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Impact of immune cell-derived exosomes and miRNAs on brain function and behavior

Award Number: R01MH113645
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/16/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Impact of immune cell-derived exosomes and miRNAs on brain function and behavior - ABSTRACT Adaptive immune cells in the periphery (T and B cells) and innate immune cells in the brain (microglia) have been implicated in the brain homeostasis in health and disease. Rodent studies using immunodeficient mice have revealed that the loss of adaptive immune cells (T and B cells) led to impaired learning and memory, anxiety-like behaviors, and impaired sociability. Nevertheless, it is not clear how adaptive immune cells communicate with microglia and affect brain development and function. Our long-term goal is to understand the molecular and cellular mechanisms underlying the communication between adaptive immune cells and brain cells during brain development and in adulthood. Our preliminary studies revealed that Rag1-/- and [Rag2- /-mice], lacking both T and B cells, exhibited impaired social behaviors. In Rag1-/- mice, increased c-Fos expression and altered microglial phenotypes in the medial prefrontal cortex (mPFC) were observed. This is consistent with previous reports that mPFC dysfunction is involved in social behaviors. [Notably, adoptive transfer of wild-type (WT) splenocytes (containing T and B cells) rescued Rag1-/- social behavioral deficits. Further, injection of WT serum exosomes rescued the same phenotype. The social behavioral deficits were also observed in Rag2-/- mice despite the fact that Rag2 is normally absent in the WT brain. Together, these findings suggest that T and B cells contribute to social behaviors via exosomes.] Indeed, we observed that exosomes from the sera of Rag1-/- mice lacked the expression of T and B cell markers and multiple microRNAs (miRNAs) presumably derived from T and B cells. The expression of predicted target gene(s) of these miRNAs, such as Ski, was enhanced in the PFC of Rag1-/- mice. In contrast, WT serum exosomes decreased Ski expression in microglia. Recent studies showed that microglia control neuronal synapses. Thus, our data suggest that deficient adaptive immune cell-microglia communication via exosomes impairs social behaviors by altering mPFC function. Hence, in this study, we will test our hypothesis that the lack of adaptive immune cell-derived exosomes and their miRNAs results in impaired social behaviors via altered microglial control of neuronal function in the medial PFC. We will first validate and extend our findings on serum exosomes and the mPFC neurons in Rag1-/- mice, and determine the causal role for the lack of adaptive immune cells by restoring them back into Rag1-/- mice with adoptive transfer technique (Aim 1). We will also examine the direct impact of impaired exosome release and miRNA production in adaptive immune cells on microglia and neurons in the mPFC and social behaviors by genetic approaches (Aim 2). [In addition, we will address the contribution of pyramidal neurons and microglia in the mPFC to impaired social behaviors (Aim 3).] This study will reveal novel mechanisms whereby adaptive immune cell-derived exosomes influence brain function and behavior and may eventually lead to novel therapeutic strategies in psychiatric disorders.


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 = -$41,027 )
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	5	5/21/2024	NON-COMPETING CONTINUATION	-$41,027
														Subtotal = -$41,027

Issue Date FY: 2022 ( Subtotal = $348,538 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	5	1/5/2022	NON-COMPETING CONTINUATION	$313,685
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	001	5	5/12/2022	NON-COMPETING CONTINUATION	$34,853
														Subtotal = $348,538

Issue Date FY: 2021 ( Subtotal = $717,683 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	002	4	4/16/2021	SUPPLEMENT FOR EXPANSION	$371,250
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	4	12/11/2020	NON-COMPETING CONTINUATION	$311,790
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	001	4	4/12/2021	NON-COMPETING CONTINUATION	$34,643
														Subtotal = $717,683

Issue Date FY: 2020 ( Subtotal = $346,433 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	000	3	1/7/2020	NON-COMPETING CONTINUATION	$346,433
														Subtotal = $346,433

Issue Date FY: 2019 ( Subtotal = $358,558 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	001	2	4/5/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$358,558
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	003	2	4/29/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$56,346
2019	2018	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	000	1	3/21/2019	NEW	$0
2019	2018	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	002	1	4/29/2019	NEW	-$56,346
														Subtotal = $358,558

Issue Date FY: 2018 ( Subtotal = $409,166 )
2018	2018	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	000	1	3/16/2018	NEW	$409,166
														Subtotal = $409,166

Grand Total All Awards = $2,139,351

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Impact of immune cell-derived exosomes and miRNAs on brain function and behavior

Award Number: R01MH113645

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/16/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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