Altered emotion regulation and low mood states in major depressive disorder (MDD) are thought to reflect altered corticolimbic structure and function in affected individuals, and involve the dorsolateral prefrontal cortex (DLPFC), the subgenual anterior cingulate cortex (sgACC) and the amygdala. Specifically, low GABA-related inhibition may underlie inadequate sensing and relaying of emotionally-salient stimuli by the amygdala and deficient integration of this relayed information by the sgACC with higher DLPFC processing. However, primary cellular and molecular evidence for these proposals are sparse. We have now identified a selective downregulation of somatostatin (SST), an inhibitory neuropeptide expressed in a subset of GABA neurons, in the DLPFC, sgACC and amygdala of subjects with MDD. Low SST was confirmed across cohorts, affected female subjects more robustly, and moderately correlated with the severity of the illness. At the microcircuitry level, SST GABA neurons target the distal dendrites of pyramidal neurons, but different subsets of SST neurons display different anatomical localizations and physiological properties, potentially mediating different information processing. Together, this lead us to hypothesize that low SST levels in specific cortical layers and amygdala nuclei are critical risk factors for MDD, and that additional factors determine the severity of the illness. Accordingly, we further hypothesize that, under challenging conditions, suboptimal SST function may trigger cellular and molecular maladaptive changes that lead to altered emotion regulation and low mood states, changes that will provide leads for the future development of novel therapeutics. Hence, to investigate the contribution of SST in mood regulation, we will first characterize the anatomical and microcircuitry specificity of changes in the human postmortem brains of MDD subjects (cortical layer &amygdala nuclei) (Aim 1). We will then test the "low SST - risk factor" hypothesis in a rodent model, and predict that mice with low SST (heterozygous mutant) will display increased vulnerability to develop high anxiety-like/depressive-like behaviors (defined as "emotionality") after unpredictable chronic mild stress (Aim 2). Finally, we will use mice expressing green fluorescent protein in the SST interneuron subtype(s), which most closely corresponds to the subtype affected in MDD, to investigate low SST- and stress-associated cell-specific maladaptive molecular changes (Aim 3). In summary, low SST in MDD provide a cellular and molecular lead to investigate mechanisms of the illness, and a potential molecular link between foremost hypotheses for biological disturbances in MDD (neural network dysfunction and reduced GABA-related function). However, SST also assumes several central and peripheral functions, and pharmacological manipulation has multiple (side-)effects, so it is essential to identify maladaptive molecular changes in SST GABA neurons, as potential mediators of the phenotype and as novel and potentially selective targets for the future investigation and development of novel therapeutics aimed at relieving the burden of MDD.

Public Health Relevance

Major Depressive Disorder (MDD) is a severe mental illness, the leading cause of disability and of years of productivity lost worldwide in men and women, and a significant contributor to the development and progression of systemic and organ diseases. We have now identified in the human postmortem brain of depressed subjects, a specific downregulation in somatostatin (SST), a signaling molecule, which affects three brain regions known to be critical in the illness. The characterization of the cellular context of these changes and of their potential causal role in MDD, using both human postmortem samples and a validated rodent model, will provide new insight into mechanisms of the disease and reveal potential selective targets for novel therapeutic strategies aimed at relieving the burden of MDD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Meinecke, Douglas L
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University of Pittsburgh
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Guilloux, Jean-Philippe; Bassi, Sabrina; Ding, Ying et al. (2015) Testing the predictive value of peripheral gene expression for nonremission following citalopram treatment for major depression. Neuropsychopharmacology 40:701-10
Seney, Marianne L; Tripp, Adam; McCune, Samuel et al. (2015) Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression. Neurobiol Dis 73:213-9
Soumier, Amelie; Sibille, Etienne (2014) Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice. Neuropsychopharmacology 39:2252-62
Northoff, G; Sibille, E (2014) Why are cortical GABA neurons relevant to internal focus in depression? A cross-level model linking cellular, biochemical and neural network findings. Mol Psychiatry 19:966-77
Chang, Lun-Ching; Jamain, Stephane; Lin, Chien-Wei et al. (2014) A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies. PLoS One 9:e90980
Gaiteri, C; Ding, Y; French, B et al. (2014) Beyond modules and hubs: the potential of gene coexpression networks for investigating molecular mechanisms of complex brain disorders. Genes Brain Behav 13:13-24
Nikolova, Yuliya S; Koenen, Karestan C; Galea, Sandro et al. (2014) Beyond genotype: serotonin transporter epigenetic modification predicts human brain function. Nat Neurosci 17:1153-5
Sibille, Etienne (2013) Molecular aging of the brain, neuroplasticity, and vulnerability to depression and other brain-related disorders. Dialogues Clin Neurosci 15:53-65
Tseng, George C; Ghosh, Debashis; Feingold, Eleanor (2012) Comprehensive literature review and statistical considerations for microarray meta-analysis. Nucleic Acids Res 40:3785-99
Wang, Xingbin; Lin, Yan; Song, Chi et al. (2012) Detecting disease-associated genes with confounding variable adjustment and the impact on genomic meta-analysis: with application to major depressive disorder. BMC Bioinformatics 13:52

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