Facilitating Memory Consolidation through Light Exercise: The Role of the Locus Coeruleus-Hippocampal Dopaminergic Pathway

Introduction : Exercise benefits the hippocampus and promotes learning and memory.We have focused on light exercise (LEX) and have revealed that this accessible form of exercise can effectively increase hippocampal activity and enhance memory performance.However, the neural mechanism underlying this benefit remains largely undetermined.Our recent findings demonstrate that LEX can stimulate noradrenaline-producing neurons in the locus coeruleus (LC) and dopamineproducing neurons in the ventral tegmental area (VTA), and increase noradrenaline and dopamine release in the hippocampus.This raises the hypothesis that dopaminergic and/or noradrenergic pathways to the hippocampus mediate the LEXinduced memory enhancement. Methods :We employed a rat treadmill exercise model combined with a spatial memory test (the object location task).We used antagonists for the D1/D5 dopamine receptor (D1R) and the -adrenergic receptor (AR) to suppress dopaminergic and noradrenergic hippocampal activation and applied the novel neuroscientific approach DREADD to selectively activate or inhibit neurons at the LC or the VTA.Retrograde tracing was conducted to identify the hippocampus-projecting neurons at the LC and VTA and evaluate their activation during LEX.Hippocampal dopamine and noradrenaline levels were measured using HPLC-ECD.Results : Acute LEX after a learning session enhanced memory retention over 24 hours in a hippocampal D1R-dependent but AR-independent manner.Retrograde tracing analyses showed that LEX activated hippocampus-projecting neurons at the LC, but not the VTA.Surprisingly, we revealed that DREADD-mediated activation of noradrenergic neurons in the LC increased dopamine release in the hippocampus and mimicked LEX-enhanced memory retention via the hippocampal D1R.Conversely, DREADD-mediated inhibition of the LC neurons diminished LEX-enhanced memory. Conclusions :Our findings unveil a pivotal role for the non-canonical dopaminergic pathway from the noradrenergic LC neurons to the hippocampus in LEX-induced memory consolidation.This research illuminates the neural mechanisms of light-exercise-enhanced memory and opens avenues for LEX-based accessible memory-enhancing strategies.