PROJECT SUMMARY/ABSTRACT Estrogen levels increase dramatically during pregnancy, but quickly plummet to below pre-pregnancy levels after birth and remain suppressed for weeks to months. During this time, approximately 15% of women are diagnosed with a mood and/or anxiety disorder, making postpartum psychological disorders the most common complication associated with childbirth. Although there is strong evidence that the sudden drop in estrogen following birth can lead to an “estrogen withdrawal” state that is related to the symptoms of postpartum psychological disorders, few studies have directly tested the impact of postpartum estrogen withdrawal on the brain, and none have examined the impact of postpartum estrogen withdrawal on the mesolimbic dopamine circuitry. The objective of this proposal is therefore to uncover how postpartum estrogen withdrawal impacts the mesolimbic circuitry and associated motivated behaviors. A hormone-simulated pseudopregnancy model in rodents allows researchers to directly test the impact of estrogen withdrawal on the brain and on behavior. In this model, estrogen withdrawal increases ∆FosB, a mediator of long-term plasticity, in the nucleus accumbens (NAc). Further, this neuroplastic change is associated with deficits in motivated and affective behaviors. The experiments in this proposal will examine a novel neural mechanism for postpartum changes in motivation/affect; specifically, it is proposed that reduced binding at estrogen receptors during postpartum estrogen withdrawal decreases the excitability of ventral tegmental area (VTA) dopamine neurons, resulting in decreased dopamine release into the NAc and an increase in the downstream induction of ∆FosB in the NAc. Aim 1 will test the hypothesis that postpartum estrogen withdrawal decreases dopamine release into the NAc. These experiments will use fast scan cyclic voltammetry to measure dopamine release in the NAc following a hormone-simulated pseudopregnancy. Aim 2 will test the hypothesis that reducing binding at estrogen receptors in the VTA increases DFosB levels in the NAc during the postpartum period. These experiments will use a pharmacological approach to block estrogen receptors in the VTA during estrogen withdrawal, and measure ∆FosB in cell-type-specific neurons in the NAc. Aim 3 will test the hypothesis that increased ΔFosB in the NAc following estrogen withdrawal is required for the decreased motivation seen in estrogen-withdrawn females. These experiments will use a viral-mediated gene transfer approach to prevent ΔFosB-mediated transcription in the NAc during a hormone-simulated pseudopregnancy and measure the impact on motivated behaviors. Taken together, these experiments will uncover how postpartum estrogen withdrawal mechanistically impacts the mesolimbic brain circuitry. Ultimately, this will yield novel information about how peripartum estrogen fluctuations confer heightened vulnerability to psychological disorders.