Distinct structural and functional connectivity of genetically segregated thalamoreticular subnetworks

• Published in: Cell reports (Cambridge) 2024-12, Vol.43 (12), p.115037, Article 115037
• Main Authors: Hartley, Nolan D., Krol, Alexandra, Choi, Soonwook, Rome, Nita, Levandowski, Kirsten, Pasqualoni, Samuel, Jones, Carter, Tian, Jiawen, Lee, Sihak, Lee, Husang, Kast, Ryan, Feng, Guoping, Fu, Zhanyan
• Format: Article
• Language: English
• Subjects: CP: Neuroscience; EEG; electrophysiology; neurodevelopmental disorders; neuropsychiatric disorders; thalamic reticular nucleus, TRN; thalamocortical circuits; TRN subnetwork synaptic connectivity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.115037

The thalamic reticular nucleus (TRN), the major inhibitory source of the thalamus, plays essential roles in sensory processing, attention, and cognition. However, our understanding of how TRN circuitry contributes to these diverse functions remains limited, largely due to the lack of genetic tools for selectively targeting TRN neurons with discrete structural and physiological properties. Here, we develop Cre mouse lines targeting two genetically segregated populations of TRN neurons that engage first-order (FO) and higher-order (HO) thalamic nuclei, respectively. In addition to substantially distinct electrophysiological properties, these TRN subnetworks are further distinguished by biases in top-down cortical and bottom-up thalamic inputs, along with significant differences in brain-wide synaptic convergence. Furthermore, we demonstrate that dysfunction of each subnetwork results in distinct cortical electroencephalogram (EEG) and sensory processing deficits commonly observed in neuropsychiatric disorders, underscoring the potential involvement of TRN subnetworks in the pathophysiology of these conditions. [Display omitted] •Generation of Spp1-Cre and Ecel1-Cre mice provides access to FO and HO TRN subnetworks•Spp1 and Ecel1 TRN subnetwork neurons have distinct passive and active membrane properties•Cortical and thalamic afferents are differentially biased onto Spp1 and Ecel1 TRN neurons•FO vs. HO TRN subnetwork dysfunction produces distinct cortical sensory processing deficits Hartley et al. generate Spp1-Cre and Ecel1-Cre mouse lines targeting genetically segregated thalamoreticular subnetworks to identify diverse differences in physiology and brain-wide synaptic inputs to the TRN. They further demonstrate how dysfunction of the FO and HO TRN subnetworks contributes to distinct cortical sensory processing deficits typical of psychiatric endophenotypes.