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Neural Circuit Control of Postnatal Quiescent Neural Stem Cell Activation

Award Number: R01MH105416
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/19/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Neural Circuit Control of Postnatal Quiescent Neural Stem Cell Activation - ABSTRACT It has become increasingly clear that systemic signals and external stimuli can alter neurodevelopmental programs, and that early developmental defects become significant contributors to behavioral sequelae later in life. Despite our current understanding of neurogenesis control, it remains largely unclear what functions neural circuit activity patterns may exert on NSC proliferation and differentiation during development. The rodent postnatal lateral ventricular (LV) germinal matrix/neurogenic niche is a specialized environment housing GFAP+ astrocytes functioning as NSCs, producing mainly GABAergic interneurons. It is analogous to the postnatal human LV germinal matrix, where robust neurogenesis persists for up to two years after birth. The postnatal LV niche serves as an excellent model system to study molecular mechanisms regulating neurogenesis, both in health and in disease states. Postnatal LV neurogenesis is regulated by NSC-intrinsic mechanisms, interacting with extracellular/niche-driven cues. It has been generally accepted that these local effects are responsible for sustaining neurogenesis, though behavioral paradigms and disease states have suggested possibilities for neural circuit-level modulations. It is currently unclear if activity patterns from groups of neurons, or discrete neural circuits, can respond to external stimuli and control NSC proliferation in the postnatal brain. We have identified long-range neuronal projections that can provide excitatory drive to local neurons within the postnatal LV niche. Our preliminary results have uncovered putative downstream targets of this previously undescribed neural circuit, the quiescent NSCs, suggesting an exciting connection between external inputs and NSC activation. We plan to further explore these observations by determining the following: 1) the cellular identity of the postnatal LV quiescent NSCs; 2) which brain regions can serve as a relay for external stimuli to induce LV NSC proliferation; and 3) which postnatal radial glial progenitors, and their activity-dependent maturation process, are responsible for constructing the neural circuits to direct quiescent NSC activation. Our proposal explores a direct connection between neuronal activity patterns from discrete circuits and postnatal NSC proliferation. To make this research question tractable, we have developed new mouse reagents, as well as experimental platforms to measure the interactions between patterns of neuronal activity and NSC proliferation. We believe findings from these experiments will significantly advance our understanding of how neural circuit activity controls stem cell proliferation in the postnatal brain in health and 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 = $513,687 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Mental Health Research Grants	000	10	4/23/2024	NON-COMPETING CONTINUATION	$513,687
														Subtotal = $513,687

Issue Date FY: 2023 ( Subtotal = $513,687 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Mental Health Research Grants	000	9	5/24/2023	NON-COMPETING CONTINUATION	$513,687
														Subtotal = $513,687

Issue Date FY: 2022 ( Subtotal = $513,687 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	000	8	4/13/2022	NON-COMPETING CONTINUATION	$513,687
														Subtotal = $513,687

Issue Date FY: 2021 ( Subtotal = $513,687 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	001	7	4/7/2021	NON-COMPETING CONTINUATION	$513,687
2021	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	000	6	12/18/2020	COMPETING CONTINUATION	$0
														Subtotal = $513,687

Issue Date FY: 2020 ( Subtotal = $534,283 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	001	6	6/15/2020	COMPETING CONTINUATION	$534,283
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	003	6	9/2/2020	COMPETING CONTINUATION	$11
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	002	5	9/2/2020	NON-COMPETING CONTINUATION	-$11
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	000	5	4/15/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $534,283

Issue Date FY: 2019 ( Subtotal = $397,500 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	000	5	10/26/2018	NON-COMPETING CONTINUATION	$397,500
														Subtotal = $397,500

Issue Date FY: 2018 ( Subtotal = $397,500 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	000	4	10/26/2017	NON-COMPETING CONTINUATION	$357,750
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	001	4	6/15/2018	NON-COMPETING CONTINUATION	$39,750
														Subtotal = $397,500

Issue Date FY: 2017 ( Subtotal = $397,500 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	001	3	5/7/2017	NON-COMPETING CONTINUATION	$39,750
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	000	3	11/1/2016	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $397,500

Issue Date FY: 2016 ( Subtotal = $397,500 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	001	2	3/12/2016	NON-COMPETING CONTINUATION	$39,750
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	000	2	11/11/2015	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $397,500

Issue Date FY: 2015 ( Subtotal = $394,166 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Mental Health Research Grants	000	1	11/14/2014	NEW	$394,166
														Subtotal = $394,166

Grand Total All Awards = $4,573,197

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Neural Circuit Control of Postnatal Quiescent Neural Stem Cell Activation

Award Number: R01MH105416

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/19/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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