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Molecular, cellular and physiological correlates of sustained attention in the locus coeruleus to anterior cingulate cortex circuit

Award Number: R21MH130066
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2023
PERIOD OF PERFORMANCE END DATE: 09/12/2025

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Molecular, cellular and physiological correlates of sustained attention in the locus coeruleus to anterior cingulate cortex circuit - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2023	LIEBER INSTITUTE INC	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	1	1/23/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $443,671 )
2023	2023	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Mental Health Research Grants	000	1	9/13/2023	NEW	$443,671
														Subtotal = $443,671

Grand Total All Awards = $443,671

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Molecular, cellular and physiological correlates of sustained attention in the locus coeruleus to anterior cingulate cortex circuit

Award Number: R21MH130066

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/13/2023

PERIOD OF PERFORMANCE END DATE: 09/12/2025

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