综述: 大脑新皮层和神经发育疾病

哺乳动物进化过程中,大脑皮层逐渐增大增厚和脑容量增大,从而构成了脑神经环路复杂性的细胞生物学基础.皮层出现皱褶是非人类灵长类演化的重要特征.成体人脑大约由近860多亿个神经细胞组成,其中,在人脑神经发生高峰,每小时有近400多万个兴奋性神经细胞产生.如此高速的神经生成过程需要精确的细胞与分子调控机制.本文主要讨论调控大脑皮层增大增厚的细胞与分子机制和相关的脑发育疾病.     

The anatomy of the cerebral cortex of the echidna (Tachyglossus aculeatus)

The cerebral cortex of the echidna is notable for its extensive folding and the positioning of major functional areas towards its caudal extremity. The gyrification of the echidna cortex is comparable in magnitude to prosimians and cortical thickness and neuronal density are similar to that seen in rodents and carnivores. On the other hand, many pyramidal neurons in the cerebral cortex of the echidna are atypical with inverted somata and short or branching apical dendrites. All other broad classes of neurons noted in therian cortex are also present in the echidna, suggesting that the major classes of cortical neurons evolved prior to the divergence of proto- and eutherian lineages. Dendritic spine density on dendrites of echidna pyramidal neurons in somatosensory cortex and apical dendrites of motor cortex pyramidal neurons is lower than that found in eutheria. On the other hand, synaptic morphology, density and distribution in somatosensory cortex are similar to that in eutheria. In summary, although the echidna cerebral cortex displays some structural features, which may limit its functional capacities (e.g. lower spine density on pyramidal neurons), in most structural parameters (e.g. gyrification, cortical area and thickness, neuronal density and types, synaptic morphology and density), it is comparable to eutheria.     

Orchestrated neuronal migration and cortical folding: A computational and experimental study

Brain development involves precisely orchestrated genetic, biochemical, and mechanical events. At the cellular level, neuronal proliferation in the innermost zone of the brain followed by migration towards the outermost layer results in a rapid increase in brain surface area, outpacing the volumetric growth of the brain, and forming the highly folded cortex. This work aims to provide mechanistic insights into the process of brain development and cortical folding using a biomechanical model that couples cell division and migration with volumetric growth. Unlike phenomenological growth models, our model tracks the spatio-temporal development of cohorts of neurons born at different times, with each cohort modeled separately as an advection-diffusion process and the total cell density determining the extent of volume growth. We numerically implement our model in Abaqus/Standard (2020) by writing user-defined element (UEL) subroutines. For model calibration, we apply in utero electroporation (IUE) to ferret brains to visualize and track cohorts of neurons born at different stages of embryonic development. Our calibrated simulations of cortical folding align qualitatively with the ferret experiments. We have made our experimental data and finite-element implementation available online to offer other researchers a modeling platform for future study of neurological disorders associated with atypical neurodevelopment and cortical malformations.     

Density of Sgt1-immunopositive neurons is decreased in the cerebral cortex of Alzheimer's disease brain

Sgt1 was discovered as a protein required for the mitotic activity of kinetochore and for the activity of ubiquitin ligase in yeast [Kitagawa, K., Skowyra, D., Elledge, S.J., Harper, J.W., Hieter, P., 1999. SGT1 encodes an essential component of the yeast kinetochore assembly pathway and a novel subunit of the SCF ubiquitin ligase complex. Mol. Cell 4, 21-33.]. Later, Sgt1 was identified in different organisms including mammals where it was found at high level in the brain. To understand Sgt1 function in this tissue we analyzed its localization in human brain by immunohistochemistry. In normal brain we observed Sgt1-immunostaining in Purkinje cells of the cerebellum, in granule cells of the dentate gyrus of the hippocampus and in multiple neurons of the cortex. By Western blotting we found a higher level of this protein in the cortex than in the cerebellum. Subsequent morphometric analyses showed that the density of Sgt1-immunopositive neurons varied in different cortical regions. The highest density of Sgt1-immunopositive cells was seen in the temporal cortex (from 1.2% to 5.7%), and the lowest - in the entorhinal cortex (from 0 to 1.1% of all neurons). We next compared the density of Sgt1-immunopositive neurons in cortical layers of healthy aged and Alzheimer's disease (AD) brain sections. A significant decrease in Sgt1-immunopositive neurons was found in the temporal (up to 25-fold), angular (up to 11-fold) and posterior cingulate cortex (up to five-fold). In the entorhinal and precentral cortex the reduction of Sgt1-immunopositive neurons was only about two-fold in AD brains as compared to healthy aged ones. The presence of Sgt1 in post-mitotic neurons indicates the involvement of this protein in a process different from that required for activity of the kinetochore. Decreased immunostaining in AD cortex point to Sgt1 as a possible marker of neurons degenerating in AD.     

Regulation of cerebral cortex size and folding by expansion of basal progenitors

Size and folding of the cerebral cortex increased massively during mammalian evolution leading to the current diversity of brain morphologies. Various subtypes of neural stem and progenitor cells have been proposed to contribute differently in regulating thickness or folding of the cerebral cortex during development, but their specific roles have not been demonstrated. We report that the controlled expansion of unipotent basal progenitors in mouse embryos led to megalencephaly, with increased surface area of the cerebral cortex, but not to cortical folding. In contrast, expansion of multipotent basal progenitors in the naturally gyrencephalic ferret was sufficient to drive the formation of additional folds and fissures. In both models, changes occurred while preserving a structurally normal, six‐layered cortex. Our results are the first experimental demonstration of specific and distinct roles for basal progenitor subtypes in regulating cerebral cortex size and folding during development underlying the superior intellectual capability acquired by higher mammals during evolution.     

On the Possible Shapes of the Brain

The human brain is unique among primates in its complexity and variability. Here I argue that this variability is, however, strongly constrained by developmental processes common to all mammals. Comparative analyses of grey and white matter volume, cortical surface area and cortical folding show that the rostro?Ccaudal axis of the central nervous system is a main direction along which mammalian neuroanatomical diversity is organised. Phylogenetically, rostral structures are often disproportionately larger and more differentiated in large mammals compared with small ones. Ontogenetically, caudal structures differentiate earlier but show less variation among species than rostral structures, which differentiate later and for a longer period. Theoretical considerations suggest that growth oriented along the rostro?Ccaudal axis should produce non-linear differences in white matter volume and cortical folding. Growth appears then as a fundamental parameter to understand mammalian neuroanatomical variability, whose effects should be common to all species. This seems to be indeed the case for humans: the volume of different brain structures as well as changes in the extension and folding of the cerebral cortex resemble the trends observed across mammals. A strong global pattern of coordinated variability emerges, where differences in total brain volume are non-linearly related to local neuroanatomical changes. Finally, I review evidence suggesting that the changes related to this global pattern of variability may have an influence on the organisation of behaviour, modulating the development of certain cognitive traits or even affecting the susceptibility to psychiatric disorders.     

Mechanical role of a growing solid tumor on cortical folding

Cortical folding, or convolution of the brain, is a vital process in mammals that causes the brain to have a wrinkled appearance. The existence of different types of prenatal solid tumors may alter this complex phenomenon and cause severe brain disorders. Here we interpret the effects of a growing solid tumor on the cortical folding in the fetal brain by virtue of theoretical analyses and computational modeling. The developing fetal brain is modeled as a simple, double-layered, and soft structure with an outer cortex and an inner core, in combination with a circular tumor model imbedded in the structure to investigate the developmental mechanism of cortical convolution. Analytical approaches offer introductory insight into the deformation field and stress distribution of a developing brain. After the onset of instability, analytical approaches fail to capture complex secondary evolution patterns, therefore a series of non-linear finite element simulations are carried out to study the crease formation and the influence from a growing solid tumor inside the structure. Parametric studies show the dependency of the cortical folding pattern on the size, location, and growth speed of a solid tumor in fetal brain. It is noteworthy to mention that there is a critical distance from the cortex/core interface where the growing tumor shows its pronounced effect on the cortical convolution, and that a growing tumor decreases the gyrification index of cortical convolution while its stiffness does not have a profound effect on the gyrification process.     

The unfolding story of two lissencephaly genes and brain development

Formation of our highly structured human brain involves a cascade of events, including differentiation, fate determination, and migration of neural precursors. In humans, unlike many other organisms, the cerebral cortex is the largest component of the brain. As in other mammals, the human cerebral cortex is located on the surface of the telencephalon and generally consists of six layers that are formed in an orderly fashion. During neuronal development, newly born neurons, moving in a radial direction, must migrate through previously formed layers to reach their proper cortical position. This is one of several neuronal migration routes that takes place in the developing brain; other modes of migration are tangential. Abnormal neuronal migration may in turn result in abnormal development of the cortical layers and deleterious consequences, such as Lissencephaly. Lissencephaly, a severe brain malformation, can be caused by mutations in one of two known genes:LIS1 anddoublecortin (DCX). Recent in vitro and in vivo studies, report on possible functions for these gene products.     

Supersize me—new insights into cortical expansion and gyration of the mammalian brain

EMBO J 32 13, 1817–1828 doi:10.1038/emboj.2013.96; published online April262013During evolution, the mammalian brain massively expanded its size. However, the exact roles of distinct neural precursors, identified in the developing cortex during embryogenesis, for size expansion and surface folding (i.e., gyration) remain largely unknown. New findings by Nonaka-Kinoshita et al advance our understanding of embryonic neural precursor function by identifying cell type-selective functions for size expansion and folding, and challenge previously held concepts of mammalian brain development.Over the course of evolution, the mammalian brain massively expanded its size and complexity, which is believed to be responsible for an increase in cognitive functions and intellectual skills. The increase in brain size and number of cortical neurons is primarily due to an increased surface area by generating folds (gyrations) while the cortical thickness remained relatively constant (Lui et al, 2011). In the last decade, substantial progress has been made in identifying the cellular sources of cortex development. Using genetic lineage tracing of individual cell populations and time-lapse imaging of rodent and human slices of the embryonic cortex, radial glial cells (RGCs) were identified as the primary progenitors or neural stem cells (NSCs) in the developing cortex (Gotz and Huttner, 2005). Simplified, RG in the ventricular zone (VZ) line the ventricular surface and self-renew through symmetric divisions or give rise to basal progenitors (BPs; also called intermediate progenitors) in the subventricular zone (SVZ) that typically divide symmetrically and generate neurons. In contrast to the lissencephalic rodent brain, the developing cortex of gyrated mammals (e.g., humans and ferrets) contains a large number of basal radial glial (bRG) cells that reside in the outer subventricular zone (OSVZ), retain a cellular process that is connected to the pial surface and that are, in contrast to BPs, multipotent, meaning that they have the potency to generate diverse neural cell types (Fietz et al, 2010; Hansen et al, 2010; Reillo et al, 2011).Largely based on the anatomical differences between the developing cortex of lissencephalic and gyrencephalic brains, several hypotheses have been formulated aiming to explain the massive increase in size and induction of brain folding during mammalian evolution. One prominent hypothesis, called the radial unit hypothesis, suggests that the expansion of RGCs lining the ventricle leads to an increase of radial units that generate neurons and thus is responsible for the increase of surface area (Rakic, 1995). Others proposed that the increase in size and folding could be due to an increase in BP expansion in the SVZ compared to RGC numbers in the VZ, a hypothesis called the intermediate progenitor model (Kriegstein et al, 2006). These hypotheses were helpful to start explaining mammalian brain evolution, but testing the exact role of different neural precursors remained extremely challenging due to technical difficulties to selectively manipulating the proliferative activity of distinct precursor populations. Even though previous approaches were successful in enhancing brain size/neuron numbers in mouse models (e.g., by ectopically enhancing WNT signalling activity or manipulating the activity of the small RhoGTPase Cdc42 in neural precursors), these strategies had the drawback that the normal six-layered cortical topography was disrupted, making it difficult to draw definite conclusions (Chenn and Walsh, 2002; Cappello et al, 2006).In a collaborative work from the Calegari and Borrell laboratories, Nonaka-Kinoshita et al, 2013 now used an elegant approach to selectively enhance proliferation of distinct precursor populations in the mouse and ferret developing cortex. They used a previously described approach manipulating cell cycle length and subsequently proliferation by overexpressing the cell cycle regulators cdk4 and cyclinD1 that is sufficient to enhance neurogenesis without affecting cortical layering (a system called 4D) (Lange et al, 2009). For their mouse experiments, Nonaka-Kinoshita et al used a transgenic strategy to transiently overexpress 4D in nestin-expressing precursors using a tetracycline-controlled gene expression system (nestin^rtTA/tetbi^4D). With this approach, they selectively enhanced proliferation of BPs in the SVZ without affecting the number or proliferation of RGCs in the VZ (Nonaka-Kinoshita et al, 2013). Strikingly, targeted expansion of BPs induced a substantial increase in surface area but was not sufficient to induce cortical folding in the otherwise smooth mouse cortex, challenging the radial unit hypothesis and the intermediate progenitor model with regard to their predictions on the effects on size and/or gyration of the cortex upon expansion of the BP pool. Complementing their findings of BP expansion in the lissencephalic mouse brain, Nonaka-Kinoshita et al used retroviral vectors and electroporation of 4D expression constructs to target 4D expression to neural precursors in the developing ferret cortex that is gyrated under physiological conditions. In the ferret, 4D expression induced proliferation of multipotent bRG located in the OSVZ, as outlined above, a cell type that is found predominantly in gyrated cortices compared to lissencephalic brains. Notably, enhanced proliferation of bRG triggered the formation of novel cortical folds, suggesting that indeed the expansion of bRG may represent a key event during evolution to induce gyration and subsequent surface expansion of the mammalian brain (Borrell and Reillo, 2012; Nonaka-Kinoshita et al, 2013) (Figure 1). This now experimentally supported hypothesis is strongly reinforced by two recent publications: one from (Tuoc et al, 2013) who found that deletion of the chromatin remodelling protein BAF170 increases the BP pool and subsequently enhances brain size; and another one from the Götz laboratory where it was found that experimentally reduced expression levels of the DNA-associated protein Trnp1 substantially increased the expansion of bRG and BPs, inducing folding of the normally lissencephalic mouse brain (Stahl et al, 2013). Taken together, these studies suggest that bRG in the OSVZ play an important role in cortical folding by enhancing the generation of neurons and by providing a glial scaffold for newborn neurons to disperse more laterally and thus to form folds in the developing brain (Reillo et al, 2011).Open in a separate windowFigure 1How different neural precursors appear to regulate size expansion and folding during mammalian brain development. (A) Shown are the main cellular components of the cortex of the lissencephalic mouse brain during embryonic development with RGCs (blue) lining the lateral ventricles in the VZ that generate BPs (yellow) in the SVZ and provide a scaffold for migrating neurons (left; green). Note that the mouse developing brain contains only a few bRG in the OSVZ (red). Notably, expansion of BPs using the 4D strategy developed in the Calegari laboratory increases surface area of the murine cortex without inducing the folding of the smooth mouse brain surface (right panel). (B) In contrast to lissencephalic animals, the developing cortices of species with gyrated brains (e.g., humans and ferrets) contain a substantial number of bRG located in the OSVZ (left panel). 4D-based, virus-mediated expansion of bRG in the ferret cortex leads to the induction of additional folds in the ferret cortex, indicating that the proliferative activity of bRG is critically involved in the extent of folding in physiologically gyrated brains (right panel).Even though this new study challenges previously held concepts regarding size expansion and folding of the mammalian brain, future studies are required that even more selectively enhance the proliferation and expansion of distinct precursor subtypes with high temporal and spatial control. Thus, the combination of sophisticated genetic tools to enhance precursor activity with detailed molecular analyses (e.g., analysing gene expression in highly folded versus unfolded brain regions, an approach that already showed differential levels of Trnp1 expression; Stahl et al, 2013) and live-imaging studies in the developing mammalian cortex will further enhance the understanding how our brains developed during evolution.     

Emerging roles of neural stem cells in cerebral cortex development and evolution

Expansion and folding of the cerebral cortex are landmark features of mammalian brain evolution, which are recapitulated during embryonic development. Neural stem cells and their derived germinal cells are coordinated during cerebral cortex development to produce the appropriate amounts and types of neurons. This process is further complicated in gyrencephalic species, where newborn neurons must disperse in the tangential axis to expand the cerebral cortex in surface area. Here, we review advances that have been made over the last decade in understanding the nature and diversity of telencephalic neural stem cells and their roles in cortical development, and we discuss recent progress on how newly identified types of cortical progenitor cell populations may have evolved to drive the expansion and folding of the mammalian cerebral cortex.     

Cortical Folding of the Primate Brain: An Interdisciplinary Examination of the Genetic Architecture,Modularity, and Evolvability of a Significant Neurological Trait in Pedigreed Baboons (Genus Papio)

Folding of the primate brain cortex allows for improved neural processing power by increasing cortical surface area for the allocation of neurons. The arrangement of folds (sulci) and ridges (gyri) across the cerebral cortex is thought to reflect the underlying neural network. Gyrification, an adaptive trait with a unique evolutionary history, is affected by genetic factors different from those affecting brain volume. Using a large pedigreed population of ∼1000 Papio baboons, we address critical questions about the genetic architecture of primate brain folding, the interplay between genetics, brain anatomy, development, patterns of cortical–cortical connectivity, and gyrification’s potential for future evolution. Through Mantel testing and cluster analyses, we find that the baboon cortex is quite evolvable, with high integration between the genotype and phenotype. We further find significantly similar partitioning of variation between cortical development, anatomy, and connectivity, supporting the predictions of tension-based models for sulcal development. We identify a significant, moderate degree of genetic control over variation in sulcal length, with gyrus-shape features being more susceptible to environmental effects. Finally, through QTL mapping, we identify novel chromosomal regions affecting variation in brain folding. The most significant QTL contain compelling candidate genes, including gene clusters associated with Williams and Down syndromes. The QTL distribution suggests a complex genetic architecture for gyrification with both polygeny and pleiotropy. Our results provide a solid preliminary characterization of the genetic basis of primate brain folding, a unique and biomedically relevant phenotype with significant implications in primate brain evolution.     

C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment

Neuronal migration is integral to the development of the cerebral cortex and higher brain function. Cortical neuron migration defects lead to mental disorders such as lissencephaly and epilepsy. Interaction of neurons with their extracellular environment regulates cortical neuron migration through cell surface receptors. However, it is unclear how the signals from extracellular matrix proteins are transduced intracellularly. We report here that mouse embryos lacking the Ras family guanine nucleotide exchange factor, C3G (Rapgef1, Grf2), exhibit a cortical neuron migration defect resulting in a failure to split the preplate into marginal zone and subplate and a failure to form a cortical plate. C3G-deficient cortical neurons fail to migrate. Instead, they arrest in a multipolar state and accumulate below the preplate. The basement membrane is disrupted and radial glial processes are disorganised and lack attachment in C3G-deficient brains. C3G is activated in response to reelin in cortical neurons, which, in turn, leads to activation of the small GTPase Rap1. In C3G-deficient cells, Rap1 GTP loading in response to reelin stimulation is reduced. In conclusion, the Ras family regulator C3G is essential for two aspects of cortex development, namely radial glial attachment and neuronal migration.     

Molecular mechanisms of projection neuron production and maturation in the developing cerebral cortex

The cerebral cortex is a brain structure unique to mammals and highly adapted to process complex information. Through multiple developmental steps, the cerebral cortex is assembled as a huge diversity of neurons comprising a complex laminar structure, and with both local and long-distance connectivity within the nervous system. Key processes must take place during its construction, including: (i) regulation of the correct number of neurons produced by progenitor cells, (ii) temporal and spatial generation of neuronal diversity, and (iii) control of neuron migration and laminar positioning as well as terminal differentiation within the mature cortex. Here, we seek to highlight recent cellular and molecular findings underlying these sequential steps of neurogenesis, cell fate specification and migration during cortical development, with particular emphasis on cortical projection neurons.     

Development of the cerebral cortex in rodents and man

Studies mainly in rodents and man have contributed to new vistas on mammalian cerebral cortex development. Due to the much longer development in man and the larger size of the human brain, particular features (such as the existence of the subplate and tangential migration) were first detected in the human cortex. In addition, experimental techniques that can only be applied in nonhuman mammals revealed the pattern of neuronal generation, and demonstrated the different ways of neuronal migration and the formation of neuronal pathways. In this short review the present vistas on neuronal generation and migration, and the occurrence of transient layers are summarized.     

Dendritic morphology and spine density is not altered in motor cortex and dentate granular cells in mice lacking the ganglioside biosynthetic gene B4galnt1 - A quantitative Golgi cox study

Gangliosides are characteristic plasma membrane constituents of vertebrate brain used as milestones of neuronal development. As neuronal morphology is a good indicator of neuronal differentiation, we analyzed how lack of the ganglioside biosynthetic gene Galgt1 whose product is critical for production of four major adult mammalian brain complex gangliosides (GM1, GD1a, GD1b and GT1b) affects neuronal maturation in vivo. To define maturation of cortical neurons in mice lacking B4galnt1 we performed a morphological analysis of Golgi-Cox impregnated pyramidal neurons in primary motor cortex and granular cells of dentate gyrus in 3, 21 and 150 days old B4galnt1-null and wild type mice. Quantitative analysis of basal dendritic tree on layer III pyramidal neurons in the motor cortex showed very immature dendritic picture in both mice at postnatal day 3. At postnatal day 21 both mice reached adult values in dendritic length, complexity and spine density. No quantitative differences were found between B4galnt1-null and wild type mice in pyramidal cells of motor cortex or granular cells of dentate gyrus at any examined age. In addition, the general structural and neuronal organization of all brain structures, qualitatively observed on Nissl and Golgi-Cox, were similar Our results demonstrate that neurons can develop normal dendritic complexity and length without presence of complex gangliosides in vivo. Therefore, behavioral differences observed in B4galnt1-null mice may be attributed to functional rather than morphological level of dendrites and spines of cortical pyramidal neurons.     

Characterization of Age-Dependent and Progressive Cortical Neuronal Degeneration in Presenilin Conditional Mutant Mice

Presenilins are the major causative genes of familial Alzheimer''s disease (AD). Our previous study has demonstrated essential roles of presenilins in memory and neuronal survival. Here, we explore further how loss of presenilins results in age-related, progressive neurodegeneration in the adult cerebral cortex, where the pathogenesis of AD occurs. To circumvent the requirement of presenilins for embryonic development, we used presenilin conditional double knockout (Psen cDKO) mice, in which presenilin inactivation is restricted temporally and spatially to excitatory neurons of the postnatal forebrain beginning at 4 weeks of age. Increases in the number of degenerating (Fluoro-Jade B+, 7.6-fold) and apoptotic (TUNEL+, 7.4-fold) neurons, which represent ∼0.1% of all cortical neurons, were first detected at 2 months of age when there is still no significant loss of cortical neurons and volume in Psen cDKO mice. By 4 months of age, significant loss of cortical neurons (∼9%) and gliosis was found in Psen cDKO mice. The apoptotic cell death is associated with caspase activation, as shown by increased numbers of cells immunoreactive for active caspases 9 and 3 in the Psen cDKO cortex. The vulnerability of cortical neurons to loss of presenilins is region-specific with cortical neurons in the lateral cortex most susceptible. Compared to the neocortex, the increase in apoptotic cell death and the extent of neurodegeneration are less dramatic in the Psen cDKO hippocampus, possibly in part due to increased neurogenesis in the aging dentate gyrus. Neurodegeneration is also accompanied with mitochondrial defects, as indicated by reduced mitochondrial density and altered mitochondrial size distribution in aging Psen cortical neurons. Together, our findings show that loss of presenilins in cortical neurons causes apoptotic cell death occurring in a very small percentage of neurons, which accumulates over time and leads to substantial loss of cortical neurons in the aging brain. The low occurrence and significant delay of apoptosis among cortical neurons lacking presenilins suggest that loss of presenilins may induce apoptotic neuronal death through disruption of cellular homeostasis rather than direct activation of apoptosis pathways.     

A two-component theory of encephalization in mammals

The evolutionary increase in relative brain size in mammals is shown to be correlated with an addition of neuronal elements to the cerebral cortex. From a theory of encephalization, based on these findings, it appears that the number of modules (or neurons) in the cerebral cortex associated with higher order brain functions at the same time depends upon the size of the animal. This supports the thesis that the two major components, which determine the volume of the brain, viz. a body size related component and a non-somatic evolutionary component, are inter-related.     

Power-law inter-spike interval distributions infer a conditional maximization of entropy in cortical neurons

The brain is considered to use a relatively small amount of energy for its efficient information processing. Under a severe restriction on the energy consumption, the maximization of mutual information (MMI), which is adequate for designing artificial processing machines, may not suit for the brain. The MMI attempts to send information as accurate as possible and this usually requires a sufficient energy supply for establishing clearly discretized communication bands. Here, we derive an alternative hypothesis for neural code from the neuronal activities recorded juxtacellularly in the sensorimotor cortex of behaving rats. Our hypothesis states that in vivo cortical neurons maximize the entropy of neuronal firing under two constraints, one limiting the energy consumption (as assumed previously) and one restricting the uncertainty in output spike sequences at given firing rate. Thus, the conditional maximization of firing-rate entropy (CMFE) solves a tradeoff between the energy cost and noise in neuronal response. In short, the CMFE sends a rich variety of information through broader communication bands (i.e., widely distributed firing rates) at the cost of accuracy. We demonstrate that the CMFE is reflected in the long-tailed, typically power law, distributions of inter-spike intervals obtained for the majority of recorded neurons. In other words, the power-law tails are more consistent with the CMFE rather than the MMI. Thus, we propose the mathematical principle by which cortical neurons may represent information about synaptic input into their output spike trains.     

THE ACTIVITIES OF BUTYRYLCHOLINESTERASE AND CARBONIC ANHYDRASE, THE RATE OF ANAEROBIC GLYCOLYSTS, AND THE QUESTION OF A CONSTANT DENSITY OF GLIAL CELLS IN CEREBRAL CORTICES OF VARIOUS MAMMALIAN SPECIES FROM MOUSE TO WHALE

Abstract— The question of a constant density of glial cells in mammalian cerebral cortex regardless of species was examined by surveying the cortical activities of two enzymes primarily localized to dial cells. The cortical activity of butyrylcholinesterase (EC 3.1.1.8) was essentially constant at a rate of approx. 0.1 μmol of butyrylthiocholine hydrolysed min^-1 g^-1 over the range of species from rat (brain wt., 1.6 g) to fin whale and sperm whale (brain wt., 6800 and 7800 g, respectively). Over the same range the activity of cortical acetylcholinesterase, a neuronal enzyme, decreases by a factor of 7. Thus, butyrylcholinesterase ranged from < 2 per cent (in small rodent brains) to approximately 10 per cent (in whale brain) of the cortical acetylcholinesterase activity. The cortical activity of carbonic anhydrase (EC 4.2.1.1) was constant at a rate of 6.2 (± 0.25) μmol of CO₂ evolved min^-1 g^-1 over the range of species from guinea-pig (brain wt., 4.75 g) to fin whale (brain wt., 6800 g). These data obtained by assaying the dehydration reaction were confirmed by limited assays of the esterase activity of the enzyme (with p-nitrophenylacetate as substrate) and agreed with limited, previously reported data for the hydration reaction. Thus, the circumstantial evidence strongly favoured a relative constancy of cortical glial cell density regardless of species. The rates of anaerobic glycolysis in the cerebral cortex of various species were also investigated. For six species from mouse (brain wt., 0.4 g) to beef (brain wt., 380 g) cortical anaerobic glycolysis varied only slightly in the range of 50–62 μmol of CO₂ evolved h^-1 g^-l, whereas cortical oxygen consumption for the same range of species decreased by a factor of 3. Previously frozen samples of beef cortex glycolysed at 35 per Cent of the rate of fresh (unfrozen) samples. Since identical rates were obtained for previously frozen samples of fin whale cerebral cortex, we concluded that the relative constancy of cortical anaerobic glycolysis could be extended to the range from mouse to whale and that this aspect of cortical metabolism is probably primarily glial in localization. Some implications of the latter conclusion for the proposed role of astrocytes as modulators of neuronal activity have been discussed.     

Cerebral cortex expansion and folding: what have we learned?

One of the most prominent features of the human brain is the fabulous size of the cerebral cortex and its intricate folding. Cortical folding takes place during embryonic development and is important to optimize the functional organization and wiring of the brain, as well as to allow fitting a large cortex in a limited cranial volume. Pathological alterations in size or folding of the human cortex lead to severe intellectual disability and intractable epilepsy. Hence, cortical expansion and folding are viewed as key processes in mammalian brain development and evolution, ultimately leading to increased intellectual performance and, eventually, to the emergence of human cognition. Here, we provide an overview and discuss some of the most significant advances in our understanding of cortical expansion and folding over the last decades. These include discoveries in multiple and diverse disciplines, from cellular and molecular mechanisms regulating cortical development and neurogenesis, genetic mechanisms defining the patterns of cortical folds, the biomechanics of cortical growth and buckling, lessons from human disease, and how genetic evolution steered cortical size and folding during mammalian evolution .