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 involving VM in mice of either sex. 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 GABA_A 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.<b>Significance statement</b> Here we use anatomy, slice physiology, and optogenetics to examine how subcortical inputs are routed through the ventral medial thalamus (VM) to the medial prefrontal cortex (mPFC). We first find that the main subcortical input to thalamocortical (TC) cells arises from substantia nigra pars reticulata (SNr), rather than cerebellum or internal globus pallidus. We then use electrophysiology and optogenetics to show that SNr input is inhibitory, mediated by GABA_A receptors, and sufficient to silence TC cell firing. Lastly, we demonstrate that SNr inputs are channeled via TC cells in VM to engage NDNF+ interneurons in layer 1 (L1) of the mPFC. Together, our findings illustrate how subcortical inputs can signal through higher-order thalamus to influence frontal cortical circuits.