PROJECT SUMMARY The ability to discriminate between what is “good” and “bad” is termed valence processing, and pathological perturbations in valence processing can explain mental health disorders ranging from anxiety and depression to compulsivity and bipolar disorder. The key to developing more effective treatments for mental health disorders with fewer side-effects will be in the synaptic, cellular, and circuit mechanisms. This proposal not only lays out a very specific research plan to probe the functional role of a neuropeptide, neurotensin (NT), but it also lays out a comprehensive, systematic approach to investigating neuromodulatory systems. The general approach includes: 1) Identify a circuit that plays a causal and critical role in valence processing, 2) Profile the transcriptome of this circuit component, 3) Select for surface receptors or other druggable targets, 4) Determine the contribution of this neuromodulatory signal on plasticity, 5) Establish the input-output architecture of the neuromodulatory innervation and postsynaptic, downstream targets, and 6) Establish a causal role for this particular neuromodulatory signal in neural activity and behavior associated with valence processing. The specific hypotheses included in this proposal are: that NT serves to guide plasticity to the appropriate target, that there are parallel circuits that have some local interaction in the BLA, and that NT alters the coding dynamics by increasing signal-to-noise ratio by amplifying signal by modulation of glutamatergic transmission. A successful outcome of this project will provide a specific model for how a neuromodulatory signal such as NT can solve the “valence assignment problem.”