Thalamus gates active dendritic computations in cortex during sensory processing

Perception is causally linked to a calcium-dependent spiking mechanism that is built into the distal dendrites of layer 5 pyramidal tract neurons – the major output cell type of the cerebral cortex. It is yet unclear which circuits activate this cellular mechanism upon sensory stimulation. Here we found that the same thalamocortical axons that relay sensory signals to layer 4 also densely target the dendritic domain by which pyramidal tract neurons initiate calcium spikes. Distal dendritic inputs, which normally appear greatly attenuated at the cell body, thereby generate bursts of action potentials in cortical output during sensory processing. Our findings indicate that thalamus gates an active dendritic mechanism to facilitate the combination of sensory signals with top-down information streams into cortical output. Thus, in addition to being the central hub for sensory signals, thalamus is also likely to ensure that the signals it relays to cortex are perceived by the animal.

Thalamocortical axons regulate neurogenesis and laminar fates in early sensory cortex

Area-specific axonal projections from the mammalian thalamus shape unique cellular organization in target areas in the adult neocortex. How these axons control neurogenesis and early neuronal fate specification is poorly understood. By using mutant mice lacking the majority of thalamocortical axons, we show that these axons increase the number of layer 4 neurons in primary sensory areas by enhancing neurogenesis and shifting the fate of superficial layer neurons to that of layer 4 by the neonatal stage. Part of these area-specific roles are played by the thalamus-derived molecule, VGF. Our work reveals that extrinsic cues from sensory thalamic projections have an early role in the formation of cortical cytoarchitecture by enhancing the production and specification of layer 4 neurons.

Early construction of the thalamocortical axon pathway requires JNK signaling within the ventral forebrain

Thalamocortical connectivity is essential for normal brain function. This important pathway is established during development, when thalamic axons extend a long distance through the forebrain before reaching the cerebral cortex. In this study, we identify a novel role for the c-Jun N-terminal Kinase (JNK) signaling pathway in guiding thalamocortical axons through intermediate target territories. Complete genetic removal of JNK signaling from the Distal-less 5/6 (Dlx5/6) domain in mice prevents thalamocortical axons from crossing the diencephalon-telencephalon boundary (DTB) and the internal capsule fails to form. Ventral telencephalic cells critical for thalamocortical axon extension including corridor and guidepost neurons are also disrupted. In addition, corticothalamic, striatonigral, and nigrostriatal axons fail to cross the DTB. Analyses of different JNK mutants demonstrates that thalamocortical axon pathfinding has a non-autonomous requirement for JNK signaling. We conclude that JNK signaling within the Dlx5/6 territory enables the construction of major axonal pathways in the developing forebrain.

Fundamentals of the Development of Connectivity in the Human Fetal Brain in Late Gestation: From 24 Weeks Gestational Age to Term

During the second half of gestation, the human cerebrum undergoes pivotal histogenetic events that underlie functional connectivity. These include the growth, guidance, selection of axonal pathways, and their first engagement in neuronal networks. Here, we characterize the spatiotemporal patterns of cerebral connectivity in extremely preterm (EPT), very preterm (VPT), preterm and term babies, focusing on magnetic resonance imaging (MRI) and histological data. In the EPT and VPT babies, thalamocortical axons enter into the cortical plate creating the electrical synapses. Additionally, the subplate zone gradually resolves in the preterm and term brain in conjunction with the growth of associative pathways leading to the activation of large-scale neural networks. We demonstrate that specific classes of axonal pathways within cerebral compartments are selectively vulnerable to temporally nested pathogenic factors. In particular, the radial distribution of axonal lesions, that is, radial vulnerability, is a robust predictor of clinical outcome. Furthermore, the subplate tangential nexus that we can visualize using MRI could be an additional marker as pivotal in the development of cortical connectivity. We suggest to direct future research toward the identification of sensitive markers of earlier lesions, the elucidation of genetic mechanisms underlying pathogenesis, and better long-term follow-up using structural and functional MRI.

Thalamocortical axons control the cytoarchitecture of neocortical layers by area-specific supply of secretory proteins

Neuronal abundance and thickness of each cortical layer is specific to each area, but how this fundamental feature arises during development remains poorly understood. While some of area-specific features are controlled by intrinsic cues such as morphogens and transcription factors, the exact influence and mechanisms of action by extrinsic cues, in particular the thalamic axons, have not been fully established. Here we identify a thalamus-derived factor, VGF, which is indispensable for thalamocortical axons to maintain the proper amount of layer 4 neurons in the mouse sensory cortices. This process is prerequisite for further maturation of the primary somatosensory area, such as barrel field formation instructed by a neuronal activity-dependent mechanism. Our results also provide an insight into regionalization of brain in that highly site-specific axon projection anterogradely confers further regional complexity upon the target field through locally secreting signaling molecules from axon terminals.

An early cortical progenitor-specific mechanism regulates thalamocortical innervation

The cortical subplate is critical in regulating the entry of thalamocortical sensory afferents into the cortex. These afferents reach the subplate at embryonic day (E)15.5 in the mouse, but “wait” for several days, entering the cortical plate postnatally. We report that when transcription factor Lhx2 is lost in E11.5 cortical progenitors, which give rise to subplate neurons, thalamocortical afferents display premature, exuberant innervation of the E15.5 cortex. Embryonic mutant subplate neurons are correctly positioned below the cortical plate, but they display an altered transcriptome and immature electrophysiological properties during the waiting period. The sensory thalamus in these cortex-specific Lhx2 mutants displays atrophy, eventually leading to severe deficits in thalamocortical innervation. Strikingly, these phenotypes do not manifest if Lhx2 is lost in postmitotic subplate neurons. These results demonstrate a mechanism operating in subplate progenitors that has profound consequences on the growth of thalamocortical axons into the cortex.

FGF3 from the Hypothalamus Regulates the Guidance of Thalamocortical Axons

Thalamus is an important sensory relay station: afferent sensory information, except olfactory signals, is transmitted by thalamocortical axons (TCAs) to the cerebral cortex. The pathway choice of TCAs depends on diverse diffusible or substrate-bound guidance cues in the environment. Not only classical guidance cues (ephrins, slits, semaphorins, and netrins), morphogens, which exerts patterning effects during early embryonic development, can also help axons navigate to their targets at later development stages. Here, expression analyses reveal that morphogen Fibroblast growth factor (FGF)-3 is expressed in the chick ventral diencephalon, hypothalamus, during the pathfinding of TCAs. Then, using in vitro analyses in chick explants, we identify a concentration-dependent effect of FGF3 on thalamic axons: attractant 100 ng/mL FGF3 transforms to a repellent at high concentration 500 ng/mL. Moreover, inhibition of FGF3 guidance functions indicates that FGF3 signaling is necessary for the correct navigation of thalamic axons. Together, these studies demonstrate a direct effect for the member of FGF7 subfamily, FGF3, in the axonal pathfinding of TCAs.

The role of the diencephalon in the guidance of thalamocortical axons in mice

Thalamocortical axons (TCAs) cross several tissues on their journey to the cortex. Mechanisms must be in place along the route to ensure they connect with their targets in an orderly fashion. The ventral telencephalon acts as an instructive tissue, but the importance of the diencephalon in TCA mapping is unknown. We report that disruption of diencephalic development by Pax6 deletion results in a thalamocortical projection containing mapping errors. We used conditional mutagenesis to test whether these errors are due to the disruption of pioneer projections from prethalamus to thalamus and found that, while this correlates with abnormal TCA fasciculation, it does not induce topographical errors. To test whether the thalamus contains navigational cues for TCAs, we used slice culture transplants and gene expression studies. We found the thalamic environment is instructive for TCA navigation and that the molecular cues Netrin1 and Semaphorin3a are likely to be involved. Our findings indicate that the correct topographic mapping of TCAs onto the cortex requires the order to be established from the earliest stages of their growth by molecular cues in the thalamus itself.

Timing and Duration of Gbx2 Expression Delineates Thalamocortical and Dopaminergic Medial Forebrain Bundle Circuitry

SUMMARYGene expression is a dynamic process, which is highly coordinated during development to ensure the proper allocation and identity of neuronal cell types within the brain. Equally important during neurodevelopment is how cohorts of neurons establish axonal projections that innervate terminal target sites. We sought to bridge the temporal dynamics of gene expression, within a specific genetic lineage, to the establishment of neuronal circuits derived from cohorts of the lineage-specific progenitors. A central goal was to be able to accomplish genetic inducible circuit mapping non-invasively and with commonly available CreER/loxP technology. Specifically, we genetically marked thalamic neuron progenitors that expressed the transcription factor Gbx2 at an early embryonic stage and tracked the formation of lineage-derived thalamocortical axons during embryogenesis. We then assessed the neural circuitry at an early postnatal stage. We show that the temporal specificity of lineage marking provides a high degree of clarity for following neural circuit development. We also determined that the onset and duration of gene expression can delineate subsets of neural circuits derived from a common lineage. For example, we uncovered a novel contribution of Gbx2-expressing progenitors to midbrain dopamine neurons and dopaminergic axons of the medial forebrain bundle. We anticipate that this system can be instructive in elucidating changes in neural circuit development in both normal development and in mutant mice in which neural circuit formation is altered.