The hippocampus (HPC) and prefrontal cortex (PFC) are implicated in anxiety disorders. In rodents, the ventral HPC (vHPC) and medial PFC (mPFC) form a circuit that regulates anxiety-related behavior in the elevated plus maze (EPM). The vHPC and mPFC synchronize in the theta-frequency (4-12 Hz) range during exploration of anxiogenic regions, and disrupting communication between the vHPC and mPFC prevents mice from avoiding the anxiety-provoking open arms of the EPM. Here we propose to reveal the detailed circuit interactions between the vHPC and mPFC that are crucial for anxiety-related behavior. In particular, our preliminary data has shown that populations of vHPC neurons are recruited during exploration of the open arms in the EPM, and inhibiting vHPC neurons disrupts open arm avoidance. However it is not known whether certain classes of mPFC neurons have preferential access to anxiety-related input from the vHPC. To answer this question, we will study vHPC neurons which project to specific classes of neurons in the mPFC, as mice explore the EPM. We will also study mPFC neurons which project to specific targets, e.g., the basolateral amygdala, to determine how they encode anxiety-related information. We hypothesize that classes of mPFC projection neurons which receive anxiety-related input from the vHPC will also encode anxiety-related information. Finally, we will study how prefrontal interneurons respond to theta-frequency input from the vHPC and regulate the anxiety-related responses of mPFC projection neurons. Our preliminary studies have shown that specific inhibitory neurons in the mPFC regulate prefrontal responses to vHPC input and contribute to anxiety-related avoidance. Here, we will test the hypothesis that in the EPM, theta-frequency input from the vHPC recruits these interneurons, thereby enhancing prefrontal responses to anxiety-related input from the vHPC and anxiety-related avoidance. Specifically, we will examine whether prefrontal inhibitory neurons synchronize to theta-frequency input from the vHPC during exploration of the EPM. Finally, we will examine how prefrontal interneurons regulate anxiety-related activity within specific classes of mPFC projection neurons. Together, these studies will elucidate cell-type specific and circuit-level mechanisms underlying the role of hippocampal- prefrontal networks in a commonly studied anxiety behavior. They will also answer general questions about how complex brain circuits operate. E.g., can one source of input differentially transmit emotionally-relevant information to various neuronal subtypes in a downstream target? How do inhibitory interneurons organize their activity in response to a rhythmic input? Do interneurons regulate emotional representations selectively, within specific projection neurons, or nonspecifically, across a network? The answers to these questions will reveal novel targets for disrupting pathological brain states associated with anxiety disorders.
Anxiety disorders are a major cause of distress and disability in the United States and worldwide. Here we propose to study how interactions between the hippocampus and prefrontal cortex regulate anxiety-related behaviors in pathological and potentially therapeutic ways.