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Regulation of prefrontal cortical circuit function and reward-seeking behavior by stress-induced dendritic spine remodeling

Award Number: R01MH118451
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Regulation of prefrontal cortical circuit function and reward-seeking behavior by stress-induced dendritic spine remodeling - Project Summary / Abstract Depression is by definition a fundamentally episodic form of mental illness featuring discrete symptomatic periods, interposed between periods of apparent wellness. The neurobiological mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood, especially at the circuit level, but converging evidence indicates that synaptic remodeling in prefrontal cortical (PFC) circuits plays an important role. Still, despite decades of pioneering work in this area, a mechanistic understanding of how postsynaptic dendritic spine remodeling contributes to changes in PFC circuit function and depression- related behaviors over time remains elusive. To date, most studies have relied on cross-sectional comparisons of spine density in fixed tissue at a single time point, obscuring dynamic effects on spine formation, stabilization, and pruning—distinct processes with differing implications for identifying new treatment targets. How stress affects dynamic spine remodeling processes differently in the female PFC is also unclear, despite the fact that sex is a critical risk factor for stress-related psychiatric disorders. Perhaps most importantly, whether spine remodeling causes or merely correlates with behavioral changes and altered function in specific PFC circuits is unknown. This proposal will investigate how stress-induced spine remodeling in the PFC contributes to anhedonia, a core feature of depression. PFC circuits support reward-seeking behavior by mediating action valuation computations, which integrate information about the magnitude of an anticipated reward and the expected effort required to obtain it. Leveraging newly developed optogenetic and 2P imaging methods for visualizing and manipulating spine dynamics and defining their effects on circuit function, we will investigate how spine remodeling in topologically defined projection neuron subtypes contributes to the induction, remission, and recurrence of anhedonic behavioral states. We will use a two-hit stress model, whereby early life stress (ELS) induces heightened stress sensitivity and sex-specific effects on HPA axis reactivity in adulthood, imaging PFC projection neurons before and after chronic stress and longitudinally during recovery. Reward-seeking behavior will be quantified in a 2P imaging-compatible action valuation task, in which we can independently manipulate anticipated reward magnitude and expected effort. We will test the hypothesis that stress disrupts action valuation by selectively eliminating dendritic spines and disrupting multicellular ensemble activity in PFC projections that play a critical role in encoding reward predictive cues. Next, we will test pharmacological and circuit-based strategies for promoting stress resilience and recovery.


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: 2025 ( Subtotal = $718,351 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Mental Health Research Grants	000	7	12/12/2024	NON-COMPETING CONTINUATION	$718,351
2025	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Mental Health Research Grants	001	5	2/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $718,351

Issue Date FY: 2024 ( Subtotal = $845,119 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	001	6	12/5/2023	COMPETING CONTINUATION	$760,608
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Mental Health Research Grants	002	6	5/14/2024	COMPETING CONTINUATION	$84,511
2024	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	000	5	11/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $845,119

Issue Date FY: 2023 ( Subtotal = $585,136 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	001	5	3/2/2023	NON-COMPETING CONTINUATION	$58,512
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	000	5	11/9/2022	NON-COMPETING CONTINUATION	$526,624
														Subtotal = $585,136

Issue Date FY: 2022 ( Subtotal = $585,136 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	001	4	5/23/2022	NON-COMPETING CONTINUATION	$58,511
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	000	4	1/6/2022	NON-COMPETING CONTINUATION	$526,625
														Subtotal = $585,136

Issue Date FY: 2021 ( Subtotal = $585,136 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	000	3	11/6/2020	NON-COMPETING CONTINUATION	$526,625
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	001	3	4/14/2021	NON-COMPETING CONTINUATION	$58,511
														Subtotal = $585,136

Issue Date FY: 2020 ( Subtotal = $630,932 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	001	2	2/3/2020	NON-COMPETING CONTINUATION	$63,093
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	000	2	11/7/2019	NON-COMPETING CONTINUATION	$567,839
														Subtotal = $630,932

Issue Date FY: 2019 ( Subtotal = $627,635 )
2019	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	000	1	12/19/2018	NEW	$627,635
2019	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Mental Health Research Grants	001	1	9/24/2019	NEW	$0
														Subtotal = $627,635

Grand Total All Awards = $4,577,445

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Regulation of prefrontal cortical circuit function and reward-seeking behavior by stress-induced dendritic spine remodeling

Award Number: R01MH118451

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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