PROJECT SUMMARY/ABSTRACT Many lung diseases, including asthma, are associated with neurological symptoms such as stress, anxiety and depression. Joining this list is COVID19, where the growing list of post-acute sequelae of SARS-CoV-2 infection (PASC) includes anxiety and depression. Whether and how respiratory infection by SARS-CoV-2 could impact neurological state is not understood. In this supplement, we will continue the theme of the parent award to dissect the functional and neuroanatomical connections between the brain and lung at the molecular and cellular level. We will test the hypothesis that SARS-CoV-2 respiratory infection, acting through chronic changes in lung and the lung-innervating neural circuit, alters neuronal activity and neural inflammation, leading to heightened stress, anxiety and depression. We will use humanized mouse models for SARS-CoV-2 infection to test if respiratory infection alters central nervous system neuronal activity, neural inflammation, gene expression and behavioral changes in the chronic phase of infection (aim 1). We will also use single cell multiome and spatial transcriptomic technologies to define the transcriptomic and epigenomic signature of the human donor lungs in the chronic phase following SARS-CoV-2 infection (aim 2). We anticipate that a comprehensive profile of the brain, the lung, and their connection in the chronic phase of SARS-CoV-2 infection will deepen understanding and inform control of PASC.