Abstract: Primates are endowed with a brain about twice the size that of a mammal with the same body size, and humans have the largest brain relative to body size of all animals. This increase in brain size may be related to the acquisition of higher cognitive skills that permitted more complex social interactions, the evolution of culture, and the eventual ability to manipulate the environment. Nevertheless, in its internal structure, the primate brain shares a very conserved design with other mammals, being covered by a six-layered neocortex that, although expands disproportionately to other brain components, it does so following relatively well-defined allometric trends. Thus, the most fundamental events generating the basic design of the primate and human brain took place before the appearance of the first primate-like animal. Presumably, the earliest mammals already displayed a brain morphology radically different from that of their ancestors and that of their sister group, the reptiles, being characterized by the presence of an incipient neocortex that underwent an explosive growth in subsequent mammal evolution. In this chapter, we propose an integrative hypothesis for the origin of the mammalian neocortex, by considering the developmental modifications, functional networks, and ecological adaptations involved in the generation of this structure during the cretaceous period. Subsequently, the expansion of the primate brain is proposed to have relied on the amplification of the same, or very similar, developmental mechanisms as those involved in its primary origins, even in different ecological settings.
Abstract: The development of the mammalian neocortex relies heavily on subplate. The proportion of this cell population varies considerably in different mammalian species. Subplate is almost undetectable in marsupials, forms a thin, but distinct layer in mouse and rat, a larger layer in carnivores and big-brained mammals as pig, and a highly developed embryonic structure in human and non-human primates. The evolutionary origin of subplate neurons is the subject of current debate. Some hypothesize that subplate represents the ancestral cortex of sauropsids, while others consider it to be an increasingly complex phylogenetic novelty of the mammalian neocortex. Here we review recent work on expression of several genes that were originally identified in rodent as highly and differentially expressed in subplate. We relate these observations to cellular morphology, birthdating, and hodology in the dorsal cortex/dorsal pallium of several amniote species. Based on this reviewed evidence we argue for a third hypothesis according to which subplate contains both ancestral and newly derived cell populations. We propose that the mammalian subplate originally derived from a phylogenetically ancient structure in the dorsal pallium of stem amniotes, but subsequently expanded with additional cell populations in the synapsid lineage to support an increasingly complex cortical plate development. Further understanding of the detailed molecular taxonomy, somatodendritic morphology, and connectivity of subplate in a comparative context should contribute to the identification of the ancestral and newly evolved populations of subplate neurons.
Abstract: There is currently a debate about the evolutionary origin of the earliest generated cortical preplate neurons and their derivatives (subplate and marginal zone). We examined the subplate with murine markers including nuclear receptor related 1 (Nurr1), monooxygenase Dbh-like 1 (Moxd1), transmembrane protein 163 (Tmem163), and connective tissue growth factor (Ctgf) in developing and adult turtle, chick, opossum, mouse, and rat. Whereas some of these are expressed in dorsal pallium in all species studied (Nurr1, Ctgf, and Tmem163), we observed that the closely related mouse and rat differed in the expression patterns of several others (Dopa decarboxylase, Moxd1, and thyrotropin-releasing hormone). The expression of Ctgf, Moxd1, and Nurr1 in the oppossum suggests a more dispersed subplate population in this marsupial compared with mice and rats. In embryonic and adult chick brains, our selected subplate markers are primarily expressed in the hyperpallium and in the turtle in the main cell dense layer of the dorsal cortex. These observations suggest that some neurons that express these selected markers were present in the common ancestor of sauropsids and mammals.
Abstract: This article provides an overview of signaling processes during early specification of the anterior neural tube, with special emphasis on the telencephalon. A series of signaling systems based on the action of distinct morphogens acts at different developmental stages, specifying interacting developmental fields that define axes of differentiation in the rostrocaudal and the dorsoventral domains. Interestingly, many of these signaling systems are co-opted for several differentiation processes. This strategy provides a simple and efficient mechanism to generate novel structures in evolution, and may have been especially important in the origin of the telencephalon and the mammalian cerebral cortex. For example, the action of fibroblast growth factor (FGF) secreted in early stages from the anterior neural ridge, but in later stages from the dorsal anterior forebrain, may have been a key factor in the early differentiation of the ventral telencephalon and in the eventual expansion of the mammalian neocortex. Likewise, bone morphogenetic proteins (BMPs) participate at several stages in neural patterning, even if early neural induction consists of the inhibition of the BMP pathway. BMPs, secreted dorsally, interact with FGFs in the frontal aspect of the hemispheres, and with PAX6-dependent signaling sources located laterally, to pattern the dorsal telencephalon. The actions of other morphogens are also described in this context, such as the ventralizing factor SHH, the dorsalizing element GLI3, and other factors related to the dorsomedial telencephalon such as WNTs and EMXs. The main conclusion we draw from this review is the well-known phylogenetic and developmental conservatism of signaling pathways, which in evolution have been applied in different embryological contexts, generating novel interactions between morphogenetic fields and leading to the generation of new morphological structures.
Abstract: Chronic stress affects brain areas involved in learning and emotional responses. Although most studies have concentrated on the effect of stress on limbic-related brain structures, in this study we investigated whether chronic stress might induce impairments in diencephalic structures associated with limbic components of the stress response. Specifically, we analyzed the effect of chronic immobilization stress on the expression of sympathetic markers in the rat epithalamic pineal gland by immunohistochemistry and western blot, whereas the plasma melatonin concentration was determined by radioimmunoassay. We found that chronic stress decreased the expression of three sympathetic markers in the pineal gland, tyrosine hydroxylase, the p75 neurotrophin receptor and alpha-tubulin, while the same treatment did not affect the expression of the non-specific sympathetic markers Erk1 and Erk2, and glyceraldehyde-3-phosphate dehydrogenase. Furthermore, these results were correlated with a significant increase in plasma melatonin concentration in stressed rats when compared with control animals. Our findings indicate that stress may impair pineal sympathetic inputs, leading to an abnormal melatonin release that may contribute to environmental maladaptation. In addition, we propose that the pineal gland is a target of glucocorticoid damage during stress.
Abstract: Mammalian cortical development is preceded by the elaboration of a transient preplate, which is split into a superficial marginal zone and a deep subplate after the arrival of the cortical plate. There has been some controversy in the evolutionary interpretation of this transient structure, as some propose it to represent the ancestral cortex or pallium of non-mammals, while others consider it to be a phylogenetic novelty. The preplate and its derivatives contain components derived by both tangential and radial migration. Tangentially migrating elements include pioneer neurons and interneurons, both of subpallial origin, and Cajal-Retzius cells, mostly of pallial origin. Pioneer neurons were probably present in the ancestors of mammals, but may have changed their original superficial position to one below the developing cortex, thus attracting thalamic afferents in the subcortical white matter, and making them penetrate the cortex radially. In mammals, Cajal-Retzius cells appear to have increased both in number and on their level of reelin expression, perhaps in the context of controlling the final stages of migration in a radially expanding neoocortex. Radial-migrating cells are partly represented by the pyramidal-like cells of the subplate. These neurons resemble the excitatory elements of the adult reptilian cortex, but is not clear whether they are their true homologues. One possibility is that these cells appeared by virtue of a heterochronic process in which the earliest radial elements of the cortical plate began to be produced at progressively earlier developmental stages. Thus, we conclude that the mammalian preplate and its derivatives contain both ancestral and derived elements, all of which have been modified in the course of mammalian evolution to support an increasingly complex cortical plate development.
Abstract: It is generally accepted that human Alzheimer's disease (AD) neuropathology markers are completely absent in rodent brains. We report here that an aged wild-type South American rodent, Octodon degu, expresses neuronal beta-amyloid precursor protein (beta-APP695) displaying both intracellular and extracellular deposits of amyloid-beta-peptide (Abeta), intracellular accumulations of tau-protein and ubiquitin, a strong astrocytic response and acetylcholinesterase (AChE)-rich pyramidal neurons. The high amino acid homology (97.5%) between deguAbeta and humanAbeta sequences is probably a major factor in the appearance of AD markers in this aged rodent. Our results indicate that aged O. degu constitutes the first wild-type rodent model for neurodegenerative processes associated to AD.
Abstract: The purpose of this study was to evaluate the contribution of DT-diaphorase inhibition to in vivo neurodegenerative effects of dopamine (DA) oxidation to the corresponding o-quinones. The neurotoxicity to nigrostriatal DA neurons was induced by injection of manganese pyrophosphate (Mn(3+)) complex as a prooxidizing agent alone or together with the DT-diaphorase inhibitor dicumarol into the right rat substantia nigra. The behavioral effects were compared with those induced after selective lesions of dopaminergic neurons with 6-hydroxydopamine (6-OHDA). Intranigral injection of Mn(3+) and Mn(3+) plus dicumarol produced significant impairment in motor behavior compared with control animals. However, the effect seen in the Mn(3+) plus dicumarol injected group was significantly more severe than that observed in the Mn(3+) alone injected group. In motor activity and rearing behavior, the simultaneous injection of Mn(3+) plus dicumarol produced a 6-OHDA-like impairment. Similar effects were observed in the acquisition of a conditioned avoidance response (CAR). Dicumarol significantly impaired avoidance conditioning although without affecting the motor behavior. The behavioral effects were correlated to the extent of striatal tyrosine hydroxylase (TH)-positive fiber loss. Rats receiving unilateral intranigral Mn(3+) and Mn(3+) plus dicumarol injections exhibited a significant reduction in nigrostriatal TH-positive fiber density in medial forebrain bundle compared with the contralateral noninjected side. In conclusion, this study provides evidence that the neurotoxicity of Mn(3+) in vivo is potentiated by DT-diaphorase inhibition, suggesting that this enzyme could play a neuroprotective role in the nigrostriatal DA systems.
Abstract: Acetylcholinesterase-rich neurons (AChERN) are a particular group of pyramidal neurons, displaying a specific laminar and ontogenetic pattern in the cerebral cortex of human and nonhuman primates. Using histochemistry and morphometrical methods, we have found a layer 3 magnopyramidal AChERN left-right size asymmetry restricted to Brodmann's area 45, a component of Broca's language area. This structural feature could be related to functional lateralization associated to syntactic processing and phonological working memory, and is consistent with a non-cholinergic role of AChE possibly linked to neuroplastic processes in the human neocortex.
Abstract: Analysis of regional corpus callosum fiber composition reveals that callosal regions connecting primary and secondary sensory areas tend to have higher proportions of coarse-diameter, highly myelinated fibers than callosal regions connecting so-called higher-order areas. This suggests that in primary/secondary sensory areas there are strong timing constraints for interhemispheric communication, which may be related to the process of midline fusion of the two sensory hemifields across the hemispheres. We postulate that the evolutionary origin of the corpus callosum in placental mammals is related to the mechanism of midline fusion in the sensory cortices, which only in mammals receive a topographically organized representation of the sensory surfaces. The early corpus callosum may have also served as a substrate for growth of fibers connecting higher-order areas, which possibly participated in the propagation of neuronal ensembles of synchronized activity between the hemispheres. However, as brains became much larger, the increasingly longer interhemispheric distance may have worked as a constraint for efficient callosal transmission. Callosal fiber composition tends to be quite uniform across species with different brain sizes, suggesting that the delay in callosal transmission is longer in bigger brains. There is only a small subset of large-diameter callosal fibers whose size increases with increasing interhemispheric distance. These limitations in interhemispheric connectivity may have favored the development of brain lateralization in some species like humans.
Abstract: Analysis of corpus callosum fiber composition reveals that inter-hemispheric transmission time may put constraints on the development of inter-hemispheric synchronic ensembles, especially in species with large brains like humans. In order to overcome this limitation, a subset of large-diameter callosal fibers are specialized for fast inter-hemispheric transmission, particularly in large-brained species. Nevertheless, the constraints on fast inter-hemispheric communication in large-brained species can somehow contribute to the development of ipsilateral, intrahemispheric networks, which might promote the development of brain lateralization.
Abstract: The isocortex is a distinctive feature of mammalian brains, which has no clear counterpart in the cerebral hemispheres of other amniotes. This paper speculates on the evolutionary processes giving rise to the isocortex. As a first step, we intend to identify what structure may be ancestral to the isocortex in the reptilian brain. Then, it is necessary to account for the transformations (developmental, connectional, and functional) of this ancestral structure, which resulted in the origin of the isocortex. One long-held perspective argues that part of the isocortex derives from the ventral pallium of reptiles, whereas another view proposes that the isocortex originated mostly from the dorsal pallium. We consider that, at this point, evidence tends to favor correspondence of the isocortex with the dorsal cortex of reptiles. In any case, the isocortex may have originated partly as a consequence of an overall "dorsalizing" effect (that is, an expansion of the territories expressing dorsal-specific genes) during pallial development. Furthermore, expansion of the dorsal pallium may have been driven by selective pressures favoring the development of associative networks between the dorsal cortex, the olfactory cortex, and the hippocampus, which participated in spatial or episodic memory in the early mammals. In this context, sensory projections that in reptiles end in the ventral pallium, are observed to terminate in the isocortex (dorsal pallium) of mammals, perhaps owing to their participation in these associative networks.
Abstract: We propose an hypothesis on the evolutionary origin of the unique inside-out developmental gradient of the isocortex, in which deep layers originate before superficial layers. This contrasts with the development of the reptilian cortex, which originates in an outside-in gradient. In mice, a mutated protein, reelin, produces the reeler phenotype, whose cortex has an outside-in neurogenetic gradient like in reptiles. Reelin is normally located in the marginal layer of the developing cerebral cortex, and its normal function has been proposed to be a stop signal that prevents radially migrating cells from moving into the marginal zone. Additionally, mutations on the kinase Cdk5, or in its neuronal-specific activator p35, produce a deficit similar to reeler in that the neurogenetic gradient is outside-in. However, contrary to reeler, in which no cell-sparse layer I is observed, in these mice, a well-defined layer I exists, which suggests that migrating cells respond normally to reelin. Apparently, Cdk5/p35 participate in permitting cortical cells to move across pre-existing (earlier produced) cortical layers, in order to be able to contact reelin once they reach the marginal zone. We suggest that the evolutionary advent of the mammalian cortical inside-out gradient became partly possible through the activation of the Cdk5/p35 pathway, which permitted migrating cells to move across layers of older cells. At about the same time, reelin became an important element in cortical development as it prevented neuronal migration into the marginal zone (cortical layer I) and facilitated the migration of neurons past postmigratory elements.
Abstract: The isocortex is a distinctive feature of the mammalian brain, with no clear counterpart in other amniotes. There have been long controversies regarding possible homologues of this structure in reptiles and birds. The brains of the latter are characterized by the presence of a structure termed dorsal ventricular ridge (DVR), which receives ascending auditory and visual projections, and has been postulated to be homologous to parts of the mammalian isocortex (i.e., the auditory and the extrastriate visual cortices). Dissenting views, now supported by molecular evidence, claim that the DVR originates from a region termed ventral pallium, while the isocortex may arise mostly from the dorsal pallium (in mammals, the ventral pallium relates to the claustroamygdaloid complex). Although it is possible that in mammals the embryonic ventral pallium contributes cells to the developing isocortex, there is no evidence yet supporting this alternative. The possibility is raised that the expansion of the cerebral cortex in the origin of mammals was product of a generalized dorsalizing influence in pallial development, at the expense of growth in ventral pallial regions. Importantly, the evidence suggests that organization of sensory projections is significantly different between mammals and sauropsids. In reptiles and birds, some sensory pathways project to the ventral pallium and others project to the dorsal pallium, while in mammals sensory projections end mainly in the dorsal pallium. We suggest a scenario for the origin of the mammalian isocortex which relies on the development of associative circuits between the olfactory, the dorsal and the hippocampal cortices in the earliest mammals.
Abstract: The exact mechanism of cell death in neurodegenerative diseases remains obscure, although there is evidence that their pathogenesis may involve the formation of free radicals originating from the oxidative metabolism of catecholamines. The purpose of this study was to evaluate the degree of neurodegenerative changes and behavioral impairments induced by unilateral injection into the rat substantia nigra of cyclized o-quinones, aminochrome and dopachrome, derived from oxidizing dopamine and L-DOPA, respectively, with Mn(3+)-pyrophosphate complex. The behavioral changes were compared with those induced after selective lesions of dopaminergic neurons with 6-hydroxydopamine (6-OHDA). Intranigral injection of aminochrome and dopachrome produced impairment in motor and cognitive behaviors. The behavioral impairment was also revealed by apomorphine-induced rotational asymmetry. Apomorphine (0.5 mg/kg sc) significantly increased rotational behavior in rats injected with aminochrome and dopachrome. These rats presented a clear motor bias showing a significant contralateral rotation activity, similar but less vigorous that in rats injected with 6-OHDA. The avoidance conditioning was seriously impaired in rats injected with aminochrome and dopachrome although only dopachrome-injected rats showed a similar hypomotility to 6-OHDA-injected rats. The behavioral effects were correlated to the extent of striatal tyrosine hydroxylase (TH)-positive fiber loss. Rats receiving unilateral intranigral aminochrome and dopachrome injections exhibited a 47.9+/-5.1% and a 39.7+/-4.4% reduction in nigrostriatal TH-positive fiber density. In conclusion, this study provided evidence that oxidizing DA and L-DOPA to cytotoxic quinones, aminochrome and dopachrome appears to be an important mediator of oxidative damage in vivo.
Abstract: This article proposes a comprehensive view of the origin of the mammalian brain. We discuss i) from which region in the brain of a reptilian-like ancestor did the isocortex originate, and ii) the origin of the multilayered structure of the isocortex from a simple-layered structure like that observed in the cortex of present-day reptiles. Regarding question i there have been two alternative hypotheses, one suggesting that most or all the isocortex originated from the dorsal pallium, and the other suggesting that part of the isocortex originated from a ventral pallial component. The latter implies that a massive tangential migration of cells from the ventral pallium to the dorsal pallium takes place in isocortical development, something that has not been shown. Question ii refers to the origin of the six-layered isocortex from a primitive three-layered cortex. It is argued that the superficial isocortical layers can be considered to be an evolutionary acquisition of the mammalian brain, since no equivalent structures can be found in the reptilian brain. Furthermore, a characteristic of the isocortex is that it develops according to an inside-out neurogenetic gradient, in which late-produced cells migrate past layers of early-produced cells. It is proposed that the inside-out neurogenetic gradient was partly achieved by the activation of a signaling pathway associated with the Cdk5 kinase and its activator p35, while an extracellular protein called reelin (secreted in the marginal zone during development) may have prevented migrating cells from penetrating into the developing marginal zone (future layer I).
Abstract: A cross-species ultrastructural study of the corpus callosum was performed in six domestic species: the rat, the rabbit, the cat, the dog, the horse and the cow. The results indicate cross-species conservatism in callosal fiber composition with a good interspecies relation between fiber number and brain size. Across species, increases in both brain size and callosal area indicate more callosal fibers, although less than expected from the estimated increase in cortical cell number. Within each species, the correlation between fiber number and brain weight tends to disappear, although in most cases a larger callosum implies a larger number of callosal fibers. The median fiber diameter was conservative across species (0.11-0.2 microm), indicating the maintenance of conduction velocity of most callosal fibers regardless of interhemispheric distance. Nevertheless, the maximal fiber diameters tended to be higher in species with larger brains. Therefore, there is a population of coarse-diameter fibers that tend to increase their diameter and conduction velocity with increasing brain size. However, allometric calculations suggest that the associated increase in velocity in these large fibers may not be sufficient to maintain a constant interhemispheric transmission time in different species.
Abstract: In this paper we review recent evidence on the molecular control of cell migration in the isocortex, and present an hypothesis for the evolutionary origin of the inside-out neurogenetic gradient of this structure. We suggest that there are at least two key factors involved in the acquisition of the inside-out gradient: (i) the expression of the protein reelin, which arrests the migration of cortical plate cells by detaching them from the radial glial fiber. This permits younger neurons to use the same fiber to migrate past the previous neurons; and (ii) the second factor is an intracellular signaling pathway dependent on a cyclin-dependent protein kinase (Cdk5). Cdk5 may work by inhibiting N-cadherin mediated cell aggregation as young cells cross the cortical plate, permitting them to move to the more superficial layers. Interestingly, the mutation in Cdk5 affects the migration of only those cells belonging to superficial layers, which are considered to be an evolutionary acquisition of the mammalian isocortex.
Abstract: The organization of basilar dendritic patterns in the CA1 hippocampal region obtained from 13 middle-aged and elderly human subjects was assessed using the Golgi method. Neurons were classified according to hemisphere of origin and the sex of the respective subjects. Three parameters were measured: total dendritic length (TDL), number of dendritic segments (NDS) and average segment length (ASL, which is TDL divided by NDS). Dendritic segments were classified into proximal (first to third order) and distal (fourth order and above). Sex differences were found in distal TDL and in proximal and distal NDS, neurons belonging to males having larger values than those belonging to females. In addition, a hemispheric difference was detected in distal TDL, in which neurons of the left hemisphere had larger values than those of the right hemisphere.
