STRIATAL EXCITATORY AND METABOTROPIC PKA REGULATION IN STRESS AND RESILIENCEMental disorders such as anxiety and depression are major health concerns that contributeunabated to a large portion of all morbidity and mortality. These complex disorders may be viewed as mal-adaptations that arise in brain circuitry. In order to achieve more effective treatments better mechanisticunderstanding of brain circuitry integration is needed. Normally motivated behaviors and executive functionsrequire processing of sensory-triggered excitatory neurotransmission and assignment of emotional context. Thisoccurs in the striatum where cortical glutamatergic and midbrain dopaminergic inputs converge to mediate brainfunctions such as reward and stress responses. Striatal dysfunction is broadly implicated in the etiology of manymental illnesses. For example stress-induced alterations in the activity of reward-related brain regions such asthe nucleus accumbens (NAc) are linked to the pathophysiology of depression. Insight into the mechanisms bywhich glutamate and dopamine neurotransmission are integrated within the NAc may shed light on some causesof mental illness or implicate new drug targets and treatment strategies. Here we introduce a new signalingmechanism which we hypothesize is controlled by striatal glutamatergic and dopaminergic signaling to allowconcerted regulation of PKA activity. Specifically our preliminary data indicates that glutamate controlsconstitutive phosphorylation of the RII-beta (RIIb) regulatory subunit by Cdk5 which then directly affects PKAactivation by D1-type dopamine receptors via a second PKA-dependent auto-phosphorylation mechanism. Wehypothesize that this unique mechanism mediates striatal plasticity and behavioral responses to stress and thatchronic stress can cause mal-adaptations in this mechanism so that glutamate and dopamine signaling areuncoupled and PKA signaling is dysregulated. We further hypothesize that this mechanism may be targeted toimprove striatal plasticity and behavioral resilience. To pursue this novel premise we propose to 1) study theregulation of RIIb/PKA and explore downstream effectors in vitro and in vivo; 2) study the role of RIIb/PKAphosphorylation in ventral striatal neuronal excitability and synaptic plasticity and 3) study the regulation of thismechanism by acute and chronic stress and determine how it contributes to behavioral responses to stress.These studies will yield important information on the mechanisms that integrate brain circuitry and how they areaffected by stress. Thus we will better understand some of the basis by which stress may contribute to complexmental disorders such as anxiety and depression and how they may be more effectively treated.