Characterization of structure-function relationships in distinct thalamic reticular nucleus networks

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PROJECT SUMMARY Nearly all sensory information destined for the neocortex is relayed through the thalamus. The thalamic reticular nucleus (TRN), a thin shell of GABAergic neurons surrounding the dorsal thalamus, receives both collaterals from cortico-thalamic and thalamo-cortical glutamatergic inputs, but exerts its unidirectional powerful inhibition only to the thalamus. TRN thus is considered as a master controller of thalamo-cortical circuits regulating the flow of the information between thalamus and neocortex. Perturbed TRN function may underlie behavioral deficits in disorders ranging from schizophrenia, ADHD and autism. Although the importance of the TRN has long been recognized, our knowledge of its molecular identity of cell types, their organization and their functional properties has lagged behind that of the thalamocortical circuits they control. The paucity of such knowledge has limited our ability to determine exactly how TRN circuitry contributes to various brain functions, a prerequisite for determining how it malfunctions in diseases and how its circuitry can be leveraged for diagnostic and therapeutic purposes. Our most recent work has filled this critical gap in knowledge. By using single nucleus RNAseq, for the first time we have discovered that TRN neurons can be dissociated into two major subtypes with distinct transcriptomic profiles, anatomical localizations, electrophysiological properties and thalamic connectivity. One subtype, located in the “core” region of the TRN and can be marked by the expression of the Spp1 gene, targets first-order sensory thalamic nuclei, and the other, located in the “shell” region of the TRN and marked by the expression of Ecel1 gene, targets higher-order ones. We have generated transgenic mice expressing Cre recombinase in each of these two populations individually. This proposal aims to use these new knowledge and genetic tools to provide a comprehensive map of TRN cell- type specific connectivity patterns, TRN subcircuit electrophysiological properties and synaptic mechanism, and how abnormal function of distinct TRN subcircuits contribute to behavioral deficits of autism spectrum disorder (ASD) using a novel monogenic form of ASD, Ptchd1 deletion mouse model.