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Pathway-Specific Vulnerability of Dopamine-Glutamate Neurons in Aging and Memory

Award Number: R01AG103127
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Pathway-Specific Vulnerability of Dopamine-Glutamate Neurons in Aging and Memory - Project Summary Dopamine (DA) neurons in the ventral tegmental area (VTA) play a crucial role in memory and otivation, and their function declines with age. Imaging studies have consistently shown that age-related DA deficits are not uniform, possibly targeting different subpopulations. Yet, to this day, we do not know which DA neuron subpopulations are most vulnerable to aging and their contribution to cognitive deficits. This circuit-specific dysfunction may explain why brain-wide DA interventions yield mixed cognitive results. To address this knowledge gap, we used intersectional viral strategies to label different DA subpopulations. We found that DA neurons co- releasing glutamate (DA-GLU neurons) are particularly vulnerable to aging. VTA DA-GLU neurons project densely to the lateral entorhinal cortex (LEC) and nucleus accumbens (NAc) shell, regions crucial for memory and motivation, respectively. The deterioration of DA-GLU neurons with aging is observed in LEC DA terminals as early as 14 months but only progresses to the NAc shell by 24 months. We hypothesize that the progressive deterioration of DA-GLU neuron function with aging results in pathway-specific and age-specific behavioral deficits, which initially impair memory and later extend their effects to memory and motivation. We will address the central hypothesis in 3 aims. Aim 1 will determine the impact of age-related DA- GLU neuron deterioration on DA and GLU release across by combining data from Fiber photometry, patch-clamp techniques and Matrix Assisted Laser Desorption/Ionization (MALDI) imaging. This research will provide a comprehensive anatomical roadmap of pathway-specific DA dysfunctions in aging. Since molecular markers necessary for the co-release of DA and GLU from VTA DA neurons decrease with age (i.e., tyrosine hydroxylase, TH, and Vesicular GLU transporter 2, VGLUT2), Aim 2 will parse the selective contribution of TH (Aim 2.1) and VGLUT2 (Aim 2.2) from DA-GLU neurons to age-related deficits in novelty discrimination (LEC- dependent behavior) and behavioral switching (NAc-dependent behavior). Finally, Aim 3 will determine how aging affects novelty-induced dopamine release in the LEC and NAc shell using fiber photometry and DA sensors. This aim will investigate how changes DA dynamics correlate with behavioral performance in novelty discrimination and behavioral switching tasks (Aim 3.1). We will then use closed-loop optostimulation to activate DA terminals in the LEC and NAc shell of old mice and establish strategies to reverse the age-associated behavioral defects. Understanding circuits and mechanisms impacted by the decline of DA system in aging will uncover new strategies that mitigate age-related cognitive 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 = $397,689 )
2026	2026	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	85 SAINT NICHOLAS TER	NEW YORK	NY	10031	NEW YORK	USA	Aging Research	000	1	9/1/2026	NEW	$397,689
														Subtotal = $397,689

Grand Total All Awards = $397,689

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Pathway-Specific Vulnerability of Dopamine-Glutamate Neurons in Aging and Memory

Award Number: R01AG103127

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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