Regulation of short-term declarative memory by selective activation of the locus coeruleus-retrosplenial cortex dopaminergic pathway and its pathological alterations in Parkinson's disease.

Abstract

Short-term declarative memory impairment, encompassing deficits in spatial working memory and object recognition, represents a prevalent non-motor symptom of Parkinson's disease (PD). Despite its clinical significance, the neural circuit mechanisms underlying this cognitive dysfunction remain poorly understood. Here, we identify a previously underappreciated dopaminergic projection from the locus coeruleus (LC) to the retrosplenial cortex (RSC) as a critical regulator of short-term declarative memory. Using optogenetic activation of LC dopaminergic neurons, we evoked dopamine release in the RSC and combined this manipulation with fiber photometry to monitor calcium dynamics during short-term declarative memory tasks, including the Y-maze and novel object recognition (NOR). These experiments revealed task-dependent activation of the LC-RSC pathway. Notably, this pathway exhibited functional impairment in PD model mice, as LC-evoked dopaminergic signals in the RSC were markedly attenuated and accompanied by reduced tyrosine hydroxylase expression in the LC. To establish causality, we selectively inhibited the LC-RSC pathway using a chemogenetic approach, which recapitulated deficits in spatial working memory and object recognition and disrupted local field potential (LFP) activity in the RSC, demonstrating that this pathway is necessary for normal short-term declarative memory processing. Collectively, these findings demonstrate that the LC-RSC dopaminergic pathway plays a pivotal role in mediating PD-related short-term declarative memory impairment, providing a circuit-level framework and potential therapeutic target for early cognitive intervention in PD.