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Studies of major depressive disorder (MDD) in postmortem brain tissue report enhanced binding to inhibitory serotonin-1A autoreceptors in midbrain dorsal raphe and reductions in length of axons expressing the serotonin transporter (SERT) in dorsolateral prefrontal cortex. The length density of axons expressing SERT in the orbitofrontal cortex (OFC) was determined in 18 subjects with MDD and 17 age-matched control subjects. A monoclonal antibody was used to immunohistochemically label the SERT in fixed sections of OFC. The 3-dimensional length density of SERT-immunoreactive (ir) axons in layer VI of OFC was estimated. The age of subjects with MDD was negatively correlated with SERT axon length (r=−0.77, p

Background Major Depressive Disorder (MDD) is a common psychiatric disease for which available medications are often not effective. Full remission from depression is achieved by less than 50 percent of patients using medications that mainly target serotonin or norepinephrine systems (Berton and Nestler, 2006; Rush et al., 2006). The economic burden of depression in the U.S., along with comorbid conditions, is estimated at over $170B and depressive disorders are the leading contributors to global burden of disease (Greenberg et al., 2015; Whiteford et al., 2013). The high prevalence of MDD and modest response to existing therapies compels efforts to better understand and treat the disorder. One promising avenue of research suggests that decreases in hippocampal volume with increasing duration of depression results from a decrease in neurogenesis or altered gene expression (Sheline et al., 1996, Cobb et al., 2013). Methods Tissue punches from the dentate gyrus were collected from 23 subjects (MDD, medication-free) and 23 demographically-matched normal controls. Of the 23 subjects with MDD, 17 died by suicide and 17 had multiple depressive episodes. High quality total RNA, RNA Quality Index > 6, was isolated and whole transcriptome paired-end shotgun sequencing was performed using an Illumina NextSeq. 500. For each sample, raw RNA-seq reads (adapter-trimmed fastq files) were aligned to the Ensembl GRCh38 human reference genome using GSNAP (Genomic Short-read-Nucleotide Alignment Program). Differential gene expression was determined using cuffdiff, and core biological processes, molecular networks, and pathways pathologically disrupted in MDD were identified using Ingenuity Pathway Analysis. Results For each sample, 37 to 112 million reads were obtained and 64 to 96% were mapped successfully to the human genome, with most samples mapping above 85%. ‘Cuffdiff’ analysis in the Tuxedo suite revealed 30 significant genes differentially expressed in all MDD compared to controls (Lumenogix™, FDR Discussion The key finding in the primary MDD dataset as well as in the subsets is the overrepresentation of neuroinflammation related genes. Inflammatory and neurogenesis-related (ERK/MAPK) signaling pathways were significantly altered in the hippocampal dentate gyrus in MDD, with cytokine signaling and inflammatory pathways preferentially altered in MDD-suicide vs. MDD-non-suicide. Together this suggests that neuroinflammation, mediated by microglia and astrocytes may play a crucial role in major depressive disorder. These findings suggest a novel approach by seeking targets for new treatment of MDD that includes anti-inflammatory and neuroprotective properties.