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Defining neuron- and microglia-specific contributions to prefrontal cortex dysfunction in chronic stress

Award Number: R01MH123545
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/06/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Defining neuron- and microglia-specific contributions to prefrontal cortex dysfunction in chronic stress - PROJECT SUMMARY/ ABSTRACT: Clinical and preclinical studies have linked synapse loss and impaired prefrontal cortex (PFC) function to behavioral and cognitive symptoms of psychiatric diseases, such as major depressive disorder (MDD). Preclinical models, such as chronic unpredictable stress (CUS), are important tools to study these pathophysiological mechanisms as they recapitulate key neurobiological (i.e., synapse loss in PFC) and behavioral (i.e., anhedonia, working memory impairment) aspects of MDD. This is significant because exposure to psychosocial or environmental stressors increases risk of development and recurrence of psychiatric disease. Accumulating evidence shows that the brain-resident macrophages, microglia, have an active role in regulating neuroplasticity in physiological and pathological conditions. In support of this work, research in our lab indicates that dynamic neuron-microglia interactions contribute to neurobiological and behavioral consequences following chronic stress. In particular, CUS increases neuronal colony stimulating factor-1 (CSF1) signaling in the medial PFC, which provokes microglia-mediated neuronal remodeling that contributes to synaptic deficits and behavioral and cognitive consequences. Stress-induced release of glucocorticoids are implicated in the pathophysiology of psychiatric diseases. The actions of glucocorticoids are mediated by glucocorticoid receptors (GR), which regulate gene transcription. Indeed prior work shows that GR signaling alters gene networks that drive structural remodeling and synapse loss on pyramidal neurons in the PFC. Our recent studies indicate that GR signaling induces neuronal CSF1 signaling in the PFC and provokes microglia-mediated neuronal remodeling in the PFC, which contributes to development of depressive behaviors after CUS. This work also revealed that GR signaling regulates specific molecular pathways in neurons (REDD1; regulated in development and DNA damage response 1) and microglia (TNFα; tumor necrosis factor-α). These findings are relevant because both neuronal REDD1 and microglial TNFα have critical roles in regulating synaptic plasticity. Studies in this application will determine the contributions of neuronal or microglial GR signaling and respective downstream mediators in the pathophysiology underlying behavioral consequences of chronic stress. Here we will use brain region- and cell type-specific genetic and pharmacological manipulations to test two specific aims: 1) Define the role of neuronal GR signaling and downstream REDD1 in stress-induced CSF1 signaling, microglia-mediated neuronal remodeling, and associated behavioral consequences; and 2) Examine the role of microglial GR signaling and downstream TNFα in stress- induced microglia-mediated neuronal remodeling, synaptic deficits, and associated behavioral consequences. These studies are significant because they will identify molecular and cellular adaptations that initiate stress- induced synapse loss in the PFC. We expect to generate novel insight into cell type-specific pathways that drive the neurobiology of stress, which may guide treatment strategies for psychiatric disease.


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 = $384,117 )
2024	2024	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	001	5	8/14/2024	NON-COMPETING CONTINUATION	$38,411
2024	2024	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	000	5	2/15/2024	NON-COMPETING CONTINUATION	$345,706
														Subtotal = $384,117

Issue Date FY: 2023 ( Subtotal = $391,435 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	000	4	2/15/2023	NON-COMPETING CONTINUATION	$391,435
														Subtotal = $391,435

Issue Date FY: 2022 ( Subtotal = $391,435 )
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	000	3	2/18/2022	NON-COMPETING CONTINUATION	$352,289
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	001	3	6/7/2022	NON-COMPETING CONTINUATION	$39,146
														Subtotal = $391,435

Issue Date FY: 2021 ( Subtotal = $391,435 )
2021	2021	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	000	2	2/19/2021	NON-COMPETING CONTINUATION	$391,435
														Subtotal = $391,435

Issue Date FY: 2020 ( Subtotal = $422,347 )
2020	2020	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Mental Health Research Grants	000	1	5/6/2020	NEW	$422,347
														Subtotal = $422,347

Grand Total All Awards = $1,980,769

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Defining neuron- and microglia-specific contributions to prefrontal cortex dysfunction in chronic stress

Award Number: R01MH123545

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/06/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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