Dissertations, Theses, and Capstone Projects

Date of Degree

6-2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Biology

Advisor

Susana Mingote

Committee Members

Leora Yetnikoff

Joshua Brumberg

Christine Ann Denny

Christoph Kellendonk

Subject Categories

Biology | Neuroscience and Neurobiology

Keywords

Dopamine–glutamate co-transmission, Ventral tegmental area to lateral entorhinal cortex circuit, Aging and novelty discrimination, Lateral entorhinal cortex vulnerability in aging, Dual-color optogenetic closed-loop stimulation and dopamine release dynamics, Pattern separation and episodic memory encoding

Abstract

Cognitive decline during aging emerges long before widespread neuronal loss becomes evident, implying that subtle circuit-level disruptions precede overt neurodegeneration. Preserving brain function across aging requires identifying the specific circuit alterations that drive cognitive decline. The lateral entorhinal cortex (LEC) supports novelty detection and episodic memory and exhibits early vulnerability to aging-related dysfunction. Dopaminergic input from the ventral tegmental area (VTA) to this region modulates novelty, but the impact of aging on this pathway and its role in novelty discrimination remains unclear. Intersectional labeling of VTA dopamine neuron subtypes in young mice showed that the majority (93%) of projections to the LEC arose from a population of dopamine neurons that co-release glutamate. Aged mice showed reduced (~80%) expression of the dopamine–glutamate subset in both the VTA and LEC, whereas pan-dopaminergic labeling displayed preserved LEC axons, indicating a loss of molecular phenotype rather than axonal degeneration.

Within LEC dopaminergic axons, aging reduced tyrosine hydroxylase levels, suggesting diminished dopamine synthesis capacity. Simultaneously, vesicular glutamate transporter 2 expression was relatively conserved, signifying intact vesicular glutamatergic packaging. These age-related molecular changes imply reduced dopamine availability and have functional consequences. Optogenetic stimulation combined with a genetically encoded dopamine sensor demonstrated attenuated dopamine release in aged mice, but only at high frequency stimulation, the condition that placed maximal demand on synthesis. Since dopamine signaling was not abolished with aging, closed-loop wireless optogenetic stimulation of dopaminergic axons in the LEC during object exploration tested whether temporal activation could restore behavioral performance. Optostimulation targeted dopamine release specifically during encoding epochs of the novel object recognition task and produced modest, though quantifiable, improvement of novelty discrimination in aged experimental mice.

These findings indicate that aging selectively compromises a defined neuronal class, rather than uniformly degrading dopaminergic systems. This dissertation establishes that dopamine–glutamate projections to the LEC exhibit selective molecular and functional vulnerability characterized by reduced tyrosine hydroxylase expression, attenuated dopamine release at high demand, and partial behavior rescue following temporally precise stimulation. Together, these results link VTA dopamine–glutamate signaling to the LEC with age-related cognitive deficits and identify this circuit as a potential therapeutic target for supporting healthy brain aging.

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