Pathway-specific vulnerability of dopamine-glutamate neurons in aging and memory

The National Institute on Aging, a component of the Department of Health and Human Services, awarded $397,689 to the Research Foundation of The City University of New York (doing business as RFCUNY - Advanced Science Research Center) on September 1, 2026, under the Aging Research program (CFDA 93.866) for Project Grant R01AG103127. The award funds research into pathway-specific vulnerability of dopamine-glutamate neurons in aging and memory.

The research examines how dopamine neurons co-releasing glutamate in the ventral tegmental area deteriorate with age and their contribution to cognitive decline. The work employs intersectional viral strategies to characterize dopamine neuron subpopulations, combining fiber photometry, patch-clamp electrophysiology, and matrix-assisted laser desorption/ionization imaging to map age-related dysfunction across specific neural pathways projecting to the lateral entorhinal cortex and nucleus accumbens shell. The research hypothesizes that progressive deterioration of dopamine-glutamate neuron function produces pathway-specific behavioral deficits, initially impairing memory and later extending to motivation, and will assess molecular markers necessary for dopamine-glutamate co-release that decline with age.

Performance occurs in New York, New York. The period of performance extends from September 1, 2026, through May 31, 2031.

Abstract

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.