Digital archive of theses discussed at the University of Pisa


Thesis etd-06252014-135606

Thesis type
Tesi di specializzazione (5 anni)
Thesis title
Exposure to Early Life Adversity and the Effect on Dentate Gyrus Cells in Major Depressive Disorder
Course of study
relatore Prof. Mauri, Mauro
  • hippocampus
  • neurogenesis
  • childhood adversity
  • depression
Graduation session start date
Objectives: Early childhood adverse events (CAE), including abuse, neglect, and separation, enhance the risk of major depressive disorder (MDD). Animal studies have shown that stress decreases proliferation and survival of neuronal precursor cells (NPCs) in the hippocampal dentate gyrus (DG). We hypothesize that childhood adversity events affects neuroplasticity differently in untreated major depressive disorder (MDD) patients, antidepressant-treated MDD patients, and non-psychiatric controls. Among these groups, we sought to stereologically assess potential differences in hippocampal DG volume, as well as total number of neural progenitor cells (NPCs), mitotic cells (Ki-67), and granule neurons (GNs) in the DG of subjects with and without a history of childhood trauma adversity (before age 16).
Methods: We assessed whole postmortem hippocampi of CAE and non-CAE subjects that were classified into three matched groups: non-psychiatric controls, untreated major depressive disorder patients (MDDs), and antidepressant-treated MMDs. Postmortem tissue was obtained from the Macedonian/New York State Psychiatric Institute brain collection. Research was conducted with institutional review board (IRB) approval. At the time of autopsy, 2 cm-thick coronal blocks of the hemispheres were frozen in dichlorodifluoromethane (-30°C) and stored at -80C. Selected brain areas were formalin-fixed for neuropathological examination, brain pH was determined and toxicology was performed on cerebellar samples. Hippocampi were sectioned at 50 μm and immunostained for mitotic cells (Ki67-IR), mature neurons (NeuN-IR) and neuronal progenitor cells (Nestin-IR) markers at 2 mm intervals. Total cell number and volume in the DG were estimated by stereology. Subjects were diagnosed using a psychological autopsy, the SCID I or SCID NP (Non-Patient edition) and II, using a method validated for DSM axis I and II diagnoses. History of lifetime mood disorders, developmental history and recent medication history were obtained. The St. Paul Ramsey Life Experience Scale rated the impact of subjects' recent stressful life events using a seven-point scale of severity rating for events that belong to the conjugal, interpersonal, occupational, living and health domains. We analyzed the total St. Paul Ramsey Life Experience Scale score and the overall “Axis IV” score according to this scale. Cause of death, time to autopsy and freezer storage time were noted.
Results: Mature granule neurons (GNs) differed between groups in the anterior and mid DG. Controls with adversity (C*Adv) had more GNs than untreated MDDs with adversity (MDD*UAdv) in the anterior and mid DG. Treated MDDs (MDD*T) had more GNs than untreated MDDs (MDD*U) in the anterior DG. Mitotic cells (Ki-67) differed between groups in the anterior. MDD*TAdv subjects had more mitotic cells compared to the other groups. Furthermore, DG volume differed between groups in the mid DG. MDD*Ts had larger hippocampal volume than the other groups.
Limitations: The primary limitation of this study is the small sample size. Larger samples should be used for replication of the observations. Also, a limitation of any post-mortem study is the cross-sectional analysis, therefore causes and consequence cannot be discerned. The relationship between neurogenesis and clinical improvement of MDD cannot be studied postmortem and, at the moment, there are no feasible methods to assess human adult neurogenesis in vivo. Furthermore, the fact that antidepressants exposure is associated with evidence of more neurogenesis does not mean it is the mechanism of antidepressant action.
Conclusions: The study showed that non-psychiatric controls with childhood adversity had a greater number of mature neurons compared to subjects with major depressive disorder and history of childhood adversity. For subjects with history of childhood adversity, the decrease in mature neurons is associated with vulnerability to develop major depressive disorder (MDD), whereas an increase in mature neurons is associated with resilience to MDD. Furthermore, in subjects with treated MDDs, early life traumas counteract the antidepressants response, showing a reduced hippocampal volume compared to treated MDD subjects without adversity.