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Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors

Award Number: R01MH104559
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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Multiple clinical studies suggest that heightened peripheral inflammation contributes to major depressive disorder (MDD) pathogenesis. Co-morbidity of inflammatory disease with MDD is highly prevalent, and MDD patients have a higher risk of developing those diseases. It has been hypothesized that circulating inflammatory molecules are released following chronic stress, penetrate the blood brain barrier (BBB), and affect neural circuits, mediating stress vulnerability and depression. However, despite years of intensive research into the role of cytokines in depression, we have very little direct evidence of how cytokines enter the brain and in which circuits they act. Recently, we have begun to investigate the effect of chronic social defeat stress (CSDS), a mouse model of stress that induces depression-like behavior, on BBB permeability. Endothelial cells and astrocytes play critical roles in maintaining vascular impermeability. Endothelial cells, via expression of tight junction proteins, establish the paracellular barrier between the perivascular space and brain parenchyma. Breakdown of the endothelial barrier can lead to infiltration of peripheral immune signals— such as IL-6—that we have shown previously to increase stress susceptibility. Our new data shows that 10 days of CSDS downregulates expression of the tight junction protein Cldn5 in the NAc of stress-susceptible mice leading to loss of integrity of the endothelial barrier, immune infiltration and expression of depression-like behaviors. Expanding upon these preliminary observations, we will probe the detailed molecular and cellular mechanisms by which peripheral immune signals interface with mood-related brain circuitry to control depression-like behaviors following social stress. By understanding how chronic stress affects the BBB we may be able to augment current antidepressant treatment or design new therapeutic strategies promoting vascular health by preventing BBB degeneration.


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: 2024 ( Subtotal = $758,655 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	11	12/13/2023	COMPETING CONTINUATION	$758,655
														Subtotal = $758,655

Issue Date FY: 2023 ( Subtotal = $632,786 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	10	11/3/2022	NON-COMPETING CONTINUATION	$569,508
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	10	2/2/2023	NON-COMPETING CONTINUATION	$63,278
														Subtotal = $632,786

Issue Date FY: 2022 ( Subtotal = $632,786 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	9	5/12/2022	NON-COMPETING CONTINUATION	$63,279
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	9	11/1/2021	NON-COMPETING CONTINUATION	$569,507
														Subtotal = $632,786

Issue Date FY: 2021 ( Subtotal = $632,786 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	8	10/30/2020	NON-COMPETING CONTINUATION	$569,507
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	8	5/11/2021	NON-COMPETING CONTINUATION	$63,279
														Subtotal = $632,786

Issue Date FY: 2020 ( Subtotal = $1,089,839 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	7	2/3/2020	NON-COMPETING CONTINUATION	$66,609
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	7	11/5/2019	NON-COMPETING CONTINUATION	$599,480
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	002	7	8/18/2020	SUPPLEMENT FOR EXPANSION	$423,750
														Subtotal = $1,089,839

Issue Date FY: 2019 ( Subtotal = $666,089 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	004	6	9/24/2019	COMPETING CONTINUATION	$0
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	003	6	4/3/2019	COMPETING CONTINUATION	$50,926
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	6	12/19/2018	COMPETING CONTINUATION	$666,089
2019	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	002	5	4/3/2019	NON-COMPETING CONTINUATION	-$50,926
2019	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	5	12/14/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $666,089

Issue Date FY: 2018 ( Subtotal = $596,882 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	5	5/17/2018	NON-COMPETING CONTINUATION	$596,882
														Subtotal = $596,882

Issue Date FY: 2017 ( Subtotal = $596,882 )
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	4	5/20/2017	NON-COMPETING CONTINUATION	$596,882
														Subtotal = $596,882

Issue Date FY: 2016 ( Subtotal = $596,882 )
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Mental Health Research Grants	000	3	5/18/2016	NON-COMPETING CONTINUATION	$596,882
														Subtotal = $596,882

Issue Date FY: 2015 ( Subtotal = $596,882 )
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Mental Health Research Grants	000	2	6/20/2015	NON-COMPETING CONTINUATION	$596,882
														Subtotal = $596,882

Issue Date FY: 2014 ( Subtotal = $663,201 )
2014	2014	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Mental Health Research Grants	000	1	7/23/2014	NEW	$663,201
														Subtotal = $663,201

Grand Total All Awards = $7,463,670

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Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors

Award Number: R01MH104559

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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