The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, is known to regulate thalamocortical interactions critical for sensory processing, attention and cognition 1 - 5 . TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders 6 - 9 . Currently, little is known about the organizational principles underlying its divergent functions. We performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that TRN cellular heterogeneity is characterized by a transcriptomic gradient of two negatively correlated gene expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core/shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections to the functionally distinct first-order and higher-order thalamic nuclei to form molecularly defined TRN-thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. Taken together, our study provides a comprehensive atlas for TRN neurons at the single-cell resolution, and links molecularly defined subnetworks to the functional organization of the thalamo-cortical circuits.

Fundamental questions regarding collagen biosynthesis, especially with respect to the molecular origins of homotrimeric versus heterotrimeric assembly, remain unanswered. Here, we demonstrate that the presence or absence of a single cysteine in type-I collagen’s C-propeptide domain is a key factor governing the ability of a given collagen polypeptide to stably homotrimerize. We also identify a critical role for Ca2+ in non-covalent collagen C-propeptide trimerization, thereby priming the protein for disulfide-mediated covalent immortalization. The resulting cysteine-based code for stable assembly provides a molecular model that can be used to predict, a priori, the identity of not just collagen homotrimers, but also naturally occurring 2:1 and 1:1:1 heterotrimers. Moreover, the code applies across all of the sequence-diverse fibrillar collagens. These results provide new insight into how evolution leverages disulfide networks to fine-tune protein assembly, and will inform the ongoing development of designer proteins that assemble into specific oligomeric forms.

Neither cetirizine nor loratadine inhibited codeine-induced histamine release or modified the time course of its release in human skin in vivo when given in clinically used doses which are sufficient to significantly reduce weal and flare responses.