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Inflammatory Transcripts, Genes and Positive Valence System Function in Anhedonia

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A translational paradigm for inducing behavioral analogs of anhedonia in rodents and humans involves challenges that induce immune system activation and increase the gene expression of proinflammatory cytokines. This inflammation-induced change in behavior is consistent with the notion that these cytokines signal the brain to initiate 'sickness behavior,' a motivational response to infection or disease that is thought to promote recovery from illness. As such, anhedonia has been conceived of as an adaptive response to sickness that promotes recuperative behavior and prevents individuals from engaging in activities that require excessive energy. Since peripheral cytokines can cross the blood-brain-barrier (BBB), and also can propagate signals across the BBB that induce the production of cytokines from glia, measurement of peripheral markers of inflammation is a valid, if indirect assessment of CNS inflammation. The proposed study aims to test the hypothesis that within a mood disorder sample, the gene transcripts obtained from peripheral blood mononuclear cells (PBMCs), anhedonia ratings, and deficits in positive valence systems will be intercorrelated. In pilot studies of individuals presenting with various mood disorders we obtained preliminary evidence that gene expression within PBMCs is abnormal within a gene network implicated in inflammation and neurological disorders, and that the mRNA levels from these genes individually show positive correlations with anhedonia ratings in mood disordered and healthy individuals. Because the transcript levels of the implicated genes within this network are inter-correlated, we will use the covariance matrix formed by the mRNA levels in discriminant analysis type-functions to classify cases on the basis of having elevated or non-elevated gene network activity. We will assess the mRNA activity of this network along a dimension of anhedonic mood symptoms and of behavioral and neurophysiological measures that reflect multiple constructs within the positive valence systems. More specifically, we will assess interrelationships between gene transcription, anhedonia ratings, functional MRI (fMRI) measures of neurocircuits engaged during reward evaluation and initial responsiveness to reward attainment, and fMRI and behavioral responses reflecting effort evaluation/ wiIlingness to work in relation to changing reward values. The fMRI paradigms selected for this purpose involve behavioral tasks in which the emotional valence and reward value are manipulated orthogonally to changes in task difficulty. They thus afford excellent opportunities to evaluate separately the neural and behavioral responses associated with decrements in motivation versus reductions in experienced pleasure that are crucial to the development of translational models of anhedonia arising within the context of mood disorders.
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