Blanc SVSE 4 - Blanc - SVSE 4 - Neurosciences

Molecular, cellular and activity-dependent mechanisms controlling arealization and circuitry in the developing mouse neocortex. – AREAL

How to build a brain

Study of the molecular, cellular and physiological mechanisms underlying the establishment of brain areas and cortical circuits in mice.

Understanding the basic mechanisms underlying the functioning of the cerebral cortex

The mammalian cortex is organized into functional areas called «areas«. Each neocortical area is composed of six cell layers, each consisting of neuronal subtypes with unique molecular and cellular properties. The division into areas and layers originates from a tissue initially undifferentiated, in which the expression of certain factors plays a major role in the final organization of the cortex and its basic functions. The project aims to decipher the developmental mechanisms responsible for the establishment of areas, cortical layers and their circuitry within the cortex.<br /> <br />Our goal is to highlight the key role of certain factors in the differentiation of neurons into functional and interdependent networks using genetic and molecular manipulations and characterizing cortical networks with sophisticated techniques. This interdisciplinary approach will help to elucidate the mechanisms responsible for the specificity of neurons and their maturation in an area-depenedent manner. Finally, we will characterize the structural and dynamic properties of cortical microcircuitries in our genetic models and manipulate the intrinsic properties of neurons to determine their possible role in this process. This project helps to elucidate how genetic factors contribute to adaptive processes towards the construction of mature functional circuits.<br /><br />The mammalian cortex is organized into functional areas called «areas«. Each neocortical area is composed of six cell layers, each consisting of neuronal subtypes with unique molecular and cellular properties. The division into areas and layers made from a fabric initially undifferentiated, in which the expression of certain factors play a major role in the final organization of the cortex and its operation. The project is to decipher the developmental mechanisms responsible for the establishment of areas and cortical layers and their circuitry within the cortex.

The major objective of this project is to identify the molecular and cellular mechanisms involved in the differentiation of neurons and in the construction of functional neural circuits. Our proposal, as part of the field of neuroscience, has two distinct but complementary disciplinary approaches: molecular neurobiology and functional neurophysiology. We combine molecular manipulations with the functional characterization of cortical circuits using mouse genetics and sophisticated electrophysiological and histological approaches.

The first significant result of the project is the demonstration that the neocortex is more plastic than previously thought. It had been previously suggested that its organization into functional areas and laminar layers was determined at progenitor levels (a very early developmental stage). We show that this organization can still be modified at a later stage of development and at the level of differentiated neurons. We also found that the molecular codes established during development and involved in the formation of the first major classes of neurons are reused after birth to allow the final specification of cortical neuron subclasses, thanks to an epigenetic mechanism controlled by Lmo4 and set up after birth (see illustration below). We also found that endogenous neural activity, present before the arrival of sensory inputs, is involved in the establishment of the first cortical areas and their laminar and cell type organization.

This project provides a better comprehension of the mechanisms underlying the functioning of the cerebral cortex, which will contribute to the understanding of the aetiology of severe neurological disorders in humans. Recent advances in human genetics have revealed significant links between the networks that control the activity of genes expressed early during cortical development and specific neurological disorders, such as mental retardation and autism. We study a gene that has recently been found altered in children with severe cognitive impairments. Thus, our line of transgenic mice that lack the gene can be considered an excellent animal model for in vivo research and will help in unravelling the links between genetic mutations and phenotypes observed in patients, and more generally individuals with cortical malformations.

We published an article in the international journal Nature Communications on the role of postmitotic neurons during the development of areas and cortical layers, and an article on e-Life on the epigenetic mechanisms allowing the expression of certain genes during the formation of cortical layer V. These studies were presented at international and national conferences. We have also deposited an European patent on a new procedure allowing neuronal reprogramming of callosal to subcerebral neuronal subtypes in the mouse cortex (N° EP15306775).

The mammalian neocortex, the largest and most complex brain structure, is tangentially organized into functional domains referred to as "areas" that are distinguished from one another by major differences in their cytoarchitecture, input and output connections, and patterns of gene expression. In addition to this tangential subdivision, each neocortical area is radially subdivided into six layers, and each layer constitutes a unique assembly of neuronal subtypes with their distinct morphology, local circuitry, connectivity and developmental programs of gene expression. Areal and laminar identities are generated from an uniform neuroepithelial sheet by gradients of extracellular signals secreted by telencephalic patterning centers, which modulate the expression of several downstream transcription factors in neuronal progenitors; little is known on how areal identity, once established at progenitors level, is maintained in differentiated cortical pyramidal neurons during corticogenesis, and whether specific neuronal sub-populations or cortical circuits are peculiar of distinct functional areas. To date, the mechanisms sculpting cytoarchitecture, circuitry and layering of the neocortical areas remain sketchy, and our knowledge is limited to events influencing areal size and positioning.

Amongst the different patterning genes expressed as gradients in progenitor cells and required in setting up a neocortical protomap during corticogenesis, the nuclear receptor COUP-TFI is unique, since its expression is also maintained in post-mitotic cells during corticogenesis. Alterations in its expression results in the severe impairment of several areal specific features and processes, such as proper size and position of motor and somatosensory areas, subcortical connectivity, neuronal migration, cell-type specification, axonal growth, and sensorimotor behaviour. Nevertheless, the various molecular cascades relaying the activation of COUP-TFI and the functional correlates of altered arealization remain largely unknown. For example, immature cortical networks express distinct patterns of spontaneous activity hypothesized to participate in the refinement of the precise connectivity between neurons, so that the adult circuits are endowed with specific processing properties and a fine balance between excitation and inhibition activities. It is not known in which respect these activity patterns and connectivity rules are preserved or altered in cortical circuits after abnormal differentiation of cortical area specific neuronal sub-types.

With the help of molecular and genetic manipulations and the functional characterization of cortical circuits using sophisticated histological and electrophysiological approaches, we aim to unravel the importance of several molecular mechanisms in the differentiation of neurons into distinct but coordinated functional circuits. This interdisciplinary approach will help us to elucidate how areal subdivision is established and maintained in mitotic (progenitors) and/or post-mitotic (pyramidal neurons) compartments of the neocortex and whether other patterning centres, beside the known rostralmost FGF source, are involved in early events of areal patterning. We will also investigate the molecular and cellular mechanisms underlying cell-type specificity and morphological maturation across cortical areas, with particular emphasis on layer V projection neurons. Finally, we will analyse the cortical microcircuit structure and dynamics in our genetic models in which cortical arealization is perturbed and challenge the role of intrinsic activity in setting up area-dependent neuronal circuits in the immature neocortex.

We believe that this project will contribute to elucidate how genetic factors (such as COUP-TFI) interact with adaptive processes (such as activity-dependent refinement of developing neuronal networks) to provide mature cortical circuits with their peculiar processing and auto-organizing properties.


Project coordination

Michèle STUDER (Institut de Biologie Valrose/INSERM) – Michele.STUDER@unice.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

iBV/INSERM Institut de Biologie Valrose/INSERM
IMN Institut des Maladies Neurodegeneratives
INSERM INSERM

Help of the ANR 505,440 euros
Beginning and duration of the scientific project: September 2013 - 48 Months

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