PROJECT SUMMARY Since hippocampal (HPC) neural activity does not reliably and accurately predict future choices in context- dependent tasks, experience-dependent and intentional behaviors must be enabled downstream of HPC, perhaps where information about one’s internal state (e.g. level of motivation, stress, and emotion) has an opportunity to bias cortical instructions for future behaviors. Indeed often one may ‘know’ what to do in a given situation, yet the condition of one’s internal state often prevent even desired responses from occurring. The present application tests the novel hypothesis that the lateral habenula (LHb) is pivotally important for determining the expression of HPC/mPFC-dependent memory and decisions because it integrates current internal state information with HPC/mPFC output to enable (or not) responses (60). This hypothesis is not predicted by the more common but narrower view that LHb directs choice behavior because it signals negative task conditions (11,23-26). AIM 1 will test whether interactions across the HPC-mPFC- LHb circuit are necessary to perform accurately on a HPC and mPFC-dependent spatial delayed alternation task that requires flexible decision making. Exp. 1: Since there are no known direct connections between HPC and LHb, their interactions will be studied using an established (muscimol-induced) disconnection paradigm. Preliminary data show that HPC-LHb interactions are necessary for accurate performance on the delayed alternation task. Exp. 2: Direct connections between mPFC and LHb have been described (4). Thus, optical inhibition of mPFC terminals in LHb will test the necessity of mPFC-LHb interactions for accurate task performance. Aim 2 will characterize the nature of HPC-LHb theta coherence during spatial delayed alternation task performance. Then we will determine the relative contributions of memory (via mPFC input) and internal state information (via lateral hypothalamus, or LH, input) to HPC-LHb coherence. Coordinated theta phase and power relationships across structures will be studied to better understand the direction of information flow, and the nature of information shared during bouts of theta coherence. Using the same animals, we will then determine the relative influence of memory system input (via PFC) and internal state input (via LH) on HPC-LHb theta coherence using retroviral and optogenetic methods. In summary, this R21 application seeks ‘proof of concept’ evidence for a novel hypothesis that could lead to new therapeutic approaches to improve lateral habenula-mediated disorders of behavioral control.