Neuroinflammation as a Mechanism Linking Early Life Stress, Altered Functional Connectivity, and Anhedonia in Major Depression

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PROJECT SUMMARY/ABSTRACT Stressful life events are one of the strongest predictors of depressive symptom onset, and individuals exposed to early life stress (ELS) are 2 to 4 times more likely to meet diagnostic criteria for major depressive disorder (MDD). Anhedonia, or deficits in motivation, effort, and pleasure, is a core feature of MDD, and ELS has been implicated as a significant contributor in the pathophysiology and manifestation of anhedonia, which may explain higher rates of MDD in ELS. It is postulated that ELS increases anhedonia risk by potentiating cross- talk between the innate immune system and neural circuits implicated in threat- and reward-related processing. In support of this framework, there is evidence linking inflammation to increased vigilance for threats and dampened reward sensitivity. Experimentally-induced inflammation alters activation of threat- and reward- related brain regions, namely the amygdala and ventral striatum (VS). Further, higher levels of peripheral inflammation have been associated with reduced functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala, as well as the vmPFC and VS, which in turn is associated with decreased motivation and anhedonia, particularly in ELS-exposed individuals. Additionally, associations between inflammation and anhedonia have been observed in PET studies of patients with MDD using radioligands to target the 18-kDa translocator protein (TSPO), whose expression is increased in classically-activated microglia. However, prior research on ELS and anhedonia in humans lacks direct measures of neuroinflammation, and studies have rarely focused on integrating measures of reward- and threat-related neural connectivity. Thus, the goal of the proposed project is to advance a stress-induced model of anhedonia that is driven by threat- and reward-related neuroinflammatory mediators. We propose to collect simultaneous PET-fMRI from unmedicated MDD patients with clinically significant anhedonia and matched healthy controls using the radioligand [18F]PBR111 to assess TSPO expression, an index of neuroinflammation. In Aim 1, we will test the impact of early life stress on neuroinflammation (TSPO binding) in threat- and reward-related brain regions. Across both groups, we hypothesize that greater exposure to ELS will predict increased TSPO binding in brain regions implicated in reward and threat processing. In Aim 2, we will test the impact of ELS on threat- and reward-network task-based functional connectivity. Across both groups, we hypothesize that greater exposure to ELS will predict decreased threat-network functional connectivity (e.g., amygdala-vmPFC) and decreased reward-network functional connectivity (e.g., VS-vmPFC). In Aim 3, we will evaluate the impact of ELS on anhedonia severity via neuroinflammation and altered functional connectivity in MDD. In the MDD group, significant pathways will be explored using mediation analyses. Findings will yield preliminary evidence of ELS-related neuroinflammation, test putative immune mechanisms underlying the association between ELS and anhedonia, and advance our understanding of anhedonia as a transdiagnostic symptom.