Substantia nigra pars reticulata regulates prefrontal cortex via ventromedial thalamus

The ventromedial thalamus (VM) innervates layer 1 (L1) of the medial prefrontal cortex (mPFC) to influence executive function and arousal. Thalamocortical (TC) cells in VM process inputs from cortex that are important for generating persistent activity in closed reciprocal loops. However, little is known about connectivity and influence of subcortical inputs to TC cells, and how they are routed through VM to circuits in the mPFC. Here we use anatomical tracing, electrophysiology, and optogenetics to investigate subcortico-thalamo-cortical circuits in mouse VM. We first characterize the morphology and physiology of TC cells in VM and determine their main subcortical input arises from substantia nigra pars reticulata (SNr). We then show how SNr inputs make strong inhibitory connections onto TC cells, which are mediated by GABAA receptors and effectively suppress action potential firing. Lastly, we utilize intersectional approaches to show how SNr inputs are channeled via TC cells in VM to engage specific inhibitory networks in L1 of mPFC. Together, our results indicate how subcortical inputs engage higher-order thalamus to influence the frontal cortex, highlighting differences from equivalent circuits in motor systems.