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.
