The present project has been supported by the R+D programme from the Generalitat Valenciana (Regional Valencian Government) IMPIVA MIDTF/2010/95. The authors have no conflict of interest to declare.

Inflammation is associated with the development of anhedonia in major depression (MD), but the pathway by which inflammatory molecules gain access to the brain and lead to anhedonia is not clear. Molecules of the kynurenine pathway (KP), which is activated by inflammation, readily influx into the brain and generate end products that alter brain chemistry, disrupt circuit functioning, and result in the expression of inflammatory behaviors such as anhedonia. We examined the impact of plasma and CSF KP metabolites on brain chemistry and neural function using multimodal neuroimaging in 49 depressed subjects. We measured markers of glial dysfunction and distress including glutamate (Glu) and myo-inositol in the left basal ganglia using magnetic resonance spectroscopy (MRS); metrics of local activity coherence (regional homogeneity, ReHo) and functional connectivity from resting-state functional MRI measures; and anhedonia from the Inventory for Depressive Symptoms-Self Report Version (IDS-SR). Plasma kynurenine/tryptophan (KYN/TRP) ratio and cerebrospinal fluid (CSF) 3-hydroxykynurenine (3HK) were associated with increases in left basal ganglia myo-inositol. Plasma kynurenic acid (KYNA) and KYNA/QA were associated with decreases and quinolinic acid (QA) with increases in left basal ganglia Glu. Plasma and CSF KP were associated with decreases in ReHo in the basal ganglia and dorsomedial prefrontal regions (DMPFC) and impaired functional connectivity between these two regions. DMPFC-basal ganglia mediated the effect of plasma and CSF KP on anhedonia. These findings highlight the pathological impact of KP system dysregulation in mediating inflammatory behaviors such as anhedonia.

Inflammation is associated with depressive symptoms including anhedonia in patients with major depression. Nevertheless, the mechanisms by which peripheral inflammatory signals are communicated to the brain to influence central nervous system (CNS) function has yet to be fully elucidated. Based on laboratory animal studies, molecules of the kynurenine pathway (KP), which is activated by inflammation, can readily enter the brain, and generate metabolites that can alter neuronal and glial function, leading to behavioral changes. We therefore examined the relationship between KP metabolites in the plasma and cerebrospinal fluid (CSF) and brain chemistry and neural network function using multi-modal neuroimaging in 49 unmedicated, depressed subjects. CNS measures included 1) biochemical markers of glial dysfunction including glutamate (Glu) and myo-inositol (mI) in the left basal ganglia (LBG) using magnetic resonance spectroscopy (MRS); 2) local activity coherence (regional homogeneity, ReHo) and functional connectivity using resting-state functional magnetic resonance imaging; and 3) anhedonia from the Inventory for Depressive Symptoms-Self Reported. Plasma quinolinic acid (QA) was associated with increases and kynurenic acid (KYNA) and KYNA/QA with decreases in LBG Glu. Plasma kynurenine/tryptophan and CSF 3-hydroxy kynurenine (3HK) were associated with increases in LBG mI. Plasma and CSF KP were associated with decreases in ReHo in LBG and dorsomedial prefrontal cortex (DMPFC), and impaired functional connectivity between these two brain regions. DMPFC-BG connectivity mediated the effect of plasma and CSF KP metabolites on anhedonia. These findings highlight the contribution of KP metabolites to glial and neuronal dysfunction and ultimately behavior in depression.

OBJECTIVES/GOALS: In 2020 the Georgia CTSA Clinical Research Center site at Emory University developed a highly trained, credentialed research coordinator pool with a goal to expand the pool to include clinical research coordinators from our partner institutions with the ability to work across institutional barriers in support of Georgia CTSA investigators. METHODS/STUDY POPULATION: Fall 2022, an Emory Investigator requested Georgia CTSA Biorepository samples with supporting clinical data for a NIH funded study. This provided a pilot opportunity to utilize clinical research nursing support offered by the UGA Clinical and Translational Research Unit (CTRU). De-identified samples were collected from our Biorepository while Emory’s coordinators and lab collaborated with UGA’s nursing support for data collection. Our obstacle for cross-institutional support was access to Emory Healthcare (EHC) medical records that would be needed by the UGA nurses, but partnerships created with the Georgia CTSA allowed us to overcome this, granting access to the electronic medical records (EMR) needed to complete the study. RESULTS/ANTICIPATED RESULTS: As expected, the process of credentialing and gaining access to the EHC EMR for the UGA team was the most time-consuming in the development of the pool. Discussions began in June 2021 to determine needs to allow the UGA research nurses to support the Emory coordinator pool. Requirements included acquiring an EHC network ID, completion of required Emory research training, letters of support from the Georgia CTSA outlining the collaboration between institutions, and a credentialing application. All steps were completed in May 2022 and the team began to identify studies that could benefit from this collaboration. Given that all credentialing and access needs were in place, the team was able to initiate the study and complete all study requirements, from sample identification to data collection and clean up, in five weeks. DISCUSSION/SIGNIFICANCE: Workforce shortages of experienced clinical research coordinators make it imperative to overcome barriers presented by institutional rules in order to efficiently utilize available resources to conduct high quality research. The CTSAs provide the perfect opportunity for partner institutions to develop processes to allow support across sites.