Identifying the mechanism by which postpartum estrogen withdrawal impacts mesolimbic brain circuitry and motivated behaviors - 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.
