The brain structures and neural circuits regulating anxiety behavior are poorly understood. The hippocampus contribute to anxiety via its role in the behavioral inhibition system and descending outputs via the fornix to the septum and frontal cortex are thought to be critical to this modulating effect. However, it is not clear what the contributions of septal and frontal cortical outputs are to anxiety because, until now, no manipulations were available to selectively inhibit these pathways. Here we propose to develop a pharmacogenetic inhibition technology to selectively manipulate hippocampal efferents and determine the contribution of specific hippocampal outputs to anxiety behavior. The host laboratory has already developed a method for the inhibition of genetically defined cell populations in behaving mice. During the first part of the fellowship, I will develop a modified version of this technology based on axonally transported inhibitory GPCRs that allows for the pharmacological suppression of neurotransmitter release in genetically defined synapses. Later, I will use this technology to examine the behavioral effects of blocking selected hippocampal outputs, with a primary focus on hippocampus-frontal cortex projections. The expectation is that the development and validation of this technology will open up a novel approach to study brain function.