PROJECT SUMMARY Sustained attention deficits are a prominent cognitive symptom in neuropsychiatric disorders such as schizophrenia, attention-deficit hyperactivity disorder, and major depressive disorder as well as in age-related neurodegenerative disorders, including Alzheimer’s disease. In humans, continuous performance tests (CPTs) are commonly used to assess sustained attention in patients with these neuropsychiatric diseases. The anterior cingulate cortex (ACC) is essential for normal CPT performance, and patient populations often exhibit aberrant ACC function during the CPT. These results are in line with an established role for the ACC in attention-guided behavior, and point to a role for the ACC in the pathophysiology of attentional deficits in complex brain disorders. However, the cellular and molecular mechanisms that underlie the role of the ACC to regulate sustained attention remain unclear. This lack of knowledge is important because identifying these mechanisms is critical for developing targeted treatments for attention deficits. This application investigates links between expression of novel molecular and cellular targets, neural activity patterns in ACC circuits and attentional performance. Our preliminary data suggest that projection-specific pathways between the locus coeruleus (LC) and the ACC regulate distinct aspects of attention-guided behavior during the CPT. Specifically, we identified the gene encoding Apolipoprotein E (Apoe), which has been implicated in attention and disorders associated with disorders featuring deficits in attention, as a potential molecular player underlying regulation of sustained attention in the LC-ACC circuit. We leverage genetic and circuit-specific tools to dissect the molecular, cellular and circuit underpinnings of sustained attention during a touchscreen-based rodent analog of the human CPT (rCPT) in mice. Specifically, we 1) test causal relationships between Apoe gene expression, physiological function in the LC-ACC circuit and attentional performance, and 2) identify cell types and circuit- specific molecular targets in the rodent and human ACC that are critical for sustained attention. To achieve these aims we integrate a variety of molecular and systems level approaches including in vivo electrophysiology, single-cell RNA-sequencing, and CRISPR-dCas9 mediated epigenome editing coupled with quantification of attention-guided behavior. For the sequencing studies, we capitalize on the power of molecular genetic tools to target and manipulate cell-specific populations within the LC-ACC circuit in the mouse and use these data to genetically identify circuit-specific cell types in data from postmortem human brain tissue. This cross-species analysis supports our long-term goal of identifying and prioritizing therapeutic targets for disorders that feature attentional deficits. The proposed research is significant because the results will significantly advance our understanding of the circuit and molecular mechanisms underlying sustained attention, as well as provide potential avenues for anatomically and genetically-localized therapeutic targeting in disorders featuring dysregulation of attention.

PROJECT NARRATIVE Sustained attention deficits are a prominent cognitive symptom in neuropsychiatric disorders such as schizophrenia, attention-deficit hyperactivity disorder, and major depressive disorder as well as in age-related neurodegenerative disorders, including Alzheimer’s disease. In this proposal we investigate the cellular and molecular signaling pathways that govern connectivity in brainstem to cortical circuits involved in sustained attention. This proposal is relevant to the part of the NIH mission that pertains to the translation of basic mechanisms causing neurodevelopmental disorders and mental illnesses into innovative treatments.