USA ª 2007 Elsevier Inc. All rights reserved.

3.15.1 Introduction 3.15.2 How Have Brains Changed in the Course of Evolution? 3.15.2.1 Areas May Be Added to the Processing Network 3.15.2.2 The Star-Nosed Mole – A Case Study in Somatosensory Evolution 3.15.2.3 Behaviorally Important Areas Are Magnified in the Brain 3.15.2.4 A Somatosensory Fovea in the Star-Nosed Mole 3.15.2.5 Modules Represent Sensory Surfaces in Diverse Species 3.15.2.6 The Sensory Periphery Guides Aspects of Cortical Development 3.15.3 What are the Mechanisms of Evolutionary Change? 3.15.3.1 Levels of Organization 3.15.3.2 Potential Mechanisms of Change 3.15.4 Conclusions

Glossary areas

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This term is often used to describe separate subdivisions of the brain and neocortex. In the neocortex different areas generally have a number of identifying features, such as unique appearance in histological stains (cytoarchitecture), unique connections to other areas, unique cellular responses, and result in specific deficits following damage. Some well-known cortical areas include primary somatosensory cortex (S1), primary visual cortex (V1), and primary auditory cortex (A1). A circular region of the neocortex visible in various histological stains of the somatosensory area in rodents where touch information from a single whisker projects. First recognized by Woolsey and Van der Loos (1970) in mice. The relative size of a representation, or processing area for a sensory input, in the cortical map. This generally refers to the larger representations of behaviorally important sensory inputs as compared to less important inputs. A common example in humans is the large area of cortex devoted to processing touch information from the hand relative to other, larger body parts (such are the leg or back) that

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have a proportionally much smaller representation in the cortex. A mitochondrial enzyme. Processing brain tissue to reveal the distribution of this enzyme often reveals different subdivisions, particularly in the neocortex. Cortical barrels can be seen in the distribution pattern of this enzyme (Figure 1). A small (40–80 mm) swelling in the nasal epidermis of talpid moles that contains and orderly array of mechanoreceptors used for tactile discriminations. Similar to a pushrod in montotremes. Electroreception is the ability to detect weak electric fields in an aquatic environment through dedicated sensory organs (electroreceptors). This sense is sometimes used by predators (e.g., sharks) to detect the small electric fields given off by prey. The outer six-layered sheet of brain tissue in mammals where much of the information from sensory receptors projects. Often shortened to ‘cortex’ in discussions of the mammalian brain. Many investigators prefer the term ‘isocortex’ to avoid the implication of an invalid phylogenetic sequence suggested by the term ‘neo’. The large, mobile whiskers on the face of a rodent.

190 Evolution of the Somatosensory System – Clues from Specialized Species ocular dominance column

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Stripes of cortical tissue in layer 4 of primary visual cortex that receive input from the lateral geniculate nucleus, relayed from primarily only one eye. Each stripe is generally bound by similar stripes representing the opposite, contralateral eye. In this context, ‘receptors’ refers generically to the sensory organs and nerve endings that receive and communicate sensory information from the environment. More specific modality designations include mechanoreceptors, photoreceptors, electroreceptors, etc. A saccade is a sudden, jerky movement. The term ‘saccade’ is most frequently used in reference to an eye movement. In the visual system a saccade is the characteristic sudden movement of the eye that positions different parts of a visual scene on the retinal fovea. Generally refers to a topographic map of primary afferent inputs to the central nervous system (CNS). In the case of the somatosensory system, the sensory representations reflect the distribution of mechanoreceptors in the skin, and as such they form a ‘map’ of the body surface that can be identified in neocortex by recording the activity of nerve cells in response to stimulating the skin. The area of neocortex that receives and processes touch information from mechanoreceptors on the body. The descriptor draws an analogy between the high-resolution retinal fovea in the visual system and the high-resolution part of the starnosed mole’s nose used for detailed, tactile investigations of object of interest. A similar analogy with the visual system has been made in the auditory system of bats, where an ‘auditory fovea’ is said to represent the most important echolocation frequencies.

mammal bodies that have changed in the course of evolution and often challenging to identify examples of brain specializations that can be confidently attributed to specific sensory adaptations. Consider, for example, the vast difference in brain size between shrews – that resemble ancestral mammals in many respects – and humans, that have only recently emerged on the evolutionary landscape (Figure 1). This comparison highlights some of the challenges to deciphering mammalian brain evolution, as the differences between shrew and human brains may parallel the differences between the small brains of early stem mammals and the larger and more complex brains found in many modern lineages. The comparison of a human brain to a shrew brain seems appropriate as an introduction because it not only illustrates a range of mammal brain sizes, but also because insectivores hold a particularly important historical position in theories of mammalian brain evolution. Fossil evidence indicates that the earliest ancestral mammals had brains and bodies similar to those of modern insectivores, particularly shrews that have little neocortex (KielanJaworowska, 1983, 1984). As a result, a number of theories of brain evolution have been based on the premise that modern insectivore brains resemble those of ancestral species (Lende, 1969; Glezer

3.15.1 Introduction The somatosensory system provides a rich source of diversity for revealing principles of mammalian brain evolution. At the same time, it is daunting to consider the number of different aspects of

Figure 1 An adult human brain compared to the brain of a shrew. The upper panel shows the two brains at the same scale, with the shrew brain resting on a penny for scale. The lower panel shows the shrew brain enlarged.

Evolution of the Somatosensory System – Clues from Specialized Species

et al., 1988; see Deacon, 1990, for review). This historical trend was bolstered by early recording experiments in hedgehogs (Lende and Sadler, 1967) and moles (Allison and Van Twyver, 1970) which indicated that insectivore cortex was poorly differentiated with overlapping cortical subdivisions. However, recent investigations of insectivores (Catania, 2000a) have revised our conception of these species as primitive mammals with poorly organized brains and thus historical theories of brain evolution based on early investigations of insectivores need to be reconsidered. Before developing theories for how somatosensory cortex may have evolved in different lineages, it is first essential to describe what is known about the products of evolution. What are the major differences in brain organization observed across different species? What facets are unique to particular lineages, and what has been conserved across taxa? What solutions to sensory processing have recurred in the course of evolution and may thus illuminate constraints on the ways brains can be modified? Although the brains of only a small percentage of extant mammals have been examined in detail, recent investigations of somatosensory cortex have expanded our understanding of brain organization in mammals that range from standard laboratory rats (Remple et al., 2003) to monotremes (Krubitzer et al., 1995; Krubitzer, 1998) and marsupials (Beck et al., 1996; Rosa et al., 1999; Huffman et al., 1999; Catania et al., 2000) representing important branches of the mammalian radiations. By considering the organization of cortex in selected species, it is possible to draw some general conclusions about how cortical organization has changed in the course of mammalian evolution. In addition to our growing understanding of brain diversity across species, a number of recent advances in the ability to modify gene expression during the course of development have allowed investigators to mimic the process of brain evolution in the laboratory. Thus, on a small scale, some of the diversity that is observed across species can be generated within species by manipulating gene expression (Fukuchi-Shimogori and Grove, 2001). This in turn suggests potential mechanisms by which brains may have been modified in the course of evolution (Rakic, 2001). Finally, in discussing the evolution of somatosensory areas in the brain, it is important to simultaneously consider the mechanosensory periphery. After all, the main function of the somatosensory cortex is to process information from these receptors and there is an intimate association between the sensory periphery and the

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central nervous system (CNS) during the course of both development and evolution.

3.15.2 How Have Brains Changed in the Course of Evolution? 3.15.2.1 Areas May Be Added to the Processing Network

There is still much disagreement and uncertainty regarding the organization of cortex and the identity of areas in many of the most intensively investigated species (see Kaas, 2005). However, it is nevertheless clear from comparative studies that larger brains differ significantly from the smaller brains in living mammals, and by extension that larger brains of modern species differ from the small brains of ancestral species that gave rise to these lineages (see Jerison, 1973; Kaas, 1987a, 1987b, 1995, 2005; Krubitzer, 2000). This is exemplified by comparing the shared cortical areas between shrews and humans (Figure 2). Shrews are particularly interesting because many of them represent the lower size range for the mammalian body and brain (see Schmidt-Neilsen, 1984). Shrews are also particularly interesting because fossil evidence indicates that early mammals also had small brains with little neocortex. Thus, understanding constraints on the organization of a small neocortical sheet may help us infer how early mammalian cortex was organized. Shrew brains were found to have only a few cortical sensory areas with sharp borders as determined from both electrophysiological and histological evidence (Catania et al., 1999). These areas include primary and secondary somatosensory cortex (S1 and S2), primary visual cortex (V1), primary auditory cortex (A1), and motor cortex (M1). Human brains also contain these same subdivisions in similar relative position in the cortex (i.e., V1 is caudal in cortex, A1 is lateral, M1 is most rostral). This comparison demonstrates two important and very general findings in mammals. First, diverse mammal species share a number of cortical areas in common. Second, larger-brained mammals tend to have more cortical subdivisions. The greater number of intervening cortical areas is not illustrated in Figure 2 for humans, but can be appreciated from the schematic in Figure 3, which illustrates the number of cortical subdivisions in a shrew compared to the estimated number of cortical subdivisions in a macaque. Whereas shrews have only five known cortical areas with little room for additional subdivisions (Catania et al., 1999), macaques are thought to have over 50 different areas (see

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Figure 2 Shared cortical areas between a shrew and a human. Left side shows a shrew brain and cortical areas, including primary somatosensory cortex (S1), secondary somatosensory cortex (S2), primary visual cortex (V1), primary auditory cortex (A1), and primary motor cortex (M1). The same (homologous) cortical areas are depicted in the human brain on the right. Human have many additional cortical areas that are not illustrated, whereas shrews have little room for additional cortical subdivisions. OB, olfactory bulb; BS, brainstem.

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Figure 3 A schematic representation of cortical organization in a small-brained (shrew) and large-brained (macaque monkey) mammal. Shrews have as little as 0.15 cm2 of neocortex, whereas macaques have roughly 72 cm2 – a 480-fold difference. Humans, with approximately 800 cm2 of neocortex, do not fit on the figure, but have neocortex with over 5000 times the surface area of a shrew. Given that shrews are similar in size and habits to ancestral mammals, there has clearly been a tremendous enlargement of cortex in many mammalian lineages. In addition to getting larger, the internal organization of cortex has changed as well. Many cortical subdivisions have been added in larger-brained mammals, and this can be appreciated by comparing the enlarged shrew brain (far left) to the macaque brain. The letters denote visual (V), auditory (A), somatosensory (S), and motor areas (M). Shrews have only a few cortical subdivisions, whereas macaques have many. The illustration is not intended to show the relative size or location of cortical areas. Reproduced from Catania, K. C. 2004. Correlates and possible mechanisms of neocortical enlargement and diversification in mammals. Int. J. Comp. Psychol. 17, 71–91.

Kaas, 1995 for review) and additional areas will almost certainly be identified in macaque cortex. This observation is perhaps not surprising; however, it does raise additional questions regarding brain scaling and evolution. It is clear that largescale changes to brain organization have occurred in many mammalian lineages – for example, in the

primate and carnivore orders that have more cortical subdivisions than smaller-brained rodents and insectivores (Kaas, 1982). Greater numbers of cortical subdivisions are often considered to be an important underlying substrate for increased intelligence and behavioral complexity. Yet, it is difficult to separate factors related to brain scaling from

Evolution of the Somatosensory System – Clues from Specialized Species

those related to increased processing ability. For example, as brain areas increase in size, local connections must increase in length to maintain a similar degree of global connectivity. Such increases in lengths of axons and dendrites must be accompanied by increases in their diameters in order to maintain similar conduction times between cells (Ringo et al., 1994). The main point is that increasing the size of a brain and its cortical areas includes many engineering challenges and thus some cortical areas may become subdivided simply to maintain the status quo (Kaas, 2000). In addition, it is often difficult to confidently identify a particular brain specialization related to increased behavioral complexity or processing ability when comparing distantly related species, such as insectivores and primates, as some traits may be most common in a given lineage without an obvious adaptive value. This has been termed the taxon level effect (Pagel and Harvey, 1989). One way to more confidently identify specializations related to a particular behavioral or sensory ability is to look in closely related mammals of similar brain and body size, in which only one dimension of a sensory system has changed in a particular member of the group.

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a more generalized mole that resembles the kind of ancestral condition from which the star-nosed mole evolved (Catania, 2000b). How does brain organization differ between star-nosed moles and the less specialized but closely related eastern American mole? Microelectrode recordings from the brain of Scalopus reveal a somatosensory cortex similar in many general respects to that found in the starnosed mole (Figure 5a). A relatively large S1 contains a representation of the body with caudal body parts (tail and hindlimb) located medially in cortex and the face and nose represented more laterally. As in star-nosed moles, a relatively large S2 is found as a mirror image of S1 in more lateral and caudal cortex. This basic layout of two relatively large

3.15.2.2 The Star-Nosed Mole – A Case Study in Somatosensory Evolution

Comparing the somatosensory systems of different mole species provides what might be considered a natural experiment in the elaboration of the mechanosensory portion of the nose and corresponding representations in the brain. Unlike most other mammals, moles use the skin surface of the snout – rather than vibrissae – to explore their environment through touch. But the degree of elaboration of the nose and associated sensory organs differs greatly across species. Consider, for example, the eastern American mole (Scalopus aquaticus) in Figure 4. This species is

Figure 4 Comparison of two mole species. a, The eastern American mole (S. aquaticus) is the least specialized mole resembling the probable ancestral condition for moles (Catania, 2000b). b, The star-nosed mole (Condylura cristata) is the most specialized mole with a snout consisting of 22 mechanosensory appendages.

Figure 5 The results of recent investigations of cortical organization in moles. a, The eastern American mole has two somatosensory areas, primary (S1) and secondary (S2) somatosensory cortex, which include visible barrels much like those identified in rodent cortex. b, The star-nosed mole has three representations of the star (S1, S2, and S3). These areas are visibly reflected as a series of modules in flattened sections of cortex processed for cytochrome oxidase.

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somatosensory areas, S1 and S2, is also found in other moles species (Catania, 2000c) and in the sister group to moles, the shrews (Catania et al., 1999; see Figure 2). Thus, moles and shrews generally have two representations of the nose in lateral cortex. However, star-nosed moles have three representations of the star (Catania and Kaas, 1995) in lateral cortex (Figure 5b). The most parsimonious interpretation of these observations is that starnosed moles have independently evolved an extra representation of the star. This finding is from very closely related species that differ little in body weight and brain size, and it supports the conclusion that the addition of a new area to the cortical network is an important substrate for more efficient processing of sensory inputs. The most obvious difference between starnosed moles and other moles is the elaboration of the somatosensory star with a corresponding increase in innervation density accompanied by more complex foraging behaviors (e.g., foveation movements of the star – this is discussed in Section 3.15.2.4). As a result, star-nosed moles are one of the fastest and most efficient of mammalian foragers (Catania and Remple, 2005) and the larger number of cortical representations of the star may facilitate this ability, perhaps through the parallel processing of different facets of touch information. 3.15.2.3 Behaviorally Important Areas Are Magnified in the Brain

Figure 6 illustrates cortical magnification of important sensory surfaces in the naked mole-rat and the star-nosed mole showing how the most behaviorally important sensory surfaces take up a disproportionate area of cortex. This feature of cortical maps has been documented since the

Figure 6 Cortical magnification in naked mole-rats and starnosed moles. These schematics illustrate the relative proportions of the somatosensory cortex taken up by representations of different body parts in each species. Surprisingly, the naked mole-rat devotes much of its cortex (30% of S1) to the representation of the incisors. In contrast, star-nosed moles devote a huge portion of their somatosensory cortex to the representation of the star.

pioneering studies of Adrian (1943) and Woolsey et al. (1942), in which it was noted that parts of the body that have the greatest tactile acuity have the largest cortical projection zones. Cortical magnifications have since been described for different sensory systems in diverse species, and this phenomenon makes for striking imagery. However, the relationship between sensory surface size and cortical representational area also raises important and fundamental questions about brain organization and evolution. Namely, how do the most important sensory surfaces acquire the largest territories in the brain? Early investigations of this relationship in rodent barrel cortex revealed a direct linear correlation between the size of a cortical barrel (the area representing a whisker) and the innervation density of the corresponding whisker (Welker and Van der Loos, 1986). This result suggested that cortical representational area could be, in general, proportional to the innervation density of the sensory surface projecting to any given area of cortex. Such a relationship would explain the expanded representations of important areas of the skin, retina, and cochlea that had been described in a number of species. At the same time, this finding suggested that there was no ‘cortical component’ to cortical magnification and that this parameter could be predicted without even examining the brain, simply by determining the relative innervation density of a sensory surface. Lee and Woolsey (1975) recognized this possibility and suggested that cortical representations are more appropriately described by a ‘‘peripheral scaling factor’’ than a ‘‘cortical magnification factor.’’ Of course, another possibility is that cortical representational area is not proportional to number of inputs from the periphery, and instead important sensory inputs could project to a larger area of cortex than less important inputs. This has been the subject of considerable historical debate in the visual system of primates, where some studies suggest that the large cortical representation of the retinal fovea simply reflects the number of retinal ganglion cells projecting from the retina (Drasdo, 1977; Wassle et al., 1989, 1990), whereas other studies indicate that ganglion cells projecting from the fovea have a disproportionately large representation in cortex (Malpeli and Baker, 1975; Myerson et al., 1977; Perry and Cowey, 1985; Silveira et al., 1989). The weight of most recent evidence supports the contention that important inputs in the visual systems of primates are indeed overrepresented in the cortex (Azzopardi and Cowey, 1993). However, the few studies that have addressed this issue and the conflicting results from different studies in the

Evolution of the Somatosensory System – Clues from Specialized Species

primate visual system highlight the difficulty of making these determinations in most sensory systems. This is a case where the particularly specialized sensory system of the star-nosed mole has provided new insights as a result of its anatomical specialization. But before describing how star-nosed moles can shed light on visual system organization, it is necessary to outline the parallels between the star-nosed mole’s somatosensory system and the visual systems of sighted mammals. 3.15.2.4 A Somatosensory Fovea in the Star-Nosed Mole

Although the nose of the star-nosed mole is a tactile sensory surface, there are a number of behavioral and anatomical similarities between the mole’s sensory system and the visual systems of other species. This is most obvious from observations of starnosed mole behavior (Catania and Remple, 2004). The entire star is used for the detection of relevant stimuli in the environment, but once an object or food item of interest is detected, the nose is shifted in a saccadic manner for detailed investigations with the touch fovea. There are 11 finger-like appendages on each side of the star, and the ventral-most, 11th pair constitutes the fovea. The other appendages take up a much greater surface area and act as the ‘tactile periphery’ in a manner analogous to the peripheral visual receptors of the retina. Because one small area of the skin surface is the behavioral focus of the star, we can address the question of whether the most important inputs from a sensory array are allocated extra territory in the cortex, or alternatively whether the sizes of each cortical representation are simply proportional to their innervation density. This question is relatively easy to answer in the star-nosed mole because of the favorable anatomical organization of the sensory system. It is possible to quantify three different parameters: (1) the number of sensory organs on the star, (2) the number of primary afferents innervating the each appendage of the star, and (3) the area of primary somatosensory cortex devoted to each appendage (Figures 7a–7c). It is also possible to accurately measure the cortical representation of the star because of the histologically visible reflection of the appendage representations as a series of modules in somatosensory cortex. This aspect of star-nosed mole brain organization is discussed in more detail in the next section. Because these different parameters can be measured in star-nosed moles, a number of interesting comparisons can be made. First, it is possible to consider the relationship between innervation

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density (number of nerve fibers) and the number of sensory organs (Eimer’s organs) on the skin surface of each appendage (Figure 7d). This comparison shows that the number of nerve fibers and the number of Eimer’s organs co-vary almost precisely for appendages 1–9. However, for appendages 10 and 11, there are more fibers per sensory organ. This reflects the higher acuity of this behaviorally important sensory surface. But does this account for the cortical magnification of the fovea, as suggested by studies in rodent barrel cortex? Figure 7e shows this comparison (average area of cortex per afferent for each appendage of the star) clearly indicating that the higher innervation for the fovea area of the star does not account for the cortical magnification of the fovea. Instead, star-nosed moles devote a greater average area of cortex to the most important afferents from the 11th appendage of the star (the tactile fovea) and conversely a smaller average area of cortex to the representations of the afferents from remaining 10 appendages (Figure 7e). Thus, the favorable anatomy of star-nosed mole’s sensory system has allowed for the quantification of variables that are difficult to measure in many species and these findings may reflect a common relationship between sensory surfaces and the cortex in mammals. For example, the degree of cortical overrepresentation of the inputs from the fovea of the star is similar to the degree of overrepresentation of the retinal fovea in primates (Catania, 1995; Azzopardi and Cowey, 1993). Finally, the subdivision of the star-nosed mole’s sensory system into fovea and periphery is a remarkable example of the convergent evolution of similar features across disparate sensory systems. It suggests this organizational scheme is a general solution to designing a high-resolution sensory system. The most familiar and common example of a foveaperiphery organization is of course found in many visual systems of diverse mammals; however, auditory systems can have an acoustic fovea as well. This has been demonstrated in a number of studies by Suga and colleagues (Suga and Jen, 1976; Suga, 1989) for mustached bats (Pteronotus parnellii). Mustached bats emit an echolocation call that includes a narrow frequency range around 60 kHz that is particularly important for detecting the acoustic evidence of wing-beats caused by flying insect prey. A large proportion of the hair cells in the bat’s cochlea are tuned to this important echolocation frequency and a large territory of the bat’s A1 is devoted to processing sounds at this frequency. Thus, mustached bats have an acoustic fovea, and they have the acoustic equivalent of a saccade as well. This is necessary because returning

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Figure 7 Quantification of the number of sensory organs, innervating nerve fibers, and representational area of the star in primary somatosensory cortex. a, A single appendage of the star under the scanning electron microscope showing the many visible sensory organs (Eimer’s organs) covering the skin surface. b, A thin section of tissue showing a small portion of the many myelinated afferents supplying an appendage of the star. c, A potion of the cortex of a star-nosed mole that has been flattened and processed for cytochrome oxidase to reveal the primary somatosensory representation of the star. The area representing each appendage is visible as a separate subdivision. d, A graphic representation of the ratio of fibers (afferents) innervating each appendage per sensory organ on each appendage (or ray) of the star. e, The average area of cortex devoted to the primary afferents for each appendage (ray) of the star. Scale bars: a, 250 mm; b, 20 mm; c, 500 mm. Reproduced from Catania, K. C. and Kaas, J. H. 1997c. Somatosensory fovea in the star-nosed mole: Behavioral use of the star in relation to innervation patterns and cortical representation. J. Comp. Neurol. 387, 215–233.

echoes are often Doppler shifted to different frequencies depending on the speed of the bat and its target. To compensate for these Doppler shifts, bats are constantly shifting the frequency of their outgoing pulses to ‘focus’ the returning echo on the high-resolution area of the acoustic fovea. This behavior, called Doppler shift compensation (Schnitzler, 1968), is surprisingly similar to a saccade in the visual system. The most well-developed visual systems, somatosensory systems, and auditory systems, all exhibit a fovea-periphery organization. An obvious benefit of this design is the conservation of neural processing

area in the brain and innervating nerve fibers at the level of the sensory periphery. For example, making the entire sensory system high resolution would require a massive enlargement of the nerves carrying information to the brain, and a corresponding enlargement of the cortical areas processing the inputs. The ultimate result would be a staggering increase in brain size. It is far more efficient to devote a large part of the computational area of the brain to a small part of the sensory system (the retinal, tactile, or acoustic fovea) and then move that area around like a spotlight to analyze important stimuli (or in the case of bats, move the frequency of echolocation

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pulses to ensure that Dopplar shifted echoes can be analyzed by the fovea). 3.15.2.5 Modules Represent Sensory Surfaces in Diverse Species

Woolsey and Van der Loos (1970) made the discovery of modules in the somatosensory cortex that represented the important facial vibrissae, or whiskers, in mice. They described cylindrical groupings of cells that were most easily seen in sections of the cortex cut parallel to the cortical surface. Electrophysiological recording of neuronal responses revealed that each barrel corresponded to the cortical representation of a single whisker on the face. This finding was remarkable because it revealed a visible reflection of a somatosensory map and at the same time provided a useful model system for exploring many details of mammalian brain organization and development. Cortical barrels were also considered to provide anatomical support for the columnar hypothesis of cortical organization, which suggests that cylindrical columns of interconnected neurons are the fundamental organizational unit of neocortex. From the time since cortical barrels were first described, a number of investigations of cortex have revealed cortical subdivisions, or modules, related to sensory specializations in diverse species. Star-nosed moles provide one of the more dramatic examples of this relationship. Figure 8 shows details of star-nosed mole cortex. In the case of star-nosed moles, the receptors represented in cortex are part of an elongated skin surface, rather than a hair surrounded by a ring of mechanoreceptors as found in rats and mice (see Rice et al., 1993). As described previously (Figure 5b) electrophysiological recordings from the cortex of star-nosed moles reveal three representations of the star in lateral cortex. When sections of the flattened cortex are cut parallel to the cortical surface and processed for cytochrome oxidase (Wong-Riley and Carroll, 1984) three different maps of the star are visible (Figure 8b). Each of these maps represents the entire contralateral star and each cortical module representing an appendage takes the from of elongated wedge. The representations of the appendages of the star-nosed mole differ from cortical barrels of rodents in a number of ways. First, the representations of the appendages consist of elongated stripes of cortical tissue, rather than circular barrels. Second, the representation of the tactile fovea is greatly expanded in cortex relative to the size of this appendage on the star. As outlined above, the representation of this appendage reflects the

Figure 8 The unusual mechanosensory star and its corresponding cortical representation in the star-nosed mole (C. cristata). a, A star-nosed mole emerges from an underground tunnel showing its large forelimbs and the 22 fleshy appendages that surround each nostril. The 11th appendages on each side act as the somatosensory fovea and are used for detailed tactile investigations. b, A section of flattened cortex revealing all three cortical representations of the star (S1, S2, and S3 – see Figure 5b) visible as a series of modules, each representing an appendage from the contralateral star. c, An example of the specificity of callosal connections around the S1 star representation. Cells and terminals are concentrated in the septa between appendage representations and surrounding the star representation but are absent from the centers of each cortical stripe. Reproduced from Catania, K. C. and Kaas, J. H. 2001. Areal and callosal connections in the somatosensory cortex of the star-nosed mole. Somatosens. Mot. Res. 18, 303–311.

behavioral importance of the fovea, rather than the innervation density of the sensory surface. Finally, in the star-nosed mole’s cortex multiple maps of the sensory surface are uniquely visible. Three different somatosensory areas, S1, S2, and a new area we

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have termed S3, contain modules representing individual appendages. From these observations, one can conclude that cortical modules are not constrained to form traditional columns, as suggested from barrels. It is also clear that insectivores may have exceptionally wellorganized and complex cortical representations. This result is in stark contrast to results from early investigations of insectivores, including moles (Allison and Van Twyver, 1970), which suggested they had overlapping cortical areas with poorly defined topography. In this regard it is significant that the modules in the star-nose mole’s cortex have different connections than the septa between modules. For example, tracer injections into the cortex reveal that callosal connections terminate selectively in the septa between cortical modules, whereas intercortical connections terminate primarily within modules (Figure 8c). A different kind of modular representation of a sensory surface is found in the eastern American mole (S. aquaticus). This mole has an unusual and

sensitive forelimb consisting of an oval palm and heavily clawed digits. In S2 of this species cytochrome oxidase processed sections of cortex reveal a modular reflection of the forelimb. This cortical pattern appears just like the large clawed hand that it represents (Figure 9). Tracer injections into the spinal cord of the eastern American mole show that the modular forelimb representation is also the location of dense areas of corticospinal projecting neurons (Catania and Kaas, 1997a). These examples of different kinds of connections to different parts of cortical modules in moles support the general conclusion that different parts of cortical modules may be the selective substrate for the distribution of specific cortical circuitry (Chapin et al., 1987; Koralek et al., 1990; Fabri and Burton, 1991; Hayama and Ogawa, 1997; Kim and Ebner, 1999). In addition to cortical modules discussed above in rodents and insectivores, investigations of cortical organization in the duck-billed platypus have provided a different example of modules representing

Figure 9 The representation of the eastern mole forelimb (S. aquaticus) and the hand of an owl monkey (Aotus trivirgatus). a, The large clawed forelimb of the mole. b, The cortical representation of the mole’s forelimb as revealed by sections processed for cytochrome oxidase. The representation appears just like the large clawed hand it represents. c, A reconstruction of cortical recordings from an owl monkey showing the relative location of areas that responded to the digits (D1–D5) and the palm. d, Histological sections from the corresponding area of S1 (area 3B), in the same owl monkey, showing the cortical modules that represent the fingers and palm of the hand (arrowhead marks microlesions). b, Reproduced from Catania, K. C. and Kaas, J. H. 1997a. The organization of somatosensory cortex and distribution of corticospinal neurons in the eastern mole (Scalopus aquaticus). J. Comp. Neurol. 378, 337–353. d, Reproduced from Jain, N., Catania, K. C., and Kaas, J. H. 1998. A histologically visible representation of the fingers and palm in primate area 3b and its immutability following long-term deafferentations. Cereb. Cortex 8, 227–236.

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sensory surfaces. The platypus bill contains tens of thousands of mechanoreceptors and electroreceptors (Manger and Pettigrew, 1996). Microelectrode mapping of the platypus somatosensory cortex has revealed a large S1 representation of the bill in lateral cortex (Krubitzer et al., 1995). Flattened sections of cortex processed for cytochrome oxidase reveal alternating stripes of cortical tissue with dark and light regions representing higher and lower amounts of chronic neuronal activity. The dark areas represent the projection zones for mechanosensory information whereas the light zones represent the projection zones for combinations of mechanosensory and electrosensory information. Thus, S1 in the platypus contains receptor specific subdivisions very similar to the alternating bands of cortex representing rapidly adapting and slowly adapting mechanoreceptors in S1 of primates (Sur et al., 1981), cats (Stretavan and Dykes, 1983), and raccoons (Rasmusson et al., 1991). This anatomical arrangement of different sensory inputs in the platypus cortex is also reminiscent of ocular dominance columns representing inputs from the different eyes in primate area 17 (Hubel et al., 1976). The examples of cortical modules described above are from a range of particularly specialized mammals, and this raises the question of how common such representations of tactile sensory surfaces are across species and whether such findings have implications for primate and human brain organization. Relatively recent findings in primates suggest there are similar organizing principles for mechanosensory inputs across these diverse species. Jain et al. (1998) examined flattened cortex of three different primate species processed for myelin (Gallyas, 1979) and identified myelin-dense cortical modules representing the mechanoreceptors of the digits and palm in S1 (Figures 9c and 9d). Thus, the cortical representation of the primate hand, like the representation of rodent whiskers and the mole’s star, is visibly reflected in flattened sections of cortex (see also Qi and Kaas, 2004). These findings indicate that large- and smallbrained mammals share common developmental principles that segregate maps in similar ways. They also suggest there is a ubiquitous instructional role for the sensory periphery in guiding the formation of central representational maps. 3.15.2.6 The Sensory Periphery Guides Aspects of Cortical Development

The finding of histologically visible cortical maps of sensory surfaces that reflect the details of mechanoreceptor topography raises the question of how somatosensory areas become matched to the

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sensory periphery. Because the development of the somatosensory system begins with the skin surface and ends at the cortex (see Killackey et al., 1995) there is opportunity for the sensory surface to instruct the cortex. Evidence for such an instructive role of the sensory periphery comes from the somatosensory system of rodents where it has been shown that early damage to a whisker disrupts the formation of the corresponding cortical barrel (Andres and Van der Loos, 1985; Woolsey, 1990). A different but related kind of evidence comes from strains of mice bred for variations in the whisker pattern. Van der Loos and Dorfl (1978) noted that strains of mice born with extra whiskers on the face also developed extra barrels in the cortex in the appropriate topographic location (see Epigenetic Responses to a Changing Periphery – Wagging the Dog). They argued that it was unlikely for a single mutation to have simultaneously altered the entire sensory system from whisker to barrel, but rather a mutation acting at the level of the early developing skin surface was more likely to have been communicated to the subcortical nuclei and then to the developing cortex. Similar results have more recently been reported in star-nosed moles, where wild-caught animals have an unusually high rate (5%) of extra or missing nasal appendages. The different nose configurations are invariably reflected in the cortical maps (Catania and Kaas, 1997b). Although Van der Loos and Dorfl made a compelling argument, they could not entirely rule out the possibility of a single genetic modification simultaneously and independently altered the brain and the whiskers of mice. Recently, however, their interpretation of an instructive role for the skin surface has received strong support from investigations in which altered whisker patterns were induced during embryonic development by transfecting the epidermis of mice with a virus containing the patterning gene Sonic hedgehog (Shh). This manipulation resulted in the formation of extra whiskers on the face, and later extra barrels in the cortex (Ohsaki et al., 2002). However, in this case the genetic change was clearly restricted to the skin surface, supporting the hypothesis that the skin surface instructs the later-developing cortex. Another possible role for the periphery in guiding the formation of cortex may be found in the timing of developmental events. For example, the retinal fovea in primates develops earlier than the peripheral retina, and inputs from the fovea have a preferentially magnified representation in cortex (as previously described). Similarly, the tactile fovea in star-nosed moles develops earlier than the more peripheral parts of the star. This can be

200 Evolution of the Somatosensory System – Clues from Specialized Species

Figure 10 An embryonic mole showing the developing star. The appendages are numbered 1–11, as in adults. Note however, the relatively much larger area of the star taken up by the 11th, foveal appendage (arrow) at this early stage of development compared to appendage 11 in adults (see Figure 8a). Examination of this development sequence (Catania, 2001) reveals that the fovea leads the development of the star, and this may allow afferents from the developing fovea to capture a larger area of cortex (e.g., Figure 7e) in a competition for cortical territory. Photo copyright 2005 Catania.

appreciated by examining embryonic (Figure 10) and adult (Figure 8a) star-nosed moles and comparing the size of the 11th appendage (the tactile fovea) at these different stages. The 11th appendage takes up a far greater proportion of the star in embryos than it does in adults. More detailed investigations of this relationship (Catania, 2001) reveals that the tactile fovea leads the development of the star, such that it grows large early, has the largest innervated sensory surface in embryos, and develops sensory organs (Eimer’s organs) before the peripheral appendages of the star (appendages 1–10). Yet later in development the peripheral appendages grow larger than the fovea, until in adults the 11th appendage is dwarfed by the rest of the star (Figure 8a). The early development of these important sensory surfaces may give them an advantage in a competition for cortical territory during development. Evidence for this possibility comes from studies of the primate visual system. When one eye is sutured shut and deprived of visual input during critical periods of development, ocular dominance columns related to that eye are greatly reduced in size compared to the open eye (Hubel et al. 1977). Activity dependent expansions have also been documented for the somatosensory system, where the most active

regions of barrel cortex undergo the greatest amount of growth during development (Riddle et al., 1993; Purves et al., 1994). These studies suggest that the most active inputs during critical periods of development have a competitive advantage in capturing representational space in the cortex. So far, I have highlighted some of the evidence for changes that may have commonly occurred in the course of the evolution of the somatosensory system. These include the magnification of behaviorally important areas of sensory maps, the addition of new areas to cortical networks, the formation of a fovea-periphery organization for high-resolution sensory systems, and the subdivision of areas into modules representing segregated sensory surfaces in the periphery. In this last section I will outline some ideas for potential mechanisms by which some of these changes may occur. Additional details may be found in Epigenetic Responses to a Changing Periphery –Wagging the Dog.

3.15.3 What are the Mechanisms of Evolutionary Change? 3.15.3.1 Levels of Organization

The examples outlined above for the somatosensory system suggest two different levels of organizational change in the evolving neocortex that may be altered by two different mechanisms. The first level involves alterations of details of cortical representations that stem from the developmental link between the sensory periphery and the brain. Evidence for this possibility comes from a number of sources as outlined in the previous sections, including surgical alterations to the whiskers that change barrel patterns in mice, strains of mice bred with supernumerary whiskers that have extra barrels in the cortex, wild-caught star-nosed moles with extra appendages on the star and extra representational stripes in the cortex (indicating this occurs in natural populations), and evidence that changes in the timing of developmental events at the sensory surface may have an important impact on cortical development. A second level of organizational change is the addition of completely new areas to the cortex, in the form of new maps of the sensory periphery. Evidence for this kind of change comes from comparative studies that illustrate the variation in numbers of cortical subdivisions in differently specialized species. The extra somatosensory area in star-nosed moles (Figure 5) compared to other mole species provides one example that can be

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Figure 11 Cortical organization in megachiropteran and microchiropteran bats, demonstrating visual and auditory specializations, respectively. a, Summary of cortical areas in the megachiropteran flying fox (Pteropus poliocephalus). This fruit-eating species relies heavily on vision and this is reflected in the proportion of cortex devoted to vision and the number of corresponding visual areas. Roughly half of the cortex is taken up by a series of at least six visual areas (shaded areas) and a number of additional areas are likely to be found in more rostral-lateral cortex. b, Summary of cortical areas in the microchiropteran mustached bat (Pteronotus parnellii). In contrast to megachiropteran bats, microchiropteran bats have reduced visual systems and depend heavily on echolocation to navigate and locate flying prey. This is reflected in the organization of their neocortex which is dominated by a network of eight or more auditory areas (shaded areas) that largely process information in the frequency range of returning echolocation pulses. These closely related species provide an example of how cortex has evolved in parallel with the more complex visual and auditory abilities of each respective species. a, Data from Rosa, M. G., Krubitzer, L. A., Molnar, Z., and Nelson, J. E. 1999. Organization of visual cortex in the northern quoll, Dasyurus hallucatus: Evidence for a homologue of the second visual area in marsupials. Eur. J. Neurosci. 11(3), 907–915. b, Data from Suga, N. 1989. Principles of auditory information-processing derived from neuroethology. J. Exp. Biol. 146, 277–286.

confidently attributed to the elaboration of the somatosensory system. Other examples include comparison of the many visual areas in highly visual megachiropteran bats to the few visual areas in echolocating microchripteran bats, and conversely comparison of many auditory areas for processing echos in the microchiropteran bats to the few auditory areas in nonecholocating, megachropteran bats (Figure 11). 3.15.3.2 Potential Mechanisms of Change

As described above, the intimate developmental relationship between receptor arrays and cortical maps suggests that many changes to cortical areas in the course of evolution may initially occur simply by altering the body. It seems likely that cortical and subcortical areas of the brain are flexible enough to accommodate changes to the sensory periphery that may provide a selective advantage. For example, the expansion of a sensory surface allows for a greater area of the environment to be investigated per unit time. This is presumably the selective pressure that drove star-nosed moles in the direction of enlargement of their mechanosensory snout relative to other species. In support of this possibility, starnosed moles eat relatively small prey items compared to other species of moles, and this requires locating more prey per unit time to satisfy metabolic requirements (Catania and Remple, 2005). The evidence of supernumerary appendages in some moles suggests a simple mechanism by which such an

expansion of the sensory surface can occur – that is, change the star locally and the sensory processing areas will accommodate the alterations through a developmental cascade. Yet changes to cortical areas to accommodate different configurations of a sensory surface may have important, negative consequences for sensory processing (Figure 12). In this respect, a cortical area may be challenged in the same general ways that have been outlined for increasing the size of the entire brain (Deacon, 1990; Kaas, 2000). One problem is the lengths and numbers of interconnections within a cortical area. As neurons become more widely separated, the diameters of their axons and dendrites must become greater to maintain similar conduction times between neurons (Ringo et al., 1994). This in turn typically requires increases in the size of the supporting neuronal cell body in order to supply the metabolic requirements of the neurites. In addition, as the number of neurons in larger areas increases, the number of connections between neurons must increase drastically to maintain a similar degree of global connectivity between neurons within the area (Deacon, 1990). All of these changes require more space in the cortex, which compounds the problem. Thus, increasing the size of a cortical area could result in a suboptimal processing area and set the stage for the adaptive benefits of adding a new area to the cortex. Figure 12 provides a schematic outline for how some of these changes may occur. The progressive

202 Evolution of the Somatosensory System – Clues from Specialized Species Sensory surface

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Figure 12 Schematic illustration of possible steps in the progressive evolution of a more complex cortex with new areas. Steps 1–4 represent a progression of changes in the species over successive generations. The graph at the bottom represents the proposed adaptive value of each evolutionary change for steps 1–4. In this proposal, the sensory surface leads the evolutionary process of brain reorganization through a cascade of developmental events in steps 1–3. This begins with the expansion of the sensory surface and a corresponding expansion of the representation of the sensory surface in cortex. The far right side represents the level of connectivity between neurons needed for sensory processing. Although each step is presumed to provide a net advantage (lower panels), by step 3, the cortical processing area is strained and no longer processing the information at peak efficiency. This sets the stage for step 4, during which the cortical area is duplicated (through developmental mechanisms centers in the cortex – see text for example) allowing for the two smaller areas to efficiently process information. Although not illustrated, the two areas are now free to specialize in processing different facets of sensory information and this is considered to be part of the adaptive value of this step (lower panel).

evolution of a sensory system is illustrated from top to bottom of the figure. The initial stages (1–3) reflect the progressive elaboration of the sensory surface (left side) and the corresponding expansion of the representation in cortex (right side) through a

developmental cascade. The graph at the bottom illustrates the proposed adaptive value of each change. Initially the developmental changes to the sensory surface are accommodated by the laterdeveloping brain, and there is a steep rise in adaptive

Evolution of the Somatosensory System – Clues from Specialized Species

value (1–2). However, at some point (3) the cortical area is no longer at an optimal size for processing information from the sensory surface (as illustrated in red). Although the expansion of the sensory surface has still resulted in an increased net adaptive value for the sensory system as a whole (bottom panel), the stage is now set for the addition of a cortical area to optimize sensory processing. With the addition of a cortical area (4) there is another steep rise in adaptive value of the sensory system (4). Although not illustrated, the ability for the two daughter areas to specialize for processing different facets of sensory information may provide the most important advantaged for sensory processing. There seems to be ample evidence from both experimental manipulations of development and naturally occurring variants that steps 1 and 2 can occur. That is, changes to the sensory system localized to the sensory periphery may cause alterations of the representations in the CNS. However, evidence for variation in the number of cortical areas is much less obvious, and must usually be inferred and reconstructed from comparative studies across species. Although there may be some ongoing variations in numbers of cortical areas in a given species, so few brains are processed and examined in detail for any species that the chances of such variants being identified are small. This can be contrasted with variants in body parts and sensory systems that can be readily identified by simply examining an animal’s body (e.g., Van der Loos and Do¨rfl, 1978). As a result, the potential mechanisms for altering cortical area number are most readily deduced from laboratory investigations of patterning-gene expression.

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Recent investigations and manipulations of gene expression patterns in developing mouse cortex suggest some of the mechanisms that control cortical area position, orientation, and number (Cecchi, 2002; Fukuchi-Shimogori and Grove, 2001; Ohsaki et al., 2002; O’Leary and Nakagawa, 2002). These investigations have revealed graded expression of patterning proteins in the developing cortex that can be manipulated to cause predictable alterations in the positions of entire cortical subdivisions. One growth factor in particular – FGF8 (a member of the fibroblast growth factor family) – has been the focus of a number of recent studies. FGF8 is normally expressed at the rostral pole of the developing neocortex. In a landmark experiment, FukuchiShimogori and Grove (2001) introduced a second source of FGF8 at the caudal pole of developing mouse neocortex. When they later examined the adult somatosensory cortex in these mice, some individuals had generated a partial mirror-image duplication of the S1 barrel field (Figure 13) that presumably was supplied by its own set of thalamocortical axons (O’Leary and Nakagawa, 2002). This experiment has profound implications because the generation of a new, mirror-image representation of a sensory surface has clearly occurred many times in the course of mammalian brain evolution. Thus, addition of a new FGF8 source to developing cortex produces a phenotype in the laboratory that mimics a common product of cortical evolution. Long before genetic manipulation of patterning genes was possible, previous investigators of mammalian cortical diversity had suggested that sudden duplications of cortical areas might occur as

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Figure 13 Schematic illustration of recent experiments that have induced the partial duplication of the cortical barrel field by adding a new source of FGF8 to the caudal part of developing cortex. a, FGF8, a member of the fibroblast growth factor family, is normally expressed rostrally in developing cortex. b, When a second source of FGF8 was introduced by electroporation during fetal development, adults were later found to have a partially duplicated barrel field (arrow). This results suggests a mechanism by which mirror image duplications of a cortical area might occur in the course of mammalian evolution. Reproduced from FukuchiShimogori, T. and Grove, E. A. 2001. Neocortex patterning by the secreted signaling molecule FGF8. Science 294, 1071–1074.

204 Evolution of the Somatosensory System – Clues from Specialized Species

mammalian brains evolved (Allman and Kaas, 1971; Kaas, 1982). The idea was that a new area could then become specialized to perform new functions while releasing the original area from some of its functions. There are a number of attractive features to this theory of cortical elaboration. Meristic changes – or alterations to a standard part – are a common mechanism of evolutionary change that has been well documented from the level of genes (see Ohno, 1970) to entire body parts (Raff, 1996). That this can occur for cortical areas seems likely in light of the recent findings of Fukuchi-Shimogori and Grove (2001). In addition to this recent evidence from FGF8 expression, there are a number of considerations related to cortical area organization that suggest duplication of an area may be an efficient mechanism for expanding cortical functions. For example, such a mechanism (dependent on chemical gradients) would likely result in mirror-image maps (see Figure 13b and Catania, 2004), as observed for the supernumerary barrel representation in mice with an extra FGF8 source. Most adjacent cortical areas are mirror images of one another and share a congruent border (Kaas, 1982). This results in areas that are more topographic as a group, than non-mirror-image areas (i.e., neighbor relationships are maintained at, and across the congruent border between areas). It seems likely that such topographic representations are a particularly efficient configuration of cortex. Such an organization groups neurons that interact together, reducing fiber lengths and minimizing conduction delays. Topographic representations may also facilitate detection of movement and the refinement of acuity through center-surround receptive field configurations. An alternative possibility for cortical elaboration is that cortical areas slowly fission by gradual separation. However, this seems less likely, as the result would be two daughter areas with the same (nonmirror image) orientation – and this is seldom observed. In addition, areas that gradually separate from one another would pass through a very nontopographic and presumably less efficient intermediate stage. Finally, if chemical gradients play a major role in the positioning and orienting of cortical areas during development, gradual separation of two areas may be difficult to achieve and the resulting, non-mirrorimage representations may be difficult or impossible to code with chemical gradients (Catania, 2004).

3.15.4 Conclusions Investigations of specialized mammals reveal a number of clear trends in mammalian brain evolution. This includes the expansion of the representations of

behaviorally important sensory surfaces, the subdivision of cortical areas into modules representing parts of a sensory surface, and the addition of entirely new cortical areas to the processing network. Surgical alterations of sensory surfaces during development and the discovery of natural variations in sensory arrays suggests that many of the changes to the representations in the cortex may occur simply as a result of changes to the sensory surface that are communicated centrally by a developmental cascade. However, larger-scale changes in brain organization, such as the addition of new cortical areas to the processing network, require alterations of gene expression that are centered in the developing brain. The most recent advances in manipulating the expression of patterning genes in the cortex suggest mechanisms by which areas may be added to the cortex. These findings support some long-standing theories for how the brains of ancestral mammals may have evolved to produce the diversity of cortical configurations observed in modern mammalian lineages.

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Further Reading Kaas, J. H. 2005. From mice to men: The evolution of the large, complex human brain. J. Biosci. 30, 155–165. Kaas, J. H. 2004. Evolution of somatosensory and motor cortex in primates. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 281, 1148–1156. Krubitzer, L. and Kaas, J. 2005. The evolution of the neocortex in mammals: How is phenotypic diversity generated? Curr. Opin. Neurobiol. 15, 444–453. Ringo, J. L. 1991. Neuronal interconnection as a function of brain size. Brain Behav. Evol. 38, 1–6. Striedter, G. F. 2005. Principles of Brain Evolution. Sinauer Associates.