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Astrocyte-neuron mechanisms of glutamatergic modulation in social novelty recognition

Award Number: R01MH137204
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/25/2024
PERIOD OF PERFORMANCE END DATE: 01/11/2026

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Astrocyte-neuron mechanisms of glutamatergic modulation in social novelty recognition - Project Summary Social behavior is a fundamental component of complex behaviors for animals to sustain healthy living patterns. Consequently, deficits or dysfunctional social behaviors are found in multiple psychiatric and neurological disorders, such as autism spectrum disorder (ASD). Recently, a growing body of research demonstrates a significant adaptation of astrocytes, non-neuronal glial cells in the brain, in the etiology of ASD. However, the detailed mechanisms underlying how astrocyte dysfunction represents social behavioral deficiency remain poorly understood. Particularly, the challenge is exaggerated by the lack of knowledge about whether and how the local astrocytes affect the ASD-phenotype brain in cell-type, circuit, and network levels. Abnormal glutamatergic transmission contributes to aberrant hyperexcitability in brain regions critical for controlling social behaviors by shifting the excitation-to-inhibition ratio. Excess glutamate is typically cleared from the synaptic cleft into astrocytes via glutamate transporters. Our recent studies revealed that astrocyte activation in the paraventricular nucleus of the thalamus (PVT), a hub of communications in thalamo-cortical circuits where processes the sensitivity to external social environmental stimuli, impairs social novelty recognition while parallelly downregulating functional astrocyte dominant glutamate transporter type 1 (GLT1; EAAT2 in humans). Interestingly, astrocyte-specific conditional knock-out of GLT1 in the PVT mimics the impairment of social novelty recognition, reinforcing the importance of the glutamatergic system in astrocyte-based social behavioral modulation. Thus, based on our findings, we hypothesize that astrocytic modulation of glutamatergic signaling has an important role in the regulation of social novelty recognition. Chemogenetic activation of astrocytes, mimicking reactive calcium-increased astrocytes and sequentially reducing GLT1 function, impairs the normal response of astrocytes in the PVT to neuronal activity and this, in turn, contributes to abnormal social recognition. In contrast, GLT1 overexpression facilitates the maintenance of normal social recognition behaviors. To investigate this hypothesis, first we will investigate the spatiotemporal glutamate and calcium signals synchronized to social behaviors in the astrocytes and neurons and their adaptation by GLT1 modulation. Second, we will examine the contribution of PVT GLT1 null and overexpression in synaptic events and metabolism in the PVT circuits, and consequent social novelty recognition behaviors. Finally, we will determine whether astrocytic glutamate modulation via GLT1 affects the brain-wide spatiotemporal signature, and the brain network coherence provides any distinguishable profiles that represent social behavioral outcomes. Our study will elucidate the detailed mechanisms of astrocyte-neuron interaction via the glutamate system encoding social novelty recognition. We will provide a rational path for the development of new therapeutic methods for the treatment of social behavioral deficits.


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 = $390,000 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Mental Health Research Grants	001	3	5/4/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$390,000
2026	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Mental Health Research Grants	002	2	5/12/2026	NON-COMPETING CONTINUATION	$0
2026	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Mental Health Research Grants	000	2	4/28/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,000

Issue Date FY: 2025 ( Subtotal = $385,000 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Mental Health Research Grants	001	2	9/19/2025	NON-COMPETING CONTINUATION	$57,750
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Mental Health Research Grants	000	2	3/17/2025	NON-COMPETING CONTINUATION	$327,250
														Subtotal = $385,000

Issue Date FY: 2024 ( Subtotal = $385,000 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Mental Health Research Grants	000	1	7/24/2024	NEW	$385,000
														Subtotal = $385,000

Grand Total All Awards = $1,160,000

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Astrocyte-neuron mechanisms of glutamatergic modulation in social novelty recognition

Award Number: R01MH137204

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/25/2024

PERIOD OF PERFORMANCE END DATE: 01/11/2026

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