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Role of astrocyte-based cholinergic neuromodulation in cognition and in the treatment of cognitive disorders

Award Number: R01MH127163
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Role of astrocyte-based cholinergic neuromodulation in cognition and in the treatment of cognitive disorders - ABSTRACT Neurons are viewed as the cellular correlate of cognition and only target of clinical therapeutics, in part because manipulating neurons rapidly and directly alters behavior. Yet, the human brain is also made of glial cells, which morphological and genetic complexification is a striking feature of the human brain. Astrocytes, in particular, are now known to orchestrate many neural functions, crystalizing the possibility of a direct astrocyte contribution to cognitive functions and mental health. However, a lack of understanding of the rules that govern astrocytes activity and their involvement in neural circuits has limited our ability to test this idea. Collective work recently showed that astrocytes transduce neuromodulatory information onto synaptic circuits. Specifically, we found that α7 nicotinic acetylcholine receptors (α7nAChRs) on astrocytes regulate the release of the astrocyte transmitter D-serine onto synapses. Neuromodulation, in particular cholinergic signaling, permits behavioral adaptations to changes in the environment, and its alteration is linked to cognitive deficits in schizophrenia. Coincidently, the α7nAChR has focalized major drug development efforts in the past decade to restore the cognitive symptoms of patients with schizophrenia. Here, we will take advantage of this new astrocyte-based α7nAChR pathway to test the role of astrocytes in cognitive functions and pro-cognitive interventions, and elucidate the mechanisms through which neuromodulation is sensed and transduced by astrocytes at the cellular and molecular levels. In doing so, we will test a set of general principles which we hypothesize govern input output fidelity in astrocytes (positional coupling). In Aim 1, we will test the hypothesis that α7nAChRs are located in the immediate vicinity of D-serine pools, directly linking Ca2+ influx through α7nAChR channel activity to the Ca2+-dependent D-serine release machinery. We will conduct fluorescence Ca2+ imaging studies to understand the spatial, temporal and molecular rules of α7nAChR-mediated Ca2+ signals and their relation to D-serine release. We will then map the physical association of α7nAChR and D-serine pools in perisynaptic astrocytic processes, using electron microscopy. In addition, we will conduct single-particle tracking studies to understand how the dynamic distribution of α7nAChR at the surface of astrocytes, with respect to D-serine pools, is influenced by the binding of endogenous and exogenous ligands. In Aim 2, we will generate cell-specific knockout mouse lines to selectively ablate α7nAChR from astrocytes, excitatory neurons or inhibitory neurons in the brain, and canvas the contribution of each cell-types to characteristic behaviors supported by α7nAChRs. We recently showed that an α7nAChR partial agonist tested in Phase-III clinical trials for the treatment of cognitive deficits in patients with schizophrenia, elevates D-serine levels in the mouse brain. Based on our observations that inactivating astrocyte-based α7nAChR signaling leads to specific alterations in D-serine levels and cognitive behavior, we will then test the hypothesis that astrocytes, but not neurons, enable the behavioral efficacy of cognitive enhancers tested in clinical trials, and that D-serine signaling is the circuit actuator of these effects.


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 = $334,688 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	5	4/16/2025	NON-COMPETING CONTINUATION	$334,688
														Subtotal = $334,688

Issue Date FY: 2024 ( Subtotal = $393,750 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Mental Health Research Grants	001	4	8/14/2024	NON-COMPETING CONTINUATION	$39,375
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Mental Health Research Grants	000	4	4/5/2024	NON-COMPETING CONTINUATION	$354,375
														Subtotal = $393,750

Issue Date FY: 2023 ( Subtotal = $393,750 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	3	3/17/2023	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2022 ( Subtotal = $393,750 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	2	3/10/2022	NON-COMPETING CONTINUATION	$354,375
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	001	2	6/21/2022	NON-COMPETING CONTINUATION	$39,375
														Subtotal = $393,750

Issue Date FY: 2021 ( Subtotal = $393,750 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	1	5/10/2021	NEW	$393,750
														Subtotal = $393,750

Grand Total All Awards = $1,909,688

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Role of astrocyte-based cholinergic neuromodulation in cognition and in the treatment of cognitive disorders

Award Number: R01MH127163

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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