CHOLINERGIC MODULATION OF DENTATE GYRUS CIRCUITS SUPPORTS LEARNING AND SYNAPTIC PLASTICITY

The hippocampus is crucial for learning and memory, with the dentate gyrus (DG) playing a key role in processing incoming information and forming distinct memory representations. Neuromodulators are known to adapt circuit processing to enable plasticity, but the underlying mechanisms remain unclear. Previous work has shown that acetylcholine (ACh) release in the DG reconfigures inhibitory circuits, leading to excitatory neuron disinhibition and enhanced synaptic plasticity. We first explored how ACh modulates synaptic plasticity in DG microcircuits by studying spike timing-dependent plasticity (STDP) and associative long-term potentiation (LTP) in hippocampal slices. As lateral and medial entorhinal cortex inputs are anatomically and functionally distinct—processing content-specific and contextual information, respectively—we examined their convergence in the DG and found that ACh selectively modulates responses from both pathways. Our findings suggest that ACh facilitates associative LTP induction by weakening inhibitory currents, potentially enhancing learning. Complementarily, we implemented a spiking computational model of the DG based on AdEx neurons to test the experimentally proposed disinhibitory mechanism and investigate how cholinergic modulation alters incoming 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, we assessed contextual discrimination in mice, employing chemogenetics (Chat-HM3DQ) to increase endogenous ACh release. Our results indicate a trend toward faster learning in animals with enhanced cholinergic activity compared to controls. These results contribute to understanding how ACh-mediated neuromodulation supports cognitive flexibility and memory formation.