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Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression.

ABSTRACT: Somatostatin (SST), a neuropeptide expressed in dendritic-targeting gamma-aminobutyric acid (GABA) neurons, is decreased across corticolimbic areas in major depressive disorder (MDD). SST-positive GABA neurons form heterogeneous subgroups with different laminar distributions and electrophysiological properties, so knowing the anatomical and cellular localization of reduced SST may provide insight into the nature of the pathology in MDD. In cohorts of MDD subjects with known reduction of SST in postmortem sgACC gray matter, we used in situ hybridization to quantify the laminar and cellular patterns of altered SST mRNA expression. SST mRNA levels were lower across all cortical layers in the MDD subjects. Expression levels per cell were also lower, but the density of labeled neurons did not differ between subject groups. Consistent with the previous tissue level analysis, differences were more robust in females. In summary, we report MDD-related reduction in SST expression per cell across cortical layers in sgACC, suggesting a general vulnerability of SST neurons independent of specific cell type.

SUBMITTER: Seney ML

PROVIDER: S-EPMC4394026 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression.

Seney Marianne L ML Tripp Adam A McCune Samuel S Lewis David A DA Sibille Etienne E

Neurobiology of disease 20141012

Somatostatin (SST), a neuropeptide expressed in dendritic-targeting gamma-aminobutyric acid (GABA) neurons, is decreased across corticolimbic areas in major depressive disorder (MDD). SST-positive GABA neurons form heterogeneous subgroups with different laminar distributions and electrophysiological properties, so knowing the anatomical and cellular localization of reduced SST may provide insight into the nature of the pathology in MDD. In cohorts of MDD subjects with known reduction of SST in p ...[more]

PMID: 25315685

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Project description:The subgenual anterior cingulate cortex is implicated in the pathology and treatment response of major depressive disorder. Low levels of brain-derived neurotrophic factor (BDNF) and reduced markers for GABA function, including in the amygdala, are reported in major depression, but their contribution to subgenual anterior cingulate cortex dysfunction is not known.Using polymerase chain reaction, we first assessed the degree to which BDNF controls mRNA expression (defined as BDNF dependency) of 15 genes relating to GABA and neuropeptide functions in the cingulate cortex of mice with reduced BDNF function (BDNF-heterozygous [Bdnf(+/-)] mice and BDNF exon-IV knockout [Bdnf(KIV)] mice). Gene expression was then quantified in the subgenual anterior cingulate cortex of 51 postmortem subjects with major depressive disorder and comparison subjects (total subjects, N=102; 49% were women) and compared with previous amygdala results.Based on the results in Bdnf(+/-) and Bdnf(KIV) mice, genes were sorted into high, intermediate, and no BDNF dependency sets. In postmortem human subjects with major depression, BDNF receptor (TRKB) expression, but not BDNF, was reduced. Postmortem depressed subjects exhibited down-regulation in genes with high and intermediate BDNF dependency, including markers of dendritic targeting interneurons (SST, NPY, and CORT) and a GABA synthesizing enzyme (GAD2). Changes extended to BDNF-independent genes (PVALB and GAD1). Changes were greater in men (potentially because of low baseline expression in women), displayed notable differences from prior amygdala results, and were not explained by demographic or clinical factors other than sex.These parallel human/mouse analyses provide direct (low TRKB) and indirect (low expression of BDNF-dependent genes) evidence in support of decreased BDNF signaling in the subgenual anterior cingulate cortex in individuals with major depressive disorder, implicate dendritic targeting GABA neurons and GABA synthesis, and, together, suggest a common BDNF-/GABA-related pathology in major depression with sex- and brain region-specific features.

Project description:Newborns and infants communicate their needs and physiological states through crying and emotional facial expressions. Little is known about individual differences in responding to infant crying. Several theories suggest that people vary in their environmental sensitivity with some responding generally more and some generally less to environmental stimuli. Such differences in environmental sensitivity have been associated with personality traits, including neuroticism. This study investigated whether neuroticism impacts neuronal, physiological, and emotional responses to infant crying by investigating blood-oxygenation-level dependent (BOLD) responses using functional magnetic resonance imaging (fMRI) in a large sample of healthy women (N = 102) with simultaneous skin conductance recordings. Participants were repeatedly exposed to a video clip that showed crying infants and emotional responses (valence, arousal, and irritation) were assessed after every video clip presentation. Increased BOLD signal during the perception of crying infants was found in brain regions that are associated with emotional responding, the amygdala and anterior insula. Significant BOLD signal decrements (i.e., habituation) were found in the fusiform gyrus, middle temporal gyrus, superior temporal gyrus, Broca's homologue on the right hemisphere, (laterobasal) amygdala, and hippocampus. Individuals with high neuroticism showed stronger activation in the amygdala and subgenual anterior cingulate cortex (sgACC) when exposed to infant crying compared to individuals with low neuroticism. In contrast to our prediction we found no evidence that neuroticism impacts fMRI-based measures of habituation. Individuals with high neuroticism showed elevated skin conductance responses, experienced more irritation, and perceived infant crying as more unpleasant. The results support the hypothesis that individuals high in neuroticism are more emotionally responsive, experience more negative emotions, and may show enhanced cognitive control during the exposure to infant distress, which may impact infant-directed behavior.

Dataset Information

Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression.

Publications

Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression.

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