Acetylcholine (ACh) is often thought of as a neurotransmitter that is important for cognition, but we have identified increased brain ACh levels in human subjects who are actively depressed. This seminar will present data that increasing activity of ACh inputs to the hippocampus selectively induces stress-dependent behaviors, including increased susceptibility to social stress. Our working hypothesis is that ACh signaling in hippocampus may be relevant to the negative encoding bias, that is, increased focus on negative events, experienced by individuals with depression.