Claustrum/dorsal Endopiriform cortex complex cell identity is determined 1 by Nurr1 and regulates hallucinogenic-like states.

The Claustrum/dorsal Endopiriform cortex complex (CLA) is an enigmatic brain region with 19 extensive glutamatergic projections to multiple cortical areas. The transcription factor Nurr1 is 20 highly expressed in the CLA, but its role in this region is not understood. By using conditional 21 gene-targeted mice, we show that Nurr1 is a crucial regulator of CLA neuron identity. Although 22 CLA neurons remain intact in the absence of Nurr1, the distinctive gene expression pattern in 23 the CLA is abolished. CLA has been hypothesized to control hallucinations, but little is known 24 of how the CLA responds to hallucinogens. After the deletion of Nurr1 in the CLA, both 25 hallucinogen receptor expression and signaling are lost. Furthermore, functional ultrasound 26 imaging and Neuropixel electrophysiological recordings revealed that the effects of 27 hallucinogenic receptor agonists on functional connectivity between the prefrontal and 28 sensorimotor cortices are altered in Nurr1-ablated mice. Our findings suggest that Nurr1-29 targeted strategies provide new avenues for functional studies of the CLA.