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Dynamic Cellular Interactions Associated with Inflammatory Monocyte Accumulation in the Neurovasculature with Social Stress

Award Number: R01MH119670
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Program Director/Principal Investigator (Sheridan, JF & Godbout JP): PROJECT SUMMARY/ABSTRACT: Dynamic inflammatory signaling in the brain may have a causative role in anxiety. We report that repeated social defeat (RSD) in mice induces sympathetic-mediated release of primed monocytes from the bone marrow that are actively recruited to the brain. Collectively, we show that RSD promotes prolonged anxiety-like behavior that depends on activation of microglia and recruitment of inflammatory monocytes to threat appraisal regions of the brain. This application demonstrates that microglial recruitment of IL-1ß producing monocytes to neurovascular endothelium is necessary for the potentiation of anxiety-like behavior in response to social stress. Despite this knowledge, three key mechanistic questions remain to be answered, which will allow for the development of novel interventions for treatment of neuropsychiatric complications associated with stress: 1) How does RSD activate microglia in threat appraisal regions? 2) How are inflammatory monocytes selectivity recruited to neurovascular endothelium in threat appraisal regions? 3) What are the key factors produced by neurovascular endothelia cells that potentiate neuroinflammation and anxiety? We show that microglial activation in response to RSD depends on neuronal activation within threat appraisal regions. Moreover, preliminary evidence suggests that this is mediated by activation of the purinergic receptor, P2RX7, on microglia. Novel data presented here show that monocyte recruitment and the development of anxiety-like behavior after RSD requires microglial activation. Furthermore, cell-specific transcriptional profiling indicates that microglia recruit monocytes to the brain via chemokine ligand (CCL2) secretion. These recruited monocytes produce IL-1¿¿and promote anxiety-like behavior by endothelial IL-1 Receptor-1 activation. Notably, this IL-1R1 activation is associated with increased neurovascular expression of COX2, the enzyme that synthesizes neuroactive prostaglandins. Thus, the goal of this project is to test the hypothesis that recruitment and subsequent interaction of inflammatory monocytes with neurovascular endothelial cells is critical for the augmentation of neuroinflammation and potentiation of anxiety-like behavior following RSD. To address this hypothesis, three specific aims are proposed. In Aim-1, we will ascertain the extent to which RSD-induced microglial activation is dependent on stimulation of the P2RX7 purinergic receptor. In Aim-2, we will determine the degree to which microglial production of CCL2 is required for monocyte recruitment to threat appraisal regions and the induction of anxiety-like behavior after RSD. In Aim-3, we will assess the role of endothelial COX2 following RSD and determine other key factors produced by IL-1R1-stimulated endothelial cells that facilitate anxiety-like behavior after RSD. Understanding how microglial recruitment of IL-1ß producing monocytes to threat appraisal regions potentiates neuroinflammation and anxiety-like behavior will lead to new interventions for neuropsychiatric complications associated with stress. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


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: 2023 ( Subtotal = $515,642 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	000	5	1/19/2023	NON-COMPETING CONTINUATION	$515,642
														Subtotal = $515,642

Issue Date FY: 2022 ( Subtotal = $515,642 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	001	4	5/23/2022	NON-COMPETING CONTINUATION	$51,564
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	000	4	1/13/2022	NON-COMPETING CONTINUATION	$464,078
														Subtotal = $515,642

Issue Date FY: 2021 ( Subtotal = $515,642 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	000	3	2/9/2021	NON-COMPETING CONTINUATION	$515,642
														Subtotal = $515,642

Issue Date FY: 2020 ( Subtotal = $542,782 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	000	2	1/23/2020	NON-COMPETING CONTINUATION	$542,782
														Subtotal = $542,782

Issue Date FY: 2019 ( Subtotal = $542,782 )
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	000	1	2/22/2019	NEW	$542,782
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Mental Health Research Grants	001	1	9/24/2019	NEW	$0
														Subtotal = $542,782

Grand Total All Awards = $2,632,490

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Dynamic Cellular Interactions Associated with Inflammatory Monocyte Accumulation in the Neurovasculature with Social Stress

Award Number: R01MH119670

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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