Resilience Is Associated With Larger Dentate Gyrus, While Suicide Decedents With Major Depressive Disorder Have Fewer Granule Neurons

Abstract

Background: Early life adversity (ELA) increases major depressive disorder (MDD) and suicide risk and potentially affects dentate gyrus (DG) plasticity. We reported smaller DG and fewer granular neurons (GNs) in MDD. ELA effects on DG plasticity in suicide decedents with MDD (MDDSui) and resilient subjects (ELA history without MDD or suicide) are unknown.

Methods: We quantified neural progenitor cells (NPCs), GNs, glia, and DG volume in whole hippocampus postmortem in four groups of drug-free, neuropathology-free subjects (N = 52 total): psychological autopsy-defined MDDSui and control subjects with and without ELA (before 15 years of age).

Results: ELA was associated with larger DG (p < .0001) and trending fewer NPCs (p = .0190) only in control subjects in whole DG, showing no effect on NPCs and DG volume in MDDSui. ELA exposure was associated with more GNs (p = .0003) and a trend for more glia (p = .0160) in whole DG in MDDSui and control subjects. MDDSui without ELA had fewer anterior and mid DG GNs (p < .0001), fewer anterior DG NPCs (p < .0001), and smaller whole DG volume (p = .0005) compared with control subjects without ELA. In MDDSui, lower Global Assessment Scale score correlated with fewer GNs and smaller DG.

Conclusions: Resilience to ELA involves a larger DG, perhaps related to more neurogenesis depleting NPCs, and because mature GNs and glia numbers do not differ in the resilient group, perhaps there are effects on process extension and synaptic load that can be examined in future studies. In MDDSui without ELA, smaller DG volume, with fewer GNs and NPCs, suggests less neurogenesis and/or more apoptosis and dendrite changes.

Keywords: Granule cell; Major depression; Neural progenitors; Postmortem; Stress; Suicide.

Figure 1.

Mature granule neurons (GNs) in the human hippocampus from subjects with and without reported early life adversity (ELA) exposure. (A) Neuronal nuclear marker (NeuN)-immunoreactive granule neurons (in brown) were found in the dentate gyrus (DG) and in the hilus and cornu ammonis (CA) regions. The blue-green outline defines the granule cell layer (GCL) region of interest for counting granule neurons with stereology. (B) NeuN-immunoreactive granule neurons (in brown) were packed within the GCL, and less dense in the molecular layer (ML) and subgranular zone (SGZ), and had their characteristic round shape, readily distinguishable from pyramidal neurons in the hilus. Glial cells in the DG were stained for Nissl with cresyl violet and were NeuN negative and identified for showing heterochromatin clumps, sparse cytoplasm, and smaller cell body size than GNs (115) (green arrows). We did not differentiate morphologically between oligodendrocytes, with their compact, darker-stained nuclei, and astrocytes and microglia, which have larger, lighter-stained nuclei with more granular chromatin (116). Few thousands of NeuN-negative and Nissl-stained cells might be neural progenitors, or young neurons, although glial cells are on the order of thousands and few thousands of glial cells would not change the results. Endothelial cells have a distinguishable elongated morphology and were not counted. Sampling of GNs and glial cells, which are very packed, was performed with a 40× air objective (numerical aperture: 0.95), which provided the same results as the tested sampling with a 60× oil objective (numerical aperture: 1.42). (C) Numbers of GNs in anterior, mid, and posterior DG in control subjects without ELA (Control-w/oELA), resilient control subjects with ELA (Control-wELA), and subjects with major depressive disorder (MDD) who died by suicide (MDDSui) with ELA (MDDSui-wELA) and without ELA (MDDSui-w/oELA). (D) Numbers of glial cells in anterior, mid, and posterior DG in Control-w/oELA, Control-wELA, MDDSui-wELA, and MDDSui-w/oELA. MDDSui had fewer anterior–mid DG GNs (p < .0001) and ELA exposure associated with more GNs (p = .0003) in both groups and all DG regions. ELA was associated with more glia in both groups (p = .0160) in all regions. Outcome value labels are shown on the original scale, although mean and SE were calculated on the log-transformed data.

Figure 2.

Neural progenitor cells (NPCs) in the dentate gyrus (DG) from subjects with major depressive disorder (MDD) and control subjects with and without reported early life adversity (ELA). (A) Multipolar NPCs with multiple dendritic processes and remodeling nestin-immunoreactive (IR) capillaries in the subgranular zone (SGZ). Granular neurons and glia are stained for Nissl with cresyl violet. NPCs, showing nestin-IR cell bodies and processes, were found in the SGZ, but not in the granular cell layer (GCL) and molecular layer (ML), and displayed processes in contact with remodeling capillaries, which are also nestin IR, have a lumen, and are quite distinguishable from NPCs, as previously described (32). (B) Enlargement of the rectangle in (A). NPC dendrites touched the capillary and extended into the GCL. Nestin-IR blood vessels displayed their characteristic tubular appearance. (C) The GCL, ML, and SGZ are outlined (red line) to define the DG, where nestin-IR NPCs (in brown) were counted. Sampling of NPCs was performed with a 60× oil objective (numerical aperture: 1.42). (D) Numbers of NPCs in anterior, mid, and posterior DG in control subjects without ELA (Control-w/oELA), resilient control subjects with ELA (Control-wELA), and subjects with MDD who died by suicide (MDDSui) with ELA (MDDSui-wELA) and without ELA (MDDSui-w/oELA). MDDSui had fewer NPCs than control subjects in anterior DG (p < .0001). ELA affected NPCs differently in MDDSui and control subjects in all regions (p = .0059), with fewer NPCs observed only in control subjects (p = .0190). Outcome value labels are shown on the original scale, although mean and SE were calculated on the log-transformed data. CA, cornu ammonis.

Figure 3.

Dentate gyrus (DG) volume in subjects with and without reported early life adversity (ELA) exposure. (A–C) Lateral (A), medial (B), and coronal (C) views of DG outlines, including granule cell layer, molecular layer, and subgranular zone, traced with stereology software and aligned from the anterior to the posterior extent of the hippocampus. Anterior, mid, and posterior DG volumes were calculated including molecular layer, granule cell layer, and subgranular zone, as previously described (43). (D) DG volume in anterior, mid, and posterior hippocampus in control subjects without ELA (Control-w/oELA), resilient control subjects with ELA (Control-wELA), subjects with major depressive disorder (MDD) who died by suicide (MDDSui) with ELA (MDDSui-wELA) and without ELA (MDDSui-w/oELA). MDDSui had smaller DG (p = .0005) than controls, and ELA was associated with larger DG in control subjects (p < .0001) but not in MDDSui.

Figure 4.

Global functioning score (Global Assessment Scale [GAS]) correlated with anterior dentate gyrus (DG) granule neuron number and DG volume. (A) Better GAS score correlated with larger anterior DG volume. (B) Better GAS score correlated with more granule neurons in anterior DG. No other correlations between GAS score and DG cell numbers and DG volume were found in any DG subregion (not shown). GAS score showed no correlation with glial cell numbers (not shown). Control-wELA, resilient control subjects with early life adversity; Control-w/oELA, control subjects without ELA; MDDSui-wELA, subjects with major depressive disorder who died by suicide with ELA; MDDSui-w/oELA, subjects with MDD who died by suicide without ELA.