From Molecules To Networks An Introduction To Cellular And Molecular Neuroscience Pdf

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Molecular neuroscience

We will only briefly depict developmental disorders that result from perturbations of these cellular or molecular mechanisms, and the most common perinatal brain injuries that could disturb normal brain development.

Human brain development starts with neurulation from the ectoderm of the embryo and it takes, on average, 20 to 25 years to mature. This protracted process is presented as both physical and experience-based maturation.

Building this most complex and highly organized organ involves the generation of a wide variety of specialized neural and non-neural cell types that must be produced in the correct numbers, at appropriate locations and with the right timing.

Additionally, accurate connections between neurons and efficient communication between distinct cell populations are crucial for the brain to exert centralized control for behaviour, perception and higher cognitive function. Brain develops in an intricately orchestrated sequence of stages. Neural tube, the origin of the entire central nervous system CNS , is formed at approximately 3—4 weeks of gestation and followed by massive cell proliferation, migration and brain expansion in size, complexity and surface area gyrification.

Neurogenesis and formation of the general architecture of brain regions are largely complete at birth, while maturation of the two principal glial cells astrocytes and oligodendrocytes , synaptogenesis and synapse pruning, and myelination represent postnatal brain growth Giedd, Furthermore, brain constantly changes at the level of connectivity throughout the life span with environmental influences. It is now known that neurogenesis precedes gliogenesis, which is the results of an inherent, exquisitely timed mechanism regulated by complex interactions between intrinsic factors for example, gene epigenetic modifications and extrinsic cues secreted or contact-mediated factors Rowitch and Kriegstein, Adequate neurogenesis and timely switch of developmental program of progenitor domains to gliogenesis are critical for proper neural circuit formation and normal brain function.

Disruptions in any of the mechanisms may lead to disorganization and eventually, dysfunction of the CNS. As a preamble to the reviews of this issue, we will provide an overview of the processes that orchestrate the successive steps of normal cortical brain development, including progenitor division and production in coordination with appropriate layer neuron production, neuron migration and maturation, synaptogenesis and at last gliogenesis.

We will only briefly discuss how alterations of such mechanisms can be related to some of the brain development disorders. Neurodevelopmental diseases will be reviewed in detail in the other articles of this issue.

The cerebral cortex, also called the neocortex in mammals to distinguish it from the more ancient paleo-cortex and archicortex, differentiates in the dorsal telencephalon, the most anterior region of the embryonic brain Rubenstein and Beachy, The neocortex is the seat of the higher cognitive functions and has a very complex cytoarchitecture, including projection neurons born in the same area and interneurons originating in ventral telencephalic regions Molyneaux et al.

Cortical projection neurons are organized into six layers that constitute a laminar structure called the cortical plate. Layer neurons are distinguished by the expression of specific combinations of molecular markers and distinct axonal projections.

Neurons occupying the deep layers V and VI are predominantly composed of corticofugal neurons that project to subcortical areas, such as the thalamus, brain stem and spinal cord. In contrast, the superficial layers IV to II are composed of intracortical neurons that project locally or to the contralateral hemisphere Greig et al.

All these neurons are excitatory glutamatergic neurons and derive from the germinative zones of the developing neocortex: the ventricular zone VZ , which lines the ventricle, and the subventricular zone SVZ , which develops from the VZ and is juxtaposed to its basal surface Angevine and Sidman, ; Anthony et al.

The first phase of neurogenesis occurs in the VZ and generates pioneer neurons, including Cajal-Retzius cells that populate the pre-plate Meyer et al. A second phase, resulting in a much more important output of neurons, principally occurs in the SVZ and gives rise to projection neurons. These primary neurons split the pre-plate into the marginal zone or layer I, and the subplate Super et al. Sequentially arising projection neurons migrate to the cortical plate in an inside-out manner, with the youngest upper-layer neurons migrating over deeper neurons born earlier Molyneaux et al.

While the laminar structure of the cortical plate has been relatively well conserved, its size has expanded remarkably with respect to both volume and surface, in particular in humans and other primates, along with the evolutionary complexification of cognitive function. Because the ventricle has not increased to a matching extent, this expansion imposes the folding of the cortical plate and the formation of convolutions or gyri Fietz et al.

Many genetic and functional studies in animal models, especially in the mouse, have provided valuable insights into the cellular and molecular mechanisms that underlie the complex development of the cerebral cortex Hansen et al. Nonetheless, understanding how these mechanisms have evolved and adapted to allow this increase in cortical size remains a major challenge in neurodevelopmental biology.

In the beginning, the neural tube corresponds to a neuroepithelium, made up of highly polarized cells called neuroepithelial cells NECs Lui et al. In the developing cortex, NECs extend long process throughout the entire cortical wall. Their apical and basal end feet are attached at the ventricular surface and the pial lamina, respectively Lui et al.

Cadherins and catenins form adherens junctions that mediate cell-cell adhesion Elias et al. NECs divide symmetrically to self-renew and to generate an adequate pool of founder progenitors Figure 1b.

This initial proliferative phase affects both lateral and radial extension and has a significant impact on the final surface area and thickness of the neocortex Florio and Huttner, ; Sun and Hevner, ; Dehay et al. They can self-renew by symmetric divisions but primarily undergo asymmetric neurogenic divisions, which produce a new aRGC and either a neuron direct neurogenesis , or an intermediary type of progenitor cell, called IPC that then gives rise to neurons indirect neurogenesis Hartfuss et al.

Ultimately, during the last stages of neuron production, aRGCs undergo a terminal symmetric division, giving birth to two neurons Noctor et al. The prevalence of indirect neurogenic divisions increases markedly as neurogenesis progresses. Recent data from the mouse have shown that each aRGC can give rise to 8—9 neurons stochastically distributed throughout the different layers Gao et al. IPCs are transiently amplifying progenitors characterized by the expression of the transcription factor Tbr2 and by a multipolar morphology.

They delaminate from the VZ to settle in the SVZ, where they divide symmetrically to self-renew before undergoing a terminal division that gives rise to two neurons Figure 1 b Noctor et al. To recapitulate, the final neuronal output is sequentially impacted by the size of the initial pool of founder progenitors NECs , by the progressive switch from symmetric autoreplicative to neurogenic divisions, and finally by the duration of the neurogenic phase, which, interestingly, presents significant variations between species Borrell and Calegari, ; Sun and Hevner, ; Dehay et al.

This is a major difference observed between lissencephalic species such as rodents, and gyrencephalic species, such as humans and other large primates. In addition, other features differentiate the structure and cell content of the SVZ in lissencephalic and gyrencephalic species Figure 1b and 1c. Contrasting with the scarcity of bRGCs in the mouse Shitamukai and Matsuzaki, , the striking expansion of bRGCs, and subsequently of IPCs, is a major hallmark of the primate OSVZ and is now commonly considered as one of the predominant events underlying the evolutionary increase in neuronal output and the related size expansion of the cerebral cortex.

In line with this, the different morphotypes of bRGCs have recently been shown to present different rates of proliferation and changes in their relative distribution have been correlated to waves of neurogenesis Betizeau et al. This cell cycle-related nuclear movement, called interkinetic nuclear movement INM , creates a pseudo-stratified structure, in which the positions of asynchronized nuclei are dependent on cell cycle phase: nuclei are located at the basal end of the cell during S phase, undertake basal to apical migration towards the ventricular surface during G2, undergo M phase at the ventricular surface and then migrate back to the basal side during G1 Taverna and Huttner, ; Kosodo et al.

The exquisite coordination between INM and cell cycle phases plays an essential role in the homoeostasis of the progenitor pool Schenk et al. The impairment of this process can lead to the loss of progenitors, due to abnormal abventricular mitosis and the consequent apoptosis or exit from the cell cycle. Interactions of motor protein complexes with microtubules play an important role in INM: Dynein, Lis1 and Nde1 are involved in basal to apical migration, while myosin II is involved in apical to basal migration.

The disruption of Lis1 function indeed results in the accumulation of heterotopic multipolar progenitors in the VZ of embryonic rat brains, along with a loss of progenitors Tsai et al.

Variations in the balance between these progenitor pools have been observed between species and have been hypothesized to account for the variations in final neuronal output and the size of the cerebral cortex. These variations imply that mechanisms influencing this balance have been adjusted during evolution to generate gyrencephalic brains Dehay et al ; Sun and Hevner, The balance between symmetric and asymmetric divisions also has a high impact on the neuronal output.

As previously discussed, symmetric divisions are important for the production of an adequate pool of founder progenitors or NECs, whose progeny will ultimately give rise to all cortical projection neurons. Hence, any alteration of this pool, even moderate, has a significant impact on the final neuronal output.

On the other hand, asymmetric divisions are important to maintain the proper distribution of the progenitor pools, including aRGCs, bRGCs and IPCs, in coordination with the sequential generation of neurons populating the six layers of the cortical plate LaMonica et al. During symmetric NEC divisions, the cleavage plane is oriented vertically and perpendicular to the ventricular surface.

The mitotic spindle is formed horizontally parallel to the ventricular surface and both sides of the spindle present equivalent volumes. Such a spatial organization requires 1 proper centrosome microtubule organizing center duplication and assembly; and 2 very well-orchestrated interactions between microtubules and various factors, such as Planar Cell Polarity PCP components, LGN, and Inscuteable Konno et al.

Alterations in the centrosome cycle affect spindle positioning, which is detrimental to division symmetry and can drive cells to prematurely exit the cell cycle and differentiate, or even to undergo apoptosis Kimura et al. Likewise, the basal process, necessary for the maintenance of progenitor fate in the VZ, is equally split between the two daughter cells or rapidly regenerated in one of them Kosodo and Huttner, ; Hansen et al.

Indeed, signals mediated by the meninges and Cajal-Retzius cells through contacts with the basal membrane of NECs and RGCs participate in the activation of proliferation Hartfuss et al. Such activation is also promoted by Notch signalling Gaiano et al. The Notch pathway activates Hes genes, which in turn repress neurogenic genes, such as neurogenins, and thus inhibit differentiative divisions.

Hence, the unequal repartition of Par3 during asymmetric divisions results in cell cycle exit and differentiation of the daughter cell inheriting the lower amount of Par3 Bultje et al.

Notch signalling is further modulated by other pathways induced by factors secreted by the choroid plexus into the cerebrospinal fluid and known to play an important role in the control of progenitor amplification such as Igf2 Lehtinen et al. Glycogen synthetase-kinase 3 GSK3 , which acts as an inhibitor of neural progenitor proliferation, appears to be a key integrative component at the centre of the complex interplay between all these signaling pathways, the net effect of which is to maintain GSK3 in an inactivated state Kim et al.

Despite the lack of experimental evidence, we can reasonably suppose that changes observed in the composition of the cerebrospinal fluid during brain development can modulate this interplay and eventually influence the transition from NECs to RGCs.

In addition, the proliferation of neural progenitors appears to be influenced by extrinsic factors, such as the Vaso-Intestinal-Peptide VIP Passemard et al. Cerebral malformations have been classified into three main groups, according to their cellular origin Barkovich et al, Each group has been further subdivided into sub-groups based on distinct morphogenic defects. The principal genes involved in each disorder are reported Barkovich et al. As previously discussed, projection neurons are born in the SVZ and then migrate through the intermediate zone or subplate to reach their layer of destination in the cortical plate.

Neuronal migration is a multifaceted process and relies on a large variety of cellular functions intervening in cell shape, polarity and motility. Time-lapse analyses have revealed several shape transitions in neurons on their way to final position. Newborn neurons leaving the SVZ transiently adopt a multipolar morphology, and then a bipolar morphology characterized by leading and trailing processes that neurons maintain during migration Gressens, ; Marin et al.

Of note, this migration proceeds along the basal process of RGCs, and thus underpins the formation of radial units of migrating neurons.

This radial organization appears to be a major process for radial extension of the cerebral cortex Rakic, All these processes are governed by a sophisticated interplay between intrinsic and extrinsic instructive cues Figure 2.

Extracellular cues, mediated by components of the extra-cellular matrix, such as cadherins, or by membrane receptor activation by Reelin, Ephrins, Wnts and RA promote the various steps involved in neuronal migration. Yellow arrows indicate pulling forces at the cell front and rear. Cytoskeleton components play a major role in the cellular functions required for cell migration, and most importantly, they are selectively implied in a very highly coordinated manner during the two main phases of cell movement associated with migration: the movement of the centrosome in the leading process, followed by the nuclear movement nucleokinesis towards the centrosome Kriegstein and Noctor, ; Tsai and Gleeson, Of note, nucleokinesis accompanying neuronal migration shares many aspects with INM in progenitors Figure 2.

The extension of the leading process results from protrusion forces exerted by actin polymerization and microtubules growth. Similarly, proteins involved in cell polarity, such as Par6 and aPKC, and proteins associated with microtubules, such as APC, Dcx and kinesins, are essential for proper migration and cortical morphogenesis Bai et al.

Kinesins participate in the directional and selective transport of cargos, such as vesicles containing neurotrophic factors or presynaptic neurotransmitters Falnikar et al. The interactions between these proteins and microtubules are largely regulated by posttranslational modification. In particular, the function of Dcx and kinesins appears to be regulated by phosphorylation by the Cdk5 kinase Hammond et al.

During migration, neurons receive important hints from diverse origins. Reelin signal transduction, which involves DAB1, nectins, affilins, Fyn, and components of the extra-cellular matrix such as cadherins, regulates cytoskeleton organization, nuclear movement and cell shape and adhesion Beffert et al.

In the reelin deficient Reeler mice, neurons do not reach their prospective final position, which results in a reversed laminar structure of the cortical plate Landrieu and Goffinet, ; Andersen et al. In humans, Reelin mutations can be associated with lissencephaly, as described in the Norman-Roberts syndrome Hong et al.

Migrating neurons express Ephrin-B1, which promotes their radial migration while limits their tangential dispersion by inhibiting neurite extension Dimidschstein et al. Interestingly, more selective informative cues can impact the migration of specific classes of neurons. These neurons fail to maintain their fate and instead acquire characteristics of layer II neurons Choi et al. This RA effect on the maintenance of neuronal identity and localization relies on the stabilisation of the beta-catenin function and the stimulation of the Wnt signalling, which is necessary for migration process Ivaniutsin et al.

Furthermore, this effect seems to be more active in the rostral region of the developing cerebral cortex, suggesting that RA can also participate in the regional variations of the neuronal subtype output.

From Molecules to Networks - An introduction to cellular and molecular neuroscience

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Cellular and molecular mechanisms

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From Molecules to Networks

Cellular and molecular introduction to brain development

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Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy , mechanisms of molecular signaling in the nervous system , the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. In molecular biology , communication between neurons typically occurs by chemical transmission across gaps between the cells called synapses.

We will only briefly depict developmental disorders that result from perturbations of these cellular or molecular mechanisms, and the most common perinatal brain injuries that could disturb normal brain development. Human brain development starts with neurulation from the ectoderm of the embryo and it takes, on average, 20 to 25 years to mature. This protracted process is presented as both physical and experience-based maturation. Building this most complex and highly organized organ involves the generation of a wide variety of specialized neural and non-neural cell types that must be produced in the correct numbers, at appropriate locations and with the right timing. Additionally, accurate connections between neurons and efficient communication between distinct cell populations are crucial for the brain to exert centralized control for behaviour, perception and higher cognitive function. Brain develops in an intricately orchestrated sequence of stages.

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