The evolution of brain lateralization: a game-theoretical analysis of population structure

In recent years, it has become apparent that behavioural and brain lateralization at the population level is the rule rather than the exception among vertebrates. The study of these phenomena has so far been the province of neurology and neuropsychology. Here, we show how such research can be integrated with evolutionary biology to understand lateralization more fully. In particular, we address the fact that, within a species, left- and right-type individuals often occur in proportions different from one-half (e.g. hand use in humans). The traditional explanations offered for lateralization of brain function (that it may avoid unnecessary duplication of neural circuitry and reduce interference between functions) cannot account for this fact, because increased individual efficiency is unrelated to the alignment of lateralization at the population level. A further puzzle is that such an alignment may even be disadvantageous, as it makes individual behaviour more predictable to other organisms. Here, we show that alignment of the direction of behavioural asymmetries in a population can arise as an evolutionarily stable strategy when individual asymmetrical organisms must coordinate their behaviour with that of other asymmetrical organisms. Brain and behavioural lateralization, as we know it in humans and other vertebrates, may have evolved under basically 'social' selection pressures.     

Analysis of patterned neuronal impulses and function of neuregulin

Compared to other cells, except neural cells, the biggest property of neural cells is to have a particular electrical activity in each cell itself. The activity that shows a specific pattern will carry different information as a history of each neural cell. At present, we have examined the roles of neural impulses and revealed that a synaptic plasticity can be controlled by different patterned neural activities, such as different frequencies or oscillation patterns. Even though neural cells have similar genetic backgrounds, different environments give cells different neural activities and finally different characters of cells. Current studies have revealed that a particular pattern of neural activity, e.g. frequency, could be effective in some diseases. In response to environmental changes occurring throughout development and adult life, the brain reorganizes itself by adjusting the pattern of activity. In some cases, a particular pattern of neural activity decides the neural fate and should be able to control brain function even in higher functions. In the future, in order to understand the role of activity patterns and mechanisms of fundamental information processing in the brain, it will be necessary that the meaning of patterns is explained from molecular, biological and morphological perspectives, i.e., not only with metaphysical "phenomena", but also at a physical "material" level.     

Generation of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in picrotoxinin-administered rat brain

The levels of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and other molecular species of monoacylglycerols in rat brain were examined. In this study, we sacrificed the animals in liquid nitrogen to minimize postmortem changes. We found that rat brain contains 0.23 nmol/g tissue of 2-arachidonoylglycerol, which accounts for 10.5% of the total monoacylglycerol present in this tissue. We next investigated the level of 2-arachidonoylglycerol after in vivo stimulation with picrotoxinin. We found that the level of 2-arachidonoylglycerol was elevated markedly in picrotoxinin-administered rat brain (4- to 6-fold over the control level). Changes in the levels of other molecular species were relatively small or negligible. Several cannabimimetic molecules as well as Delta(9)-tetrahydrocannabinol are known to depress neurotransmission and to exert anticonvulsant activities; endogenous 2-arachidonoylglycerol produced during neural excitation may play a regulatory role in calming the enhanced synaptic transmission.     

Role of uncertainty in sensorimotor control

Neural signals are corrupted by noise and this places limits on information processing. We review the processes involved in goal-directed movements and how neural noise and uncertainty determine aspects of our behaviour. First, noise in sensory signals limits perception. We show that, when localizing our hand, the central nervous system (CNS) integrates visual and proprioceptive information, each with different noise properties, in a way that minimizes the uncertainty in the overall estimate. Second, noise in motor commands leads to inaccurate movements. We review an optimal-control framework, known as 'task optimization in the presence of signal-dependent noise', which assumes that movements are planned so as to minimize the deleterious consequences of noise and thereby minimize inaccuracy. Third, during movement, sensory and motor signals have to be integrated to allow estimation of the body's state. Models are presented that show how these signals are optimally combined. Finally, we review how the CNS deals with noise at the neural and network levels. In all of these processes, the CNS carries out the tasks in such a way that the detrimental effects of noise are minimized. This shows that it is important to consider effects at the neural level in order to understand performance at the behavioural level.     

Insect–machine hybrid system for understanding and evaluating sensory-motor control by sex pheromone in Bombyx mori

To elucidate the dynamic information processing in a brain underlying adaptive behavior, it is necessary to understand the behavior and corresponding neural activities. This requires animals which have clear relationships between behavior and corresponding neural activities. Insects are precisely such animals and one of the adaptive behaviors of insects is high-accuracy odor source orientation. The most direct way to know the relationships between neural activity and behavior is by recording neural activities in a brain from freely behaving insects. There is also a method to give stimuli mimicking the natural environment to tethered insects allowing insects to walk or fly at the same position. In addition to these methods an ‘insect–machine hybrid system’ is proposed, which is another experimental system meeting the conditions necessary for approaching the dynamic processing in the brain of insects for generating adaptive behavior. This insect–machine hybrid system is an experimental system which has a mobile robot as its body. The robot is controlled by the insect through its behavior or the neural activities recorded from the brain. As we can arbitrarily control the motor output of the robot, we can intervene at the relationship between the insect and the environmental conditions.     

Measuring Information-Transfer Delays

In complex networks such as gene networks, traffic systems or brain circuits it is important to understand how long it takes for the different parts of the network to effectively influence one another. In the brain, for example, axonal delays between brain areas can amount to several tens of milliseconds, adding an intrinsic component to any timing-based processing of information. Inferring neural interaction delays is thus needed to interpret the information transfer revealed by any analysis of directed interactions across brain structures. However, a robust estimation of interaction delays from neural activity faces several challenges if modeling assumptions on interaction mechanisms are wrong or cannot be made. Here, we propose a robust estimator for neuronal interaction delays rooted in an information-theoretic framework, which allows a model-free exploration of interactions. In particular, we extend transfer entropy to account for delayed source-target interactions, while crucially retaining the conditioning on the embedded target state at the immediately previous time step. We prove that this particular extension is indeed guaranteed to identify interaction delays between two coupled systems and is the only relevant option in keeping with Wiener’s principle of causality. We demonstrate the performance of our approach in detecting interaction delays on finite data by numerical simulations of stochastic and deterministic processes, as well as on local field potential recordings. We also show the ability of the extended transfer entropy to detect the presence of multiple delays, as well as feedback loops. While evaluated on neuroscience data, we expect the estimator to be useful in other fields dealing with network dynamics.     

The expression of neural-specific genes reveals the structural and molecular complexity of the planarian central nervous system

Planarians are attractive animals in which various questions related to the central nervous system (CNS) can be addressed, such as its origin and evolution, its degree of functional conservation among different organisms, and the plasticity and regenerative capabilities of neural cells and networks. However, it is first necessary to characterize at the gene expression level how this CNS is organized in intact animals. Previous studies have shown that the planarian brain can be divided into at least three distinct domains based on the expression of otd/Otx-related genes. In order to further characterize the planarian brain, we have recently isolated a large number of planarian neural-specific genes through DNA microarrays and ESTs projects. Here, we describe new molecular domains within the brain of intact planarians by the expression of 16 planarian neural-specific genes, including the putative homologues of protein tyrosine phosphatase receptor, synaptotagmin VII, slit, G protein and glutamate and acetylcholine receptors, by in situ hybridization in both whole-mount and transverse sections. Our results indicate that planarian otd/Otx-positive domains can be further subdivided into distinct molecular regions according to the expression of different neural genes. We found differences at the gene expression level between the dorsal and ventral sides of the brain, along its antero-posterior axis and also between the proximal and distal parts of the brain lateral branches. This high level of regionalization in the planarian brain contrasts with its apparent simplicity at the morphological level.     

Evaluation of sphingolipids changes in brain tissues of rats with pentylenetetrazol-induced kindled seizures using MALDI-TOF-MS

Abnormal lipid metabolism has been implicated in the pathogenesis of many neural system diseases, including epilepsy. Pentylenetetrazol (PTZ)-induced kindling in rodents is considered a model of human absence epilepsy and myoclonic, generalized tonic-clonic seizure. In an effort to further understand the mechanism for PTZ-induced seizure, we analyzed crude lipids and sphingolipids in the cortex, hippocampus, and brain stem of normal and PTZ-rats using delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE MALDI-TOF-MS). It was found that phosphatidylcholines dominated the crude lipids in different tissues and there were no obvious differences in crude lipid profiles of different tissues between normal and PTZ-rats. However, ceramide, sphingomyelins, and ceramide-monohexoside were differently distributed in normal and PTZ-rats. Using the reference mass spectra method established in our laboratory, it was shown that sphingomyelins and ceramide-monohexoside levels were elevated in the brain tissues of PTZ-rats. Ceramide levels were found to be higher in brain stem than in cortex and hippocampus of normal rats, and PTZ caused a general decrease in ceramide levels. These data suggest that changes in sphingolipid metabolism contribute to PTZ-induced seizure.     

Extreme Sexual Brain Size Dimorphism in Sticklebacks: A Consequence of the Cognitive Challenges of Sex and Parenting?

Selection pressures that act differently on males and females produce numerous differences between the sexes in morphology and behaviour. However, apart from the controversial report that males have slightly heavier brains than females in humans, evidence for substantial sexual dimorphism in brain size is scarce. This apparent sexual uniformity is surprising given that sexually distinct selection pressures are ubiquitous and that brains are one of the most plastic vertebrate organs. Here we demonstrate the highest level of sexual brain size dimorphism ever reported in any vertebrate: male three-spined stickleback of two morphs in an Icelandic lake have 23% heavier brains than females. We suggest that this dramatic sexual size dimorphism is generated by the many cognitively demanding challenges that males are faced in this species, such as an elaborate courtship display, the construction of an ornate nest and a male-only parental care system. However, we consider also alternative explanations for smaller brains in females, such as life-history trade-offs. Our demonstration of unprecedented levels of sexual dimorphism in brain size in the three-spined stickleback implies that behavioural and life-history differences among the sexes can have strong effects also on neural development and proposes new fields of research for understanding brain evolution.     

From 'understanding the brain by creating the brain' towards manipulative neuroscience

Ten years have passed since the Japanese 'Century of the Brain' was promoted, and its most notable objective, the unique 'creating the brain' approach, has led us to apply a humanoid robot as a neuroscience tool. Here, we aim to understand the brain to the extent that we can make humanoid robots solve tasks typically solved by the human brain by essentially the same principles. I postulate that this 'Understanding the Brain by Creating the Brain' approach is the only way to fully understand neural mechanisms in a rigorous sense. Several humanoid robots and their demonstrations are introduced. A theory of cerebellar internal models and a systems biology model of cerebellar synaptic plasticity is discussed. Both models are experimentally supported, but the latter is more easily verifiable while the former is still controversial. I argue that the major reason for this difference is that essential information can be experimentally manipulated in molecular and cellular neuroscience while it cannot be manipulated at the system level. I propose a new experimental paradigm, manipulative neuroscience, to overcome this difficulty and allow us to prove cause-and-effect relationships even at the system level.     

听觉皮层信号处理

听觉系统和视觉系统的不同之处在于：听觉系统在外周感受器和听皮层间具有更长的皮层下通路和更多的突触联系。该特殊结构反应了听觉系统从复杂听觉环境中提取与行为相关信号的机制与其他感觉系统不同。听皮层神经信号处理包括两种重要的转换机制,声音信号的非同构转换以及从声音感受到知觉层面的转换。听觉皮层神经编码机制同时也受到听觉反馈和语言或发声过程中发声信号的调控。听觉神经科学家和生物医学工程师所面临的挑战便是如何去理解大脑中这些转换的编码机制。我将会用我实验室最近的一些发现来阐述听觉信号是如何在原听皮层中进行处理的,并讨论其对于言语和音乐在大脑中的处理机制以及设计神经替代装置诸如电子耳蜗的意义。我们使用了结合神经电生理技术和量化工程学的方法来研究这些问题。     

Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies

Ischaemic stroke is among the most common yet most intractable types of central nervous system (CNS) injury in the adult human population. In the acute stages of disease, neurons in the ischaemic lesion rapidly die and other neuronal populations in the ischaemic penumbra are vulnerable to secondary injury. Multiple parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. Accumulating evidence indicates that cerebral ischaemia initiates an endogenous regenerative response within the adult brain that potentiates adult neurogenesis from populations of neural stem and progenitor cells. A major research focus has been to understand the cellular and molecular mechanisms that underlie the potentiation of adult neurogenesis and to appreciate how interventions designed to modulate these processes could enhance neural regeneration in the post-ischaemic brain. In this review, we highlight recent advances over the last 5 years that help unravel the cellular and molecular mechanisms that potentiate endogenous neurogenesis following cerebral ischaemia and are dissecting the functional importance of this regenerative mechanism following brain injury.This article is part of a Directed Issue entitled: Regenerative Medicine: the challenge of translation.     

Regulation of Msx genes by a Bmp gradient is essential for neural crest specification

There is evidence in Xenopus and zebrafish embryos that the neural crest/neural folds are specified at the border of the neural plate by a precise threshold concentration of a Bmp gradient. In order to understand the molecular mechanism by which a gradient of Bmp is able to specify the neural crest, we analyzed how the expression of Bmp targets, the Msx genes, is regulated and the role that Msx genes has in neural crest specification. As Msx genes are directly downstream of Bmp, we analyzed Msx gene expression after experimental modification in the level of Bmp activity by grafting a bead soaked with noggin into Xenopus embryos, by expressing in the ectoderm a dominant-negative Bmp4 or Bmp receptor in Xenopus and zebrafish embryos, and also through Bmp pathway component mutants in the zebrafish. All the results show that a reduction in the level of Bmp activity leads to an increase in the expression of Msx genes in the neural plate border. Interestingly, by reaching different levels of Bmp activity in animal cap ectoderm, we show that a specific concentration of Bmp induces msx1 expression to a level similar to that required to induce neural crest. Our results indicate that an intermediate level of Bmp activity specifies the expression of Msx genes in the neural fold region. In addition, we have analyzed the role that msx1 plays on neural crest specification. As msx1 has a role in dorsoventral pattering, we have carried out conditional gain- and loss-of-function experiments using different msx1 constructs fused to a glucocorticoid receptor element to avoid an early effect of this factor. We show that msx1 expression is able to induce all other early neural crest markers tested (snail, slug, foxd3) at the time of neural crest specification. Furthermore, the expression of a dominant negative of Msx genes leads to the inhibition of all the neural crest markers analyzed. It has been previously shown that snail is one of the earliest genes acting in the neural crest genetic cascade. In order to study the hierarchical relationship between msx1 and snail/slug we performed several rescue experiments using dominant negatives for these genes. The rescuing activity by snail and slug on neural crest development of the msx1 dominant negative, together with the inability of msx1 to rescue the dominant negatives of slug and snail strongly argue that msx1 is upstream of snail and slug in the genetic cascade that specifies the neural crest in the ectoderm. We propose a model where a gradient of Bmp activity specifies the expression of Msx genes in the neural folds, and that this expression is essential for the early specification of the neural crest.     

Sensory experience differentially modulates the mRNA expression of the polysialyltransferases ST8SiaII and ST8SiaIV in postnatal mouse visual cortex

Polysialic acid (PSA) is a unique carbohydrate composed of a linear homopolymer of α-2,8 linked sialic acid, and is mainly attached to the fifth immunoglobulin-like domain of the neural cell adhesion molecule (NCAM) in vertebrate neural system. In the brain, PSA is exclusively synthesized by the two polysialyltransferases ST8SiaII (also known as STX) and ST8SiaIV (also known as PST). By modulating adhesive property of NCAM, PSA plays a critical role in several neural development processes such as cell migration, neurite outgrowth, axon pathfinding, synaptogenesis and activity-dependent plasticity. The expression of PSA is temporally and spatially regulated during neural development and a tight regulation of PSA expression is essential to its biological function. In mouse visual cortex, PSA is downregulated following eye opening and its decrease allows the maturation of GABAergic synapses and the opening of the critical period for ocular dominance plasticity. Relatively little is known about how PSA levels are regulated by sensory experience and neuronal activity. Here, we demonstrate that while both ST8SiaII and ST8SiaIV mRNA levels decrease around the time of eye opening in mouse visual cortex, only ST8SiaII mRNA level reduction is regulated by sensory experience. Using an organotypic culture system from mouse visual cortex, we further show that ST8SiaII gene expression is regulated by spiking activity and NMDA-mediated excitation. Further, we show that both ST8SiaII and ST8SiaIV mRNA levels are positively regulated by PKC-mediated signaling. Therefore, sensory experience-dependent ST8SiaII gene expression regulates PSA levels in postnatal visual cortex, thus acting as molecular link between visual activity and PSA expression.     

An introduction to the neurobiology of oro-facial growth

Summary Neurotrophism describes a non-membrane conductive activity by which interactions occur between neurons and other cells which initiate or control molecular modifications in other cells. Neuro-epithelial, neuro-muscular, and neuro-visceral trophism is defined and discussed in some detail. Some emphasis is given to data indicating possible neurotrophic control of genetic activity of muscle. It is considered that oro-facial growth may be conceived of as a homeostatically controlled series of processes in which the neural center regulates the peripheral tissues and the periphery, in turn, regulates the center. While this neurobiological hypothesis may stimulate future research, we must clearly understand that we must also inquire as to the means by which neurotrophism is integrated with those other processes involved in growth regulation.     

Alcoholism: protein expression profiles in a human hippocampal model

It is well known that chronic, excessive consumption of alcohol can cause brain damage/structural changes in the regions important for neurocognitive function. Some of the damages are permanent, while others are reversible. Molecular mechanisms underlying alcohol-induced and/or -related brain damage are largely unknown, although it is generally believed that three factors (ethanol, nutritious and hepatic factors) play important roles. Recently, we have been employing a high-throughput proteomics technology to investigate several alcohol-sensitive brain regions from uncomplicated and hepatic cirrhosis-complicated alcoholics to understand the mechanisms of alcohol effects on the CNS at the level of protein expression. The changes of protein expression profiles in the hippocampus of alcoholic subjects were firstly demonstrated using 2D gel electrophoresis-based proteomics. Protein expression profiles identified in the hippocampus of alcoholic subjects were significantly different from those previously identified by our group in other brain regions of the same alcoholic cases, possibly indicating that these different brain regions react differently to chronic alcohol ingestion at the level of protein expression. Identified changes of protein expression associated with astrocyte and oxidative stress may indicate the possibility that increased levels of CNS ammonia and reactive oxygen species induced by alcoholic mild hepatic damage/dysfunction could cause selective damage in astrocytes of the hippocampus. Although our data did not demonstrate any evidence of direct alcohol effects to induce the alteration of protein expression in association with brain damage, high-throughput neuroproteomics approaches have proved to have the potential to dissect the mechanisms of complex brain disorders. Proteomics studies on human hippocampus, an important region for neurocognitive function and psychiatric illnesses (e.g., Alzheimer's disease, alcoholism and schizophrenia) are still sparse, and further investigation is warranted to understand the underlying mechanisms.     

Alcoholism: protein expression profiles in a human hippocampal model

It is well known that chronic, excessive consumption of alcohol can cause brain damage/structural changes in the regions important for neurocognitive function. Some of the damages are permanent, while others are reversible. Molecular mechanisms underlying alcohol-induced and/or -related brain damage are largely unknown, although it is generally believed that three factors (ethanol, nutritious and hepatic factors) play important roles. Recently, we have been employing a high-throughput proteomics technology to investigate several alcohol-sensitive brain regions from uncomplicated and hepatic cirrhosis-complicated alcoholics to understand the mechanisms of alcohol effects on the CNS at the level of protein expression. The changes of protein expression profiles in the hippocampus of alcoholic subjects were firstly demonstrated using 2D gel electrophoresis-based proteomics. Protein expression profiles identified in the hippocampus of alcoholic subjects were significantly different from those previously identified by our group in other brain regions of the same alcoholic cases, possibly indicating that these different brain regions react differently to chronic alcohol ingestion at the level of protein expression. Identified changes of protein expression associated with astrocyte and oxidative stress may indicate the possibility that increased levels of CNS ammonia and reactive oxygen species induced by alcoholic mild hepatic damage/dysfunction could cause selective damage in astrocytes of the hippocampus. Although our data did not demonstrate any evidence of direct alcohol effects to induce the alteration of protein expression in association with brain damage, high-throughput neuroproteomics approaches have proved to have the potential to dissect the mechanisms of complex brain disorders. Proteomics studies on human hippocampus, an important region for neurocognitive function and psychiatric illnesses (e.g., Alzheimer’s disease, alcoholism and schizophrenia) are still sparse, and further investigation is warranted to understand the underlying mechanisms.     

Imaging of molecular dynamics regulated by electrical activities in neural circuits and in synapses

One of the major challenges in brain research is to unravel a network of molecules, neurons, circuits and systems that are responsible for dynamic and hierarchical brain functions. To understand molecular events that occur in synapses could be an important key to exploring the mechanism of information processing. A spatiotemporal recording method is required to observe neuronal activities in a particular local circuit and to resolve single synaptic potential with high resolution. As alternative methods, real-time imaging using fluorescent probes and optical recording methods are also a powerful approach for investigating the molecular dynamics of biological events in neurons in vitro and in vivo. Recently, optical imaging techniques have become of great importance to visualize the molecular dynamics in a micron-sized compartment of a single neuron such as neuronal synapse. In general, the presynaptic axon forms synapses at the postsynaptic site on the dendritic spines in the mammalian central nervous system. Subsets of the synapses undergo a series of enduring changes in spine shape and density as well as alterations in electrophysiological functions. Here we describe recent optical imaging studies conducted by elaborate methods and techniques that provide evidence for the link between neural activity and molecular dynamics.