Aging-related vulnerability in dopamine–glutamate neurons weakens entorhinal dopamine signaling and underlies novelty discrimination deficits

The lateral entorhinal cortex supports novelty detection and episodic memory and is highly vulnerable to aging. Dopamine conveys novelty signals in this region, but how aging alters this input is unknown. Using viral strategies to distinguish ventral tegmental area dopamine neurons with or without glutamate co-release, we show that co-releasing neurons comprise about 30% of dopamine neurons yet provide nearly all dopaminergic input to the lateral entorhinal cortex. In aged mice, these axons show reduced markers of dopamine synthesis and diminished dopamine release during high-frequency activity, whereas glutamate-related markers are reduced to a lesser extent. Stimulation of lateral entorhinal dopaminergic axons during novelty exploration restores novelty discrimination in aged mice. Together, these findings identify the age-related vulnerability of dopamine-glutamate neurons as a circuit-specific mechanism that impairs entorhinal dopamine signaling and underlies to deficits in novelty discrimination.