Cholinergic gating of entorhinal inputs promotes associative LTP and discrimination learning

The dentate gyrus (DG) plays a crucial role in hippocampal learning and memory by forming distinct representations. While neuromodulators adapt circuits to enable plasticity, the underlying mechanisms remain unclear. Previous work in the lab has shown that acetylcholine (ACh) release in the DG reconfigures inhibitory circuits, driving excitatory disinhibition and synaptic plasticity. In hippocampal slices, we explored how ACh modulates DG microcircuit plasticity by assessing spike timing-dependent plasticity (STDP) and associative long-term potentiation (LTP). Because lateral and medial entorhinal cortex inputs convey content-specific versus contextual information, we examined their convergence in the DG, finding that ACh selectively modulates both pathways and facilitates associative LTP induction by weakening inhibitory currents. Complementarily, an AdEx-based spiking computational model of the DG tested this disinhibitory mechanism and its impact on information processing. Building on these circuit-level insights, we hypothesized that ACh release boosts learning and memory. Using a head-fixed virtual reality Go/No-Go task in mice, chemogenetically enhancing endogenous ACh release (Chat-HM3DQ) produced a trend toward faster contextual discrimination learning. These results contribute to understanding how ACh-mediated neuromodulation supports cognitive flexibility and memory formation.