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Control of ETV1 transcriptional networks in amygdalar astrocytes

Award Number: R01MH132632
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Control of ETV1 transcriptional networks in amygdalar astrocytes - PROJECT ABSTRACT Glial cells of the central nervous system (CNS), such as astrocytes and microglia, are intimately involved in tuning neural circuit activity, which is crucial in brain areas where increased activity leads aberrant behavior. The amygdala is one such limbic brain area that encodes associations between environmental stimuli and fear, and fires only if a threat is detected. The basolateral amygdala (BLA) is the amygdala input nucleus that integrates processed sensory information and initiates fear responses. However, pro-inflammatory signals induced in response to recurrent environmental threats boost BLA activity and increase fear responses. Glial cells in the amygdala are integral for inhibiting inflammatory signals that otherwise drive neural activity and fear behavior. Yet, many pathways in glial cells that tune BLA immune responses underlying fear are unknown. This lack of knowledge is largely due to an absence of methods that profile the mechanisms regulating cross-talk among glial cells at high throughput. Recently, I developed a new forward genetic screening platform to profile molecules controlling cell-cell interactions called SPEAC-seq (Systematic Perturbation of Encapsulated Associated Cells followed by SEQuencing). SPEAC-seq permits the co-encapsulation of cell pairs from differing cell classes within picoliter droplets (e.g., astrocytes and microglia), where prior to encapsulation one cell type expresses an inducible state-dependent fluorescent reporter and the other cell type is randomly perturbed with an sgRNA from a genome-wide CRISPR/Cas9 library. Cell pairs are encapsulated, co-cultured, and then sorted in droplets at high throughput. Isolation of sgRNA sequences from droplets containing an activated cell permits the association of molecular regulators with cellular states. My preliminary SPEAC-seq data uncovered amphiregulin (AREG) in microglia as a negative regulator of pro-inflammatory NF-kB signals in astrocytes by signaling through EGFR. Interestingly, microglia-astrocyte AREG-EGFR signals negatively regulated expression of the BLA-restricted transcription factor ETV1 in astrocytes. In preliminary studies, I found that ETV1 drove pro-inflammatory NF-kB signaling in astrocytes and was induced in response to chronic stress in the BLA. Chemogenetic activation of BLA astrocytes boosted helplessness behavior following chronic stress while genetic perturbation of Areg in BLA microglia or Egfr in BLA astrocytes exacerbated fear responses following chronic stress. Together, these data suggest that AREG+ microglia limit the activation of NF-kB in EGFR+ astrocytes by suppressing ETV1 and stress-induced fear behavior. In this proposal, I hypothesize that AREG+ microglia limit ETV1-driven NF-kB activation in EGFR+ BLA astrocytes to decrease stress-induced fear behavior. In Aim 1, I will test the role of AREG+ BLA microglia in limiting astrocyte ETV1 expression and NF-kB signals. In Aim 2, I will uncover the transcriptional and epigenetic networks of ETV1 and its family members in BLA astrocytes by multi-omic Perturb- seq. In Aim 3, I will determine how acute or chronic activation of ETV1+ astrocytes controls fear behavior. IN SUM, this R01 proposal will study how an anti-inflammatory cell circuit in the BLA shapes stress-induced fear.


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 = $434,860 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	3	12/3/2025	NON-COMPETING CONTINUATION	$434,860
														Subtotal = $434,860

Issue Date FY: 2025 ( Subtotal = $434,860 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	2	11/20/2024	NON-COMPETING CONTINUATION	$369,631
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	2	9/18/2025	NON-COMPETING CONTINUATION	$65,229
														Subtotal = $434,860

Issue Date FY: 2024 ( Subtotal = $434,860 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	1	5/7/2024	NEW	$43,486
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	11/30/2023	NEW	$391,374
														Subtotal = $434,860

Grand Total All Awards = $1,304,580

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Control of ETV1 transcriptional networks in amygdalar astrocytes

Award Number: R01MH132632

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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