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  • Review Article
  • Published:

Thalamocortical development: how are we going to get there?

An Addendum to this article was published on 01 May 2003

Key Points

  • The mechanisms that control neocortical regionalization have been the subject of much debate. Intrinsic mechanisms, such as differential gene expression that is autonomous to the neocortex, and extrinsic influences, such as input from thalamocortical afferents, have both gained support from recent studies.

  • Most neocortical neurons, including the projection neurons, are generated within the ventricular and subventricular zones of the lateral ventricle. The first postmitotic neurons accumulate below the pial surface, and later-born neurons migrate along radial glial processes to form the cortical plate.

  • The thalamus and cortex develop synchronously — virtually all the thalamic neurons in the rat are born between embryonic day (E) 13 and E19, which coincides with the period of neuron generation in the cortex. The dorsal thalamic neurons send projections to the cortex.

  • Thalamocortical and corticothalamic projections have to cross several emerging boundary zones, including the diencephalic–telencephalic and pallial–subpallial boundaries, to reach their ultimate target cells. Their fibre trajectories and fasciculation patterns change as they cross these sharp gene expression boundaries.

  • Attractive and repulsive factors, and axon guidance molecules from the cortex are believed to have an important role in channelling thalamocortical projections through the forebrain. These factors include limbic-associated membrane proteins (LAMP), the orphan nuclear receptor Coup-tfi, Cadherin (Cdh) 6, Cdh8, Cdh11, ephrins and Eph receptors.

  • The 'handshake hypothesis' postulates that projections from the thalamus and the cortical preplate cells meet and intermingle in the basal telencephalon, such that thalamic axons grow over a scaffold of preplate axons. Errors in both corticothalamic and thalamocortical pathfinding have been described in mice with mutations in transcription factor genes that are expressed in the cortex (Tbr1), thalamus (Gbx2) or in both (Pax6).

  • Thalamic fibres arrive at the appropriate cortical regions before their ultimate target neurons are born, and they have to wait for two or three days before they can establish their final innervation pattern within the cortical plate. It has been proposed that while the thalamic axons accumulate in the subplate, they engage in activity-dependent interactions with the sensory periphery, and this might lead to their realignment before they enter the cortex.

  • Although some aspects of early cortical regionalization do not seem to require extrinsic influences, there is considerable evidence that the differentiation of many of the anatomical features that distinguish different cortical areas depends to a large extent on the input of thalamocortical axons.

  • Peripheral neurons are already generating spontaneous activity patterns by the time that sensory afferents begin to reach the thalamus, and these activity patterns could influence the formation of thalamocortical terminals within the subplate and layer IV of the cortex.

Abstract

The arealization of the mammalian cortex is believed to be controlled by a combination of intrinsic factors that are expressed in the cortex, and external signals, some of which are mediated through thalamic input. Recent studies on transgenic mice have identified families of molecules that are involved in thalamic axon growth, pathfinding and cortical target selection, and we are beginning to understand how thalamic projections impose cytoarchitectonic differentiation on the developing cortex. By unravelling these mechanisms further, we should be able to increase our understanding of the principles of cortical organization.

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Figure 1: Sensory modalities reach the cerebral cortex through different thalamic nuclei.
Figure 2: Thalamocortical axon growth through the developing mouse forebrain.
Figure 3: Signals, receptors and guidance molecules postulated in the development of area-specific thalamocortical connectivity.
Figure 4: Abnormalities in thalamic and corticofugal development in transcription factor gene mutants.
Figure 5: First contact with the cortex.
Figure 6: Formation of the periphery-related pattern in the somatosensory cortex.
Figure 7: Relationship between thalamocortical connectivity and cortical map formation.
Figure 8: When does neural activity play a part in thalamocortical development?

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Acknowledgements

We are grateful to O. Marín, R. Hevner and C. Métin for thoughtful comments on this manuscript. We also would like to thank all members of our laboratory for their help, comments and support during the realization of this article. This work was supported by the European Community, The Wellcome Trust, The Royal Society, the Swiss National Science Foundation and the Oxford McDonnell Centre for Cognitive Neuroscience (North American Network Grant). We also thank M. Wilson for inspiring figure 8.

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DATABASES

LocusLink

Adcy1

Cdh11

Cdh6

Cdh8

Coup-tfi

Ebf1

Emx1

Ephrins

Eph receptors

Fgf8

Gbx2

L1

Maoa

Mash1

mGluR1

mGluR5

Munc13-3

Munc18

netrin 1

Nkx2.1

Pax6

Plcβ1

semaphorins

Snap25

Tbr1

Glossary

EPIGENETIC

Describes a change in phenotype that is brought about by changes in the regulation of gene expression or changes in the function of gene products, rather than by a change in genotype.

VENTRICULAR ZONE

The proliferative inner layer of the developing brain and spinal cord.

SUBVENTRICULAR ZONE

A layer of cells in the developing brain that is generated by the migration of neuroblasts from the adjoining ventricular zone.

INTERNAL CAPSULE

A large bundle of axons that reciprocally connects the cortex with the subcortical structures of the brain.

STRIATUM

Part of the subpallium and one of the components of the striatopallidal complex. It comprises deep (caudate nucleus, putamen and nucleus accumbens) and superficial (olfactory tubercle) parts.

OLFACTORY TUBERCLE

A structure in the base of the telencephalon that acts as a relay centre for olfactory information. It was initially classed as a component of the olfactory (or piriform) cortex, but its cellular architecture more closely resembles that of the striatum, with which it shares a common developmental origin in the lateral ganglionic eminence. It is particularly prominent in species that rely heavily on their sense of smell, such as rodents.

AMYGDALA

A small almond-shaped structure, comprising 13 nuclei, buried in the anterior medial section of each temporal lobe.

ORPHAN NUCLEAR RECEPTOR

A receptor for which a ligand has not been identified.

HOMOTYPIC

A term that refers to interactions between cells or molecules of the same type.

HETEROTYPIC

A term that refers to interactions between cells or molecules of different types.

PALLIUM

The roof of the telencephalon. It contains both cortical structures (for example, hippocampus and neocortex) and deep-lying nuclear structures (for example, claustrum and parts of the amygdala). Pallium is not synonymous with cortex.

OCCIPITAL CORTEX

The most caudal of the four main subdivisions of the cerebral cortex.

PERIRHINAL CORTEX

One of the subdivisions of the medial temporal lobe. It is involved in learning and memory, and is believed to be particularly important for object memory.

GANGLIONIC EMINENCE

The proliferative zone of the ventral telencephalon, which gives rise to the basal ganglia, and also generates some cortical neurons and glia. It consists of lateral, caudal and medial subdivisions.

CHONDROITIN SULPHATE PROTEOGLYCANS

Important components of the extracellular matrix and connective tissue. These proteins contain hydrophilic, negatively charged polymers of glucuronic acid and sulphated N-acetyl glucosamine residues.

HEPARAN SULPHATE

A glycosaminoglycan that consists of repeated units of hexuronic acid and glucosamine residues. It usually attaches to proteins through a xylose residue to form proteoglycans.

BINOCULAR ENUCLEATION

Surgical removal of both of the eyeballs.

BARREL

A cylindrical column of neurons found in the rodent neocortex. Each barrel receives sensory input from a single whisker follicle, and the topographical organization of the barrels corresponds precisely to the arrangement of whisker follicles on the face.

PARACRINE

Signalling process that involves the secretion of molecules from a cell, which act on other cells in the immediate neighbourhood that express appropriate receptors, rather than acting on the same cell (autocrine signalling) or on remote cells (endocrine signalling).

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López-Bendito, G., Molnár, Z. Thalamocortical development: how are we going to get there?. Nat Rev Neurosci 4, 276–289 (2003). https://doi.org/10.1038/nrn1075

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