Description

Publications in this journal

• Genetic correlates of the evolving primate brain.

  Authors: Eric J Vallender

  Progress in brain research. 195:27-44.

  The tremendous shifts in the size, structure, and function of the brain during primate evolution are ultimately caused by changes at the genetic level. Understanding what these changes are and howThe tremendous shifts in the size, structure, and function of the brain during primate evolution are ultimately caused by changes at the genetic level. Understanding what these changes are and how they effect the phenotypic changes observed lies at the heart of understanding evolutionary change. This chapter focuses on understanding the genetic basis of primate brain evolution, considering the substrates and mechanisms through which genetic change occurs. It also discusses the implications that our current understandings and tools have for what we have already discovered and where our studies will head in the future. While genetic and genomic studies have identified many regions undergoing positive selection during primate evolution, the findings are certainly not exhaustive and functional relevance remains to be confirmed. Nevertheless, a strong foundation has been built upon which future studies will emerge.

• Embracing covariation in brain evolution: large brains, extended development, and flexible primate social systems.

  Authors: Christine J Charvet, Barbara L Finlay

  Progress in brain research. 195:71-87.

  Brain size, body size, developmental length, life span, costs of raising offspring, behavioral complexity, and social structures are correlated in mammals due to intrinsic life-history requirements.Brain size, body size, developmental length, life span, costs of raising offspring, behavioral complexity, and social structures are correlated in mammals due to intrinsic life-history requirements. Dissecting variation and direction of causation in this web of relationships often draw attention away from the factors that correlate with basic life parameters. We consider the "social brain hypothesis," which postulates that overall brain and the isocortex are selectively enlarged to confer social abilities in primates, as an example of this enterprise and pitfalls. We consider patterns of brain scaling, modularity, flexibility of brain organization, the "leverage," and direction of selection on proposed dimensions. We conclude that the evidence supporting selective changes in isocortex or brain size for the isolated ability to manage social relationships is poor. Strong covariation in size and developmental duration coupled with flexible brains allow organisms to adapt in variable social and ecological environments across the life span and in evolution.

• Lateralization of the human brain.

  Authors: Michael C Corballis

  Progress in brain research. 195:103-21.

  It is often suggested that cerebral asymmetry, when a consistent direction of asymmetry prevails, is unique to humans. We now know that many other species exhibit directionally consistent cerebralIt is often suggested that cerebral asymmetry, when a consistent direction of asymmetry prevails, is unique to humans. We now know that many other species exhibit directionally consistent cerebral and behavioral asymmetries. Nevertheless, the predominance of left-cerebral dominance for language and manual functions may have played a special role in human evolution, even though precursors may be found in other animals-and especially in the great apes. I argue that the common cerebral asymmetry for these functions derives from the origins of language in manual gestures. These, in turn, may originate in specialized circuits for grasping that have been identified in primates, and lateralization may have been progressively introduced as praxic and linguistic functions became more complex.

• The missing link: evolution of the primate cerebellum.

  Authors: Carol MacLeod

  Progress in brain research. 195:165-87.

  The cerebellum has too often been seen as the "little brain," subservient to the "big brain," the cerebrum. That is changing, as neuroimaging uncovers the cerebellum as the "missing link" in theThe cerebellum has too often been seen as the "little brain," subservient to the "big brain," the cerebrum. That is changing, as neuroimaging uncovers the cerebellum as the "missing link" in the neurological underpinnings of many cognitive domains. Connections between the neocortex and the cerebellum are now more precisely defined, with functionally localized areas of cerebellar cortex understood for cognitive tasks in humans. Comparative volumetric studies of the primate cerebellum have isolated some elements of circuitry, and our field is moving toward a better integration with the neurosciences in a systematic comparative framework. The next decade may show great advances, as relatively noninvasive techniques of neuroimaging have the potential to build a comparative model of the evolution of primate neurocircuitry.

• Minicolumn size and human cortex.

  Authors: Daniel P Buxhoeveden

  Progress in brain research. 195:219-35.

  Minicolumns in primates are small when compared with those of other mammals, both in absolute and relative terms. The data suggest that minicolumns in the earliest primates were especially narrow andMinicolumns in primates are small when compared with those of other mammals, both in absolute and relative terms. The data suggest that minicolumns in the earliest primates were especially narrow and increased in accordance with encephalization so that the largest minicolumns in this mammalian order are found in apes and humans. Among the evolutionary strategies that led to the successful human brain was a combination of enhanced cortical volume based on increases in the number of ontogenetic units, along with enlargement of the individual minicolumns. However, continued encephalization of the large human brain presents serious problems that may limit future growth. When further increases in brain size can no longer be sustained, the alternative for further adaptations will have to be done at the level of brain organization. A downsizing of minicolumns may be among those responses. This has the advantage of permitting increases in the number of processing units without adding surface area. However, it is argued that narrow minicolumns process information differently, which raises questions about the relation between minicolumn size and behavior. There is evidence that minicolumns may be smaller in extant humans within selected populations, and the implications of this are briefly considered.

• Hominin paleoneurology: where are we now?

  Authors: Dean Falk

  Progress in brain research. 195:255-72.

  Hominin paleoneurology is the subfield of paleoanthropology that investigates brain evolution in human ancestors. For over a century, paleoneurologists have focused on analyses of cranial capacitiesHominin paleoneurology is the subfield of paleoanthropology that investigates brain evolution in human ancestors. For over a century, paleoneurologists have focused on analyses of cranial capacities (as surrogates for brain size) and endocranial casts (endocasts), which are prepared from the interiors of fossilized braincases and reproduce details of external brain morphology. This review discusses recent improvements in our understanding of hominin brain evolution in terms of brain size, sulcal patterns, and cortical shape features. To the extent possible, the evolution of neurological reorganization is assessed in light of findings from paleoneurology. In order to make inferences about cognitive evolution, paleoneurologists interpret their data within a framework that incorporates behavioral information from comparative primatological studies and findings from comparative neuroanatomical and medical imaging investigations. Advances in our knowledge about the evolution of the prefrontal cortex (Brodmann's area 10) provide an example of a productive synthesis of comparative neuroanatomical and behavioral research with investigations of the fossil record of hominin endocasts.

• Hominins and the emergence of the modern human brain.

  Authors: Alexandra de Sousa, Eugénia Cunha

  Progress in brain research. 195:293-322.

  Evidence used to reconstruct the morphology and function of the brain (and the rest of the central nervous system) in fossil hominin species comes from the fossil and archeological records. AlthoughEvidence used to reconstruct the morphology and function of the brain (and the rest of the central nervous system) in fossil hominin species comes from the fossil and archeological records. Although the details provided about human brain evolution are scarce, they benefit from interpretations informed by interspecific comparative studies and, in particular, human pathology studies. In recent years, new information has come to light about fossil DNA and ontogenetic trajectories, for which pathology research has significant implications. We briefly describe and summarize data from the paleoarcheological and paleoneurological records about the evolution of fossil hominin brains, including behavioral data most relevant to brain research. These findings are brought together to characterize fossil hominin taxa in terms of brain structure and function and to summarize brain evolution in the human lineage.

• Self-organization and interareal networks in the primate cortex.

  Authors: Henry Kennedy, Colette Dehay

  Progress in brain research. 195:341-60.

  Variability of gene expression of cortical precursors may partially reflect the operation of the gene regulatory network and determines the boundaries of the state space within whichVariability of gene expression of cortical precursors may partially reflect the operation of the gene regulatory network and determines the boundaries of the state space within which self-organization of the cortex can unfold. In primates, including humans, the outer subventricular zone, a primate-specific germinal zone, generates a large contingent of the projection neurons participating in the interareal network. The number of projection neurons in individual pathways largely determines the network properties as well as the hierarchical organization of the cortex. Mathematical modeling of cell-cycle kinetics of cortical precursors in the germinal zones reveals how multiple control loops ensure the generation of precise numbers of different categories of projection neurons and allow partial simulation of cortical self-organization. We show that molecular manipulation of the cell cycle of cortical precursors shifts the trajectory of the cortical precursor within its state space, increases the diversity in the cortical lineage tree, and explores changes in phylogenetic complexity. These results explore how self-organization underlies the complexity of the cortex and suggest evolutionary mechanisms.

• Design principles of the human brain: an evolutionary perspective.

  Authors: Michel A Hofman

  Progress in brain research. 195:373-90.

  The evolution of the brain in mammals has been accompanied by a reorganization of the brain as a result of differential growth of certain brain regions. Consequently, the geometry of the brain, andThe evolution of the brain in mammals has been accompanied by a reorganization of the brain as a result of differential growth of certain brain regions. Consequently, the geometry of the brain, and especially the size and shape of the cerebral cortex, has changed notably during evolution. Comparative studies of the cerebral cortex suggest that there are general architectural principles governing its growth and evolutionary development and that the primate neocortex is uniformly organized and composed of neural processing units. We are beginning to understand the geometric, biophysical, and energy constraints that have governed the evolution of these neuronal networks. In this review, some of the design principles and operational modes will be explored that underlie the information processing capacity of the cerebral cortex in primates, and it will be argued that with the evolution of the human brain we have nearly reached the limits of biological intelligence.

• Evolution of the brain and intelligence in primates.

  Authors: Gerhard Roth, Ursula Dicke

  Progress in brain research. 195:413-30.

  Primates are, on average, more intelligent than other mammals, with great apes and finally humans on top. They generally have larger brains and cortices, and because of higher relative cortex volumePrimates are, on average, more intelligent than other mammals, with great apes and finally humans on top. They generally have larger brains and cortices, and because of higher relative cortex volume and neuron packing density (NPD), they have much more cortical neurons than other mammalian taxa with the same brain size. Likewise, information processing capacity is generally higher in primates due to short interneuronal distance and high axonal conduction velocity. Across primate taxa, differences in intelligence correlate best with differences in number of cortical neurons and synapses plus information processing speed. The human brain stands out by having a large cortical volume with relatively high NPD, high conduction velocity, and high cortical parcellation. All aspects of human intelligence are present at least in rudimentary form in nonhuman primates or some mammals or vertebrates except syntactical language. The latter can be regarded as a very potent "intelligence amplifier."

• Evolution of brain and language.

  Authors: P Thomas Schoenemann

  Progress in brain research. 195:443-59.

  In this chapter evolutionary changes in the human brain that are relevant to language are reviewed. Most of what is known involves assessments of the relative sizes of brain regions. Overall brainIn this chapter evolutionary changes in the human brain that are relevant to language are reviewed. Most of what is known involves assessments of the relative sizes of brain regions. Overall brain size is associated with some key behavioral features relevant to language, including complexity of the social environment and the degree of conceptual complexity. Prefrontal cortical and temporal lobe areas relevant to language appear to have increased disproportionately. Areas relevant to language production and perception have changed less dramatically. The extent to which these changes were a consequence specifically of language versus other behavioral adaptations is a good question, but the process may best be viewed as a complex adaptive system, whereby cultural learning interacts with biology iteratively over time to produce language. Overall, language appears to have adapted to the human brain more so than the reverse.

• Optogenetic excitation of neurons with channelrhodopsins: light instrumentation, expression systems, and channelrhodopsin variants.

  Authors: John Y Lin

  Progress in brain research. 196:29-47.

  Classically, temporally precise excitation of membrane potential in neurons within intact tissue can be achieved by direct electrical stimulation or indirect electrical stimulation induced byClassically, temporally precise excitation of membrane potential in neurons within intact tissue can be achieved by direct electrical stimulation or indirect electrical stimulation induced by changing magnetic fields. Both of these approaches have a predetermined selectivity based on the biophysical properties of the nervous tissue and membrane in the region of the stimulation. A recent advance in selective excitation of neurons is the "optogenetic" approach utilizing channelrhodopsins (ChRs). By expressing the light-responsive ChR in neurons using cell-type selective promoters or other methods, specific neurons can be depolarized by light in a temporally precise manner with millisecond resolution even if their membrane biophysical properties are less favorable for electrical stimulation. In addition, ChRs can be used to depolarize nonneuronal cells in the nervous tissue, and to sustain depolarization over a prolonged period of time, both of which cannot be achieved with electrical or magnetic stimulations. To conduct an experiment with ChR, experimenters need to make the correct choices on the three main components to such an experiment: the expression system, the illumination source, and the ChR variant used. This chapter aims to provide some discussions on the current developments of these aspects of the experiments. To express ChR in neurons, the common expression systems include viral vectors, in utero electroporation, and transgenic animals, each with their advantages and limitations regarding the cost, expression pattern, and the required effort. In terms of the instrumentation, an illumination source that is capable of providing the desired wavelength with high intensity is crucial for the success of the experiment. The important factors regarding the light source used include the cost, light density output, efficiency for fiber coupling for in vivo rodent experiments, and the available methods to control light intensity and onset/termination. The third component of the experiment is the choice of the appropriate variants of ChR. Many novel ChR variants with unique properties have been engineered, and it can be difficult for the experimenters to choose the right variant with the desired properties for their experiments, as some information necessary for the experimenter to make the right selection is often incomplete or unavailable. Currently, the available variants for neuroscientific research are wild-type ChR2, ChR2+H134R, ChETA, VChR1, SFO, ChD, ChEF, ChIEF, ChRGR, CatCh, and TC. The features and limitations of these different variants are presented here. Lastly, this chapter will provide some suggestion for the future development of the light source, expression system, and the development of the "next" generation of ChRs.

• Genetically encoded probes for optical imaging of brain electrical activity.

  Authors: Amélie Perron, Walther Akemann, Hiroki Mutoh, Thomas Knöpfel

  Progress in brain research. 196:63-77.

  The combination of optical imaging methods with targeted expression of protein-based fluorescent probes constitutes a powerful approach for functional analysis of selected cell populations withinThe combination of optical imaging methods with targeted expression of protein-based fluorescent probes constitutes a powerful approach for functional analysis of selected cell populations within intact neuronal circuitries. Herein, we lay out the conceptual motivation for optogenetic recording of brain electrical activity using genetically encoded voltage-sensitive fluorescent proteins (VSFPs), describe how the current generation of VSFPs has evolved, and demonstrate how VSFPs report membrane voltage signals in isolated cells, brain slices, and living animals. We conclude with a critical appraisal of VSFPs for voltage recording and highlight promising applications of this emerging methodology for bridging cellular and intact systems biology.

• Manipulating cellular processes using optical control of protein-protein interactions.

  Authors: Chandra L Tucker

  Progress in brain research. 196:95-117.

  Tools for optical control of proteins offer an unprecedented level of spatiotemporal control over biological processes, adding a new layer of experimental opportunity. While use of light-activatedTools for optical control of proteins offer an unprecedented level of spatiotemporal control over biological processes, adding a new layer of experimental opportunity. While use of light-activated cation channels and anion pumps has already revolutionized neurobiology, an emerging class of more general optogenetic tools may have similar transformative effects. These tools consist of light-dependent protein interaction modules that allow control of target protein interactions and localization with light. Such tools are modular and can be applied to regulate a wide variety of biological activities. This chapter reviews the different properties of light-induced dimerization systems, based on plant phytochromes, cryptochromes, and light-oxygen-voltage domain proteins, exploring advantages and limitations of the different systems and practical considerations related to their use. Potential applications of these tools within the neurobiology field, including light control of various signaling pathways, neuronal activity, and DNA recombination and transcription, are discussed.

• Zebrafish as an appealing model for optogenetic studies.

  Authors: Joshua Simmich, Eric Staykov, Ethan Scott

  Progress in brain research. 196:145-62.

  Optogenetics, the use of light-based protein tools, has begun to revolutionize biological research. The approach has proven especially useful in the nervous system, where light has been used both toOptogenetics, the use of light-based protein tools, has begun to revolutionize biological research. The approach has proven especially useful in the nervous system, where light has been used both to detect and to manipulate activity in targeted neurons. Optogenetic tools have been deployed in systems ranging from cultured cells to primates, with each offering a particular combination of advantages and drawbacks. In this chapter, we provide an overview of optogenetics in zebrafish. Two of the greatest attributes of the zebrafish model system are external fertilization and transparency in early life stages. Combined, these allow researchers to observe the internal structures of developing zebrafish embryos and larvae without dissections or other interference. This transparency, combined with the animals' small size, simple husbandry, and similarity to mammals in many structures and processes, has made zebrafish a particularly popular model system in developmental biology. The easy optical access also dovetails with optogenetic tools, allowing their use in intact, developing, and behaving animals. This means that optogenetic studies in embryonic and larval zebrafish can be carried out in a high-throughput fashion with relatively simple equipment. As a consequence, zebrafish have been an important proving ground for optogenetic tools and approaches and have already yielded important new knowledge about the neural circuits underlying behavior. Here, we provide a general introduction to zebrafish as a model system for optogenetics. Through descriptions and analyses of important optogenetic studies that have been done in zebrafish, we highlight the advantages and liabilities that the system brings to optogenetic experiments.

• Mouse transgenic approaches in optogenetics.

  Authors: Hongkui Zeng, Linda Madisen

  Progress in brain research. 196:193-213.

  A major challenge in neuroscience is to understand how universal behaviors, such as sensation, movement, cognition, and emotion, arise from the interactions of specific cells that are present withinA major challenge in neuroscience is to understand how universal behaviors, such as sensation, movement, cognition, and emotion, arise from the interactions of specific cells that are present within intricate neural networks in the brain. Dissection of such complex networks has typically relied on disturbing the activity of individual gene products, perturbing neuronal activities pharmacologically, or lesioning specific brain regions, to investigate the network's response in a behavioral output. Though informative for many kinds of studies, these approaches are not sufficiently fine-tuned for examining the functionality of specific cells or cell classes in a spatially or temporally restricted context. Recent advances in the field of optogenetics now enable researchers to monitor and manipulate the activity of genetically defined cell populations with the speed and precision uniquely afforded by light. Transgenic mice engineered to express optogenetic tools in a cell type-specific manner offer a powerful approach for examining the role of particular cells in discrete circuits in a defined and reproducible way. Not surprisingly then, recent years have seen substantial efforts directed toward generating transgenic mouse lines that express functionally relevant levels of optogenetic tools. In this chapter, we review the state of these efforts and consider aspects of the current technology that would benefit from additional improvement.

• Optogenetic reporters: Fluorescent protein-based genetically encoded indicators of signaling and metabolism in the brain.

  Authors: Mathew Tantama, Yin Pun Hung, Gary Yellen

  Progress in brain research. 196:235-63.

  Fluorescent protein technology has evolved to include genetically encoded biosensors that can monitor levels of ions, metabolites, and enzyme activities as well as protein conformation and evenFluorescent protein technology has evolved to include genetically encoded biosensors that can monitor levels of ions, metabolites, and enzyme activities as well as protein conformation and even membrane voltage. They are well suited to live-cell microscopy and quantitative analysis, and they can be used in multiple imaging modes, including one- or two-photon fluorescence intensity or lifetime microscopy. Although not nearly complete, there now exists a substantial set of genetically encoded reporters that can be used to monitor many aspects of neuronal and glial biology, and these biosensors can be used to visualize synaptic transmission and activity-dependent signaling in vitro and in vivo. In this review, we present an overview of design strategies for engineering biosensors, including sensor designs using circularly permuted fluorescent proteins and using fluorescence resonance energy transfer between fluorescent proteins. We also provide examples of indicators that sense small ions (e.g., pH, chloride, zinc), metabolites (e.g., glutamate, glucose, ATP, cAMP, lipid metabolites), signaling pathways (e.g., G protein-coupled receptors, Rho GTPases), enzyme activities (e.g., protein kinase A, caspases), and reactive species. We focus on examples where these genetically encoded indicators have been applied to brain-related studies and used with live-cell fluorescence microscopy.

• Genomic determinants in the phenotypic variability of Down syndrome.

  Authors: Audrey Letourneau, Stylianos E Antonarakis

  Progress in brain research. 197C:15-28.

  Down syndrome caused by trisomy 21 is a collection of phenotypes with variable expressivity and penetrance. The significant advances in exploring the human genome now provide the tools to betterDown syndrome caused by trisomy 21 is a collection of phenotypes with variable expressivity and penetrance. The significant advances in exploring the human genome now provide the tools to better understand the contribution of trisomy 21 in the different manifestations of Down syndrome, and the functional links between the genome variability and the phenotypic variability.

• Aberrant epigenetic landscape in intellectual disability.

  Authors: J V Sanchez-Mut, D Huertas, M Esteller

  Progress in brain research. 197C:53-71.

  In recent decades, epigenetics has emerged as a broad-ranging regulatory layer that modulates the whole genome and transcriptome. It largely determines the firing of transcription start sites, theIn recent decades, epigenetics has emerged as a broad-ranging regulatory layer that modulates the whole genome and transcriptome. It largely determines the firing of transcription start sites, the splicing processes, and the binding of transcription factors, among many other processes. Its wide spectrum of action has provided us with the keys to new doors to investigate many diseases, including intellectual disability syndromes. The involvement of epigenetic factors in Rett syndrome is already well established, and its involvement in alpha-thalassemia/mental retardation-X-linked and Rubinstein-Taybi syndromes is also being elucidated. Down syndrome is not an exception, and the most recent reports suggest that epigenetic factors may play a crucial role in its etiology and also have the potential to provide new panels of biomarkers and tailored treatments.

• Neurological phenotypes for Down syndrome across the life span.

  Authors: Ira T Lott

  Progress in brain research. 197C:101-121.

  This chapter reviews the neurological phenotype of Down syndrome (DS) in early development, childhood, and aging. Neuroanatomic abnormalities in DS are manifested as aberrations in gross brainThis chapter reviews the neurological phenotype of Down syndrome (DS) in early development, childhood, and aging. Neuroanatomic abnormalities in DS are manifested as aberrations in gross brain structure as well as characteristic microdysgenetic changes. As the result of these morphological abnormalities, brain circuitry is impaired. While an intellectual disability is ubiquitous in DS, there is a wide range of variation in cognitive performance and a growing understanding between aberrant brain circuitry and the cognitive phenotype. Hypotonia is most marked at birth, affecting gait and ligamentous laxity. Seizures are bimodal in presentation with infantile spasms common in infancy and generalized seizures associated with cognitive decline observed in later years. While all individuals have the characteristic neuropathology of Alzheimer's disease (AD) by age 40years, the prevalence of dementia is not universal. The tendency to develop AD is related, in part, to several genes on chromosome 21 that are overexpressed in DS. Intraneuronal accumulation of β-amyloid appears to trigger a cascade of neurodegeneration resulting in the neuropathological and clinical manifestations of dementia. Functional brain imaging has elucidated the temporal sequence of amyloid deposition and glucose metabolic rate in the development of dementia in DS. Mitochondrial abnormalities contribute to oxidative stress which is part of AD pathogenesis in DS as well as AD in the general population. A variety of medical comorbidities threaten cognitive performance including sleep apnea, abnormalities in thyroid metabolism, and behavioral disturbances. Mouse models for DS are providing a platform for the formulation of clinical trials with intervention targeted to synaptic plasticity, brain biochemistry, and morphological brain alterations.

• Perturbation of dendritic protrusions in intellectual disability.

  Authors: Josien Levenga, Rob Willemsen

  Progress in brain research. 197C:153-168.

  Intellectual disability (ID) affects 1-3% of the general population and is defined by an intelligence quotient score under 70 and the presence of two or more adaptive behaviors. Learning and memoryIntellectual disability (ID) affects 1-3% of the general population and is defined by an intelligence quotient score under 70 and the presence of two or more adaptive behaviors. Learning and memory involves the change in the transmission efficacy at the synapse (synaptic plasticity). Synaptic plasticity is the ability of the connection, or synapse, between two functional neurons to change in strength. Many molecular mechanisms are involved in the change in synaptic strength, which can result in changes in spine morphology. Spines are specialized dendritic protrusions and their change in morphology is implicated in learning and memory. In several cases of ID, the link between spine abnormalities (abnormal in number, size, and shape) and ID is well described, including nonsyndromic ID and Down, Fragile X, and Rett syndromes. This chapter discusses the underlying molecular mechanisms of this altered spine phenotype.

• Discoveries in Down syndrome: moving basic science to clinical care.

  Authors: A M Kleschevnikov, P V Belichenko, A Salehi, C Wu

  Progress in brain research. 197C:199-221.

  This review describes recent discoveries in neurobiology of Down syndrome (DS) achieved with use of mouse genetic models and provides an overview of experimental approaches aimed at development ofThis review describes recent discoveries in neurobiology of Down syndrome (DS) achieved with use of mouse genetic models and provides an overview of experimental approaches aimed at development of pharmacological restoration of cognitive function in people with this developmental disorder. Changes in structure and function of synaptic connections within the hippocampal formation of DS model mice, as well as alterations in innervations of the hippocampus by noradrenergic and cholinergic neuromodulatory systems, provided important clues for potential pharmacological treatments of cognitive disabilities in DS. Possible molecular and cellular mechanisms underlying this genetic disorder have been addressed. We discuss novel mechanisms engaging misprocessing of amyloid precursor protein (App) and other proteins, through their affect on axonal transport and endosomal dysfunction, to "Alzheimer-type" neurodegenerative processes that affect cognition later in life. In conclusion, a number of therapeutic strategies have been defined that may restore cognitive function in mouse models of DS. In the juvenile and young animals, these strategists focus on restoration of synaptic plasticity, rate of adult neurogenesis, and functions of the neuromodulatory subcortical systems. Later in life, the major focus is on recuperation of misprocessed App and related proteins. It is hoped that the identification of an increasing number of potential targets for pharmacotherapy of cognitive deficits in DS will add to the momentum for creating and completing clinical trials.

• Gene therapy for Down syndrome.

  Authors: Cristina Fillat, Xavier Altafaj

  Progress in brain research. 197C:237-247.

  The presence of an additional copy of HSA21 chromosome in Down syndrome (DS) individuals leads to the overexpression of 30-50% of HSA21 genes. This upregulation can, in turn, trigger a deregulationThe presence of an additional copy of HSA21 chromosome in Down syndrome (DS) individuals leads to the overexpression of 30-50% of HSA21 genes. This upregulation can, in turn, trigger a deregulation on the expression of non-HSA21 genes. Moreover, the overdose of HSA21 microRNAs (miRNAs) may result in the downregulation of its target genes. Additional complexity can also arise from epigenetic changes modulating gene expression. Thus, a myriad of transcriptional and posttranscriptional alterations participate to produce abnormal phenotypes in almost all tissues and organs of DS individuals. The study of the physiological roles of genes dysregulated in DS, as well as their characterization in murine models with gene(s) dosage imbalance, pointed out several genes, and functional noncoding elements to be particularly critical in the etiology of DS. Recent findings indicate that gene therapy strategies-based on the introduction of genetic elements by means of delivery vectors-toward the correction of phenotypic abnormalities in DS are also very promising tool to identify HSA21 and non-HSA21 gene candidates, contributing to DS phenotype. In this chapter, we focus on the impact of normalizing the expression levels of up or downregulated genes to rescue particular phenotypes of DS. Attempts toward gene-based treatment approaches in mouse models will be discussed as new opportunities to ameliorate DS alterations.

• From tetrapods to primates: conserved developmental mechanisms in diverging ecological adaptations.

  Authors: Francisco Aboitiz, Juan F Montiel

  Progress in brain research. 195:3-24.

  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 sizePrimates 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.

• Cerebral cortical development in rodents and primates.

  Authors: Zoltán Molnár, Gavin Clowry

  Progress in brain research. 195:45-70.

  Rodents and primates both show considerable variation in the overall size, the radial and tangential dimensions, folding and subdivisions into distinct areas of their cerebral cortex. Our currentRodents and primates both show considerable variation in the overall size, the radial and tangential dimensions, folding and subdivisions into distinct areas of their cerebral cortex. Our current understanding of brain development is based on a handful of model systems. A detailed comparative analysis of the cellular and molecular mechanisms that regulate neural progenitor production, cell migration, and circuit assembly can provide much needed insights into the working of neocortical evolution. From the limited comparative data currently available, it is apparent that the emergence and variation of the neuronal progenitor cells have led to the production of increased neuronal populations and the evolution of the cortex. Further diversification and compartmentalization of the germinal zone together with changing proportions of radial glia in the ventricular zone and various intermediate progenitors in the subventricular zone may have been the driving force behind increased cell numbers in larger brains both in rodents and primates. Radial and tangential migratory patterns are both present in rodents and primates, but in different proportions. There are apparent differences between mouse and human in the generation and elaboration of the interneuronal subtypes and also in gene expression patterns associated with the appearance of distinct cortical areas. The increased cortical dimensions and the formation of a more elaborate cortical architecture in primates require a larger and more compartmentalized transient subplate zone during development. More comparative analysis in rodent and primate species with large, small, and smooth and folded brains is needed to reveal the biological significance of the alterations in these cortical developmental programs.

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.