Modulation of Stress-Induced Anhedonia over the Menstrual Cycle: A Multi-Method Investigation of Stress and Reward Mechanisms

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Project Summary/Abstract. Major Depressive Disorder (MDD) is a debilitating clinical disorder that is associated with a host of deleterious impacts on individuals and society, including marital dissolution, unemployment, low educational attainment, and increased risk for suicide.46,47,76,77 Moreover, MDD disproportionately affects women; incidence of MDD is doubled in women as compared to men, specifically during their childbearing years.2-3 As such, it is imperative to test models elucidating the etiopathogenesis of women’s enhanced risk for MDD to expedite development of optimal screening tools and interventions for MDD in women of reproductive age. Anhedonia, or the subjective loss of reactivity to pleasurable stimuli, is a known deficit of MDD,4-7 and acute and chronic stressors have been shown to dampen behavioral and neural reactivity to rewards18-21—a phenomenon referred to as stress- induced anhedonia18 which has been linked to increased depressive symptoms.24,78 Women may be especially susceptible to stress-induced anhedonia due to their hormonal profiles. Progesterone (P4) and estradiol (E2) levels fluctuate over the course of the typical menstrual cycle and have opposing associations with both stress and reward reactivity. Stress sensitivity is increased28 and reward sensitivity is decreased35 in the mid-luteal phase of the cycle when P4 is high. However, both systems exhibit opposite effects in the late-follicular cycle phase when E2 is high, such that stress sensitivity is decreased33 and reward sensitivity is enhanced.35 Thus, while previous research suggests menstrual cycle phases and ovarian hormones impact stress reactivity and reward responsivity separately, no study has yet examined whether stress-related decreases in reward sensitivity vary as a function of hormone levels or menstrual cycle phase—which could reveal a candidate mechanism to partially explain sex differences in MDD risk and which could be targeted in future screening and intervention efforts for women of reproductive age. The current study leverages a repeated-measures design to test the novel hypothesis that systems underlying stress-induced anhedonia are modulated by ovarian hormones and cycle phases. Specifically, the current proposal aims to: 1) examine the effect of an acute social stressor on the neural reward response, 2) compare stress-related reductions in the neural reward response both in the late follicular and mid-luteal phases, 3) examine associations between hormone concentrations and stress-related reductions in the reward response, and 4) examine whether the hypothesized effects are moderated by individual differences in sensitivity to ovarian hormones as measured via ecological momentary assessment of affective and somatic symptoms across the menstrual cycle. The training experiences gained through this fellowship will prepare the applicant for an independent research career investigating endocrine and neural markers of risk for mood and anxiety psychopathology.