Hippocampal knockdown of α2 nicotinic or m1 muscarinic acetylcholine receptors in C57BL/6j male mice impairs cued fear conditioning.

Acetylcholine (ACh) signaling in the hippocampus is important for behaviors related to learning, memory and stress. In this study, we investigated the role of two ACh receptor subtypes previously shown to be involved in fear and anxiety, the M1 mAChR and the alpha 2 nAChR, in mediating the effects of hippocampal ACh on stress-related behaviors. Adeno-associated viral vectors containing short-hairpin RNAs targeting M1 or alpha 2 were infused into the hippocampus of male C57BL/6J mice, and behavior in a number of paradigms related to stress responses and fear learning was evaluated. There were no robust effects of hippocampal M1 mAChR or alpha 2 nAChR knockdown (KD) in the light/dark box, tail suspension, forced swim or novelty-suppressed feeding tests. However, effects on fear learning were observed in both KD groups. Short term learning was intact immediately after training in all groups of mice, but both the M1 and alpha 2 hippocampal knock down resulted in impaired cued fear conditioning 24 h after training. In addition, there was a trend for a deficit in contextual memory the M1 mAChR KD group 24 h after training. These results suggest that alpha 2 nicotinic and M1 muscarinic ACh receptors in the hippocampus contribute to fear learning and could be relevant targets to modify brain circuits involved in stress-induced reactivity to associated cues.