Reinforced Hippocampus-Accumbens pathway marks a shift towards cognitive decline in aging

Abstract

Aging triggers early functional alterations in brain circuits that precede cognitive impairment, yet the underlying mechanisms remain unclear. Spatial navigation and memory, among the earliest affected, depend on hippocampus and downstream targets such as the nucleus accumbens (NAc), which integrates spatial and motivational information to guide goal-directed behaviors. Here we identify age-related, sex-dependent changes of the dorsal hippocampus-NAc (dHPC[->]NAc) pathway. Combining optogenetics with electrophysiology, chemogenetics, and behavioral analyses in mice, we show that aging shifts excitation-inhibition balance in dorsal CA1 toward pyramidal neuron hyperexcitability, strengthening hippocampal outputs. This selectively enhances synaptic drive onto D1 receptor-expressing medium spiny neurons and involves a previously unrecognized long-range parvalbumin-expressing glutamatergic projection. Reducing dHPC[->]NAc excitability improves memory in aged mice. In humans, fMRI reveals heightened posterior hippocampal activity and stronger pHPC-NAc coupling during navigation. Together, we uncover a targetable pathway acting in an intervention-sensitive window of aging to correct negative cognitive trajectories.