Multiple Functions of Draxin/Netrin-1 Signaling in the Development of Neural Circuits in the Spinal Cord and the Brain

Axon guidance proteins play key roles in the formation of neural circuits during development. We previously identified an axon guidance cue, named draxin, that has no homology with other axon guidance proteins. Draxin is essential for the development of various neural circuits including the spinal cord commissure, corpus callosum, and thalamocortical projections. Draxin has been shown to not only control axon guidance through netrin-1 receptors, deleted in colorectal cancer (Dcc), and neogenin (Neo1) but also modulate netrin-1-mediated axon guidance and fasciculation. In this review, we summarize the multifaceted functions of draxin and netrin-1 signaling in neural circuit formation in the central nervous system. Furthermore, because recent studies suggest that the distributions and functions of axon guidance cues are highly regulated by glycoproteins such as Dystroglycan and Heparan sulfate proteoglycans, we discuss a possible function of glycoproteins in draxin/netrin-1-mediated axon guidance.

Cross-Streams Through the Ventral Posteromedial Thalamic Nucleus to Convey Vibrissal Information

Whisker detection is crucial to adapt to the environment for some animals, but how the nervous system processes and integrates whisker information is still an open question. It is well-known that two main parallel pathways through Ventral posteromedial thalamic nucleus (VPM) ascend to the barrel cortex, and classical theory suggests that the cross-talk from trigeminal nucleus interpolaris (Sp5i) to principal nucleus (Pr5) between the main parallel pathways contributes to the multi-whisker integration in barrel columns. Moreover, some studies suggest there are other cross-streams between the parallel pathways. To confirm their existence, in this study we used a dual-viral labeling strategy and high-resolution, large-volume light imaging to get the complete morphology of individual VPM neurons and trace their projections. We found some new thalamocortical projections from the ventral lateral part of VPM (VPMvl) to barrel columns. In addition, the retrograde-viral labeling and imaging results showed there were the large trigeminothalamic projections from Sp5i to the dorsomedial section of VPM (VPMdm). Our results reveal new cross-streams between the parallel pathways through VPM, which may involve the execution of multi-whisker integration in barrel columns.

Targeting barrel field spiny stellate cells using a vesicular monoaminergic transporter 2-Cre mouse line

Rodent primary somatosensory cortex (S1) is organized in defined layers, where layer IV serves as the main target for thalamocortical projections. Serotoninergic signaling is important for the organization of thalamocortical projections and consequently proper barrel field development in rodents, and the vesicular monoamine transporter 2 (VMAT2) can be detected locally in layer IV S1 cortical neurons in mice as old as P10, but the identity of the Vmat2-expressing neurons is unknown. We here show that Vmat2 mRNA and also Vmat2-Cre recombinase are still expressed in adult mice in a sub-population of the S1 cortical neurons in the barrel field. The Vmat2-Cre cells showed a homogenous intrinsically bursting firing pattern determined by whole-cell patch-clamp, localized radial densely spinous basal dendritic trees and almost exclusively lack of apical dendrite, indicative of layer IV spiny stellate cells. Single cell mRNA sequencing analysis showed that S1 cortical Vmat2-Cre;tdTomato cells express the layer IV marker Rorb and mainly cluster with layer IV neurons, and RNAscope analysis revealed that adult Vmat2-Cre neurons express Vmat2 and vesicular glutamate transporter 1 (Vglut1) and Vglut2 mRNA to a high extent. In conclusion, our analysis shows that cortical Vmat2 expression is mainly confined to layer IV neurons with morphological, electrophysiological and transcriptional characteristics indicative of spiny stellate cells.

Reinforcement regulates timing variability in thalamus

Learning reduces variability but variability can facilitate learning. This paradoxical relationship has made it challenging to tease apart sources of variability that degrade performance from those that improve it. We tackled this question in a context-dependent timing task requiring humans and monkeys to flexibly produce different time intervals with different effectors. We identified two opposing factors contributing to timing variability: slow memory fluctuation that degrades performance and reward-dependent exploratory behavior that improves performance. Signatures of these opposing factors were evident across populations of neurons in the dorsomedial frontal cortex (DMFC), DMFC-projecting neurons in the ventrolateral thalamus, and putative target of DMFC in the caudate. However, only in the thalamus were the performance-optimizing regulation of variability aligned to the slow performance-degrading memory fluctuations. These findings reveal how variability caused by exploratory behavior might help to mitigate other undesirable sources of variability and highlight a potential role for thalamocortical projections in this process.

High-throughput whole-brain mapping of rhesus monkey at micron resolution

Whole-brain mesoscale mapping of primates has been hindered by large brain size and the relatively low throughput of available microscopy methods. Here, we present an integrative approach that combines primate-optimized tissue sectioning and clearing with ultrahigh-speed, large-scale, volumetric fluorescence microscopy, capable of completing whole-brain imaging of a rhesus monkey at 1 µm × 1 µm × 2.5 µm voxel resolution within 100 hours. A progressive strategy is developed for high-efficiency, long-range tracing of individual axonal fibers through the dataset of hundreds of terabytes, establishing a “Serial sectioning and clearing, 3-dimensional Microscopy, with semi-Automated Reconstruction and Tracing” (SMART) pipeline. This system supports effective connectome-scale mapping of large primates that reveals distinct features of thalamocortical projections of the rhesus monkey brain at the level of individual axonal fibers.

Cheiro-oral-pedal syndrome as the presenting symptom of brainstem cavernous malformation: a case report

ABSTRACT The rare cheiro-oral-pedal syndrome (COPS) is characterized by sensory disturbances around the corner of the mouth, and in the hand and foot of the same side. The causative lesion is located in the thalamocortical projections, thalamus or brainstem and is usually due to ischemic or hemorrhagic stroke. We report a case of a patient with brain stem cavernous malformations presented as pure COPS with additional sensory disturbance in the thorax. We report this case to raise awareness of these very rare syndromes and demonstrate that mildly presenting symptoms can be caused by an underlying devastating condition.

Thalamocortical Projectional Divergence Leads to Complexity in Functional Organizations in Mouse Auditory Cortex

Frequency-related topological projections from the ventral division of the medial geniculate body (MGv) relay the tonotopic organization found in primary auditory cortex (A1). However, relaying circuits of the functional organization to higher-order, secondary auditory field (A2) have not been identified so far. Here, using tracing, we found that A2 receives dense topological projections from MGv in mice, and that tonotopy was established in A2 even when primary fields including A1 were removed. These indicate that thalamic inputs to A2 are sufficient for generating its tonotopy. Moreover, neuronal responses in the thalamocortical recipient layer of A2 showed wider bandwidth and greater heterogeneity of the best frequency distribution than those of A1, which was attributed to larger divergence of thalamocortical projections from MGv to A2 than those from MGv to A1. The current study identifies that the functional organization in the auditory cortex can be determined by the structure of thalamocortical input.Significant StatementAlthough peripheral input patterns to the primary auditory cortex (A1) of the brain are well understood, how tonal information is relayed to higher-order regions such as the secondary auditory field (A2) remains unclear. This work revealed a new source of auditory information to A2; the tonal map in mouse A2 is primarily produced by orderly projections from the primary auditory thalamus. We also found that the complex behaviour and organization of neurons in A2 is generated by divergent projections from the primary thalamus that converge on neurons in A2. Our findings indicate that thalamocortical projections constitute a major factor that determines the regional properties and functional organization of mouse A2.