Oxidative Stress Susceptibility of Oligodendrocytes in Major Depressive Disorder is Widespread in the Brain

Over 10 million people are affected by major depressive disorder (MDD) in the U.S. annually. Unfortunately, about 1/3 of these people do not achieve adequate remission of symptoms with current antidepressant drugs. It is expected that an improved understanding of the pathobiology of depression will result in the development of more effective antidepressant treatments. Research by this lab in recent years has provided evidence of elevated DNA damage in brain white matter in MDD, discovered by studying brain tissues from human brain donors that had an active diagnosis of MDD at the time of death and age-matched control donors who had no psychiatric illness. Accompanying this DNA damage was an elevation of gene expression of DNA base excision repair enzymes in white matter oligodendrocytes, a major cell type in brain white matter. In addition, gene expression of antioxidant genes in these oligodendrocytes was significantly lower in MDD than in control donors, suggesting that these cells were especially susceptible to the damaging effects of oxidative stress in MDD. This initial data was generated by measuring gene expressions in oligodendrocytes captured from two specific regions of white matter in the brain, the frontal cortex, and amygdala. In the present study, we designed experiments to determine whether these effects are found in oligodendrocytes in other areas of the brain in MDD and to determine whether another cell type in the brain, neurons, are similarly affected. Towards these aims, oligodendrocytes from two other brain regions (occipital cortical white matter and brainstem locus coeruleus) were captured by laser microdissection from MDD and control donors. In addition, CA1 pyramidal neurons were captured from the anterior hippocampus of MDD and control donors. We chose to specifically study hippocampal CA1 pyramidal neurons because these neurons are normally sensitive to oxidative stress, and reasoned that these cells would be among brain neurons most likely affected by conditions of elevated oxidative stress in MDD. Approximately 500 cells were captured from each brain area using immunohistochemically-guided laser capture microdissection. RNA isolated from these cells was converted to cDNA by reverse transcription and subjected to quantitative polymerase chain reactions (PCR). Statistically significant reductions in antioxidant gene expression was observed in oligodendrocytes from MDD donors as compared to control donors regardless of the brain area from which the cells were captured. In contrast, no significant changes in antioxidant gene expression were observed in CA1 pyramidal neurons from MDD donors. Additionally in contrast to findings in oligodendrocytes, levels of gene expression of the DNA repair enzyme, poly(ADP-ribose) polymerase 1 (PARP1) in hippocampal CA1 pyramidal neurons from MDD donors was similar to that from control donors. These findings demonstrate that pathological DNA damage and repair mechanisms occur in brain oligodendrocytes throughout the brain, and similar mechanisms do not appear to affect hippocampal neurons. A better understanding of the cellular systems engaged by oxidative damage to oligodendrocytes in MDD has the potential to lead to the identification of unique targets for the development of novel antidepressant drugs

The Study of Oligodendrocyte Pathology Using Postmortem Tissue From Brain Donors Reveals Unique Targets for the Development of Novel Antidepressants

Oligodendrocytes are predominately found in white matter of the brain, but also populate gray matter regions. Although commonly known to provide myelination of neuronal axons, these cells serve numerous other functions in the brain. A unique property of oligodendrocytes is their inherent susceptibility to oxidative stress because of several biochemical characteristics of these cells, including a high concentration of iron, high metabolic rate, and low antioxidant enzyme activity. Oxidative stress conditions are produced by inflammation, and both inflammation and oxidative stress are highly associated with major depressive disorder (MDD). Hence, the study of oligodendrocytes in the brain in MDD readily provides access to molecular mechanisms engaged by oxidative stress conditions that putatively contribute to the etiology of MDD. My laboratory studied oligodendrocytes, and other white matter cells, from postmortem tissue collected from brain donors that died as a result of suicide and other causes, focusing on those donors who had at the time of death either MDD or no psychiatric or neurologic diagnosis (controls). White matter oligodendrocytes or whole white matter in limbic brain from MDD/suicide donors demonstrated indices of elevated oxidative damage, including increased DNA oxidation, shortened telomere DNA, reduced expression of antioxidant enzyme genes, and upregulated DNA base excision repair enzymes. These abnormalities were either not observed or were only modestly evident in astrocytes collected from white matter of the same MDD/suicide donors. To determine whether this oxidative damage was restricted to white matter in the limbic brain, oligodendrocytes were captured from three other brain regions, prefrontal cortical (BA 10) white matter, occipital cortical white matter, and gray matter in the region of the brainstem locus coeruleus. Shortened telomeres and reduced expression of antioxidant enzyme genes were observed in oligodendrocytes from these additional brain regions in MDD/suicide. Since this oligodendrocyte pathology was not anatomically restricted to the limbic brain, it may be difficult to understand how it is relevant to the biological basis of emotional behaviors that are specifically associated with MDD or suicide. However, the oligodendrocyte is highly susceptible to oxidative stress; hence, the oligodendrocyte can be viewed as a “canary in the coal mine” for detecting oxidative damage to the brain. Therefore, elucidation of the molecular pathways activated by oxidative damage in these cells could reveal novel targets for the development of drugs to prevent oxidative damage and its subsequent pathological activation of downstream pathways deleterious to brain cell health. As such, drugs targeting these pathways may have antidepressant properties in humans, and could provide an alternative approach to treating depression and reducing suicide risk. In fact, we found that repeated exposure of rats to psychological stress increased DNA oxidation in prefrontal cortical white matter. Furthermore, preliminary findings using rat models of depression reveal that interruption of pathways downstream to oxidative damage produces a robust antidepressant response, correcting depressive-like behaviors elicited by psychological stress. These findings strongly implicate a role of oxidative damage in the etiology of MDD and possibly suicide, and demonstrate the utility of studying brain pathology as a logical path to identifying novel antidepressant targets

The effect of peat structure on the spatial distribution of biogenic gases within bogs

Northern peatlands are a large source of atmospheric methane (CH4) and both a source and a sink of atmospheric carbon dioxide (CO2). The rate and temporal variability in gas exchanges with peat soils is directly related to the spatial distribution of these free-phase gases within the peat column. In this paper, we present results from surface and borehole ground-penetrating radar surveys - constrained with direct soil and gas sampling - that compare the spatial distribution of gas accumulations in two raised bogs: one in Wales (UK), the other in Maine (USA). Although the two peatlands have similar average thickness, physical properties of the peat matrix differ, particularly in terms of peat type and degree of humification. We hypothesize that these variations in physical properties are responsible for the differences in gas distribution between the two peatlands characterized by (1) gas content up to 10.8% associated with woody peat and presence of wood layers in Caribou Bog (Maine) and (2) a more homogenous distribution with gas content up to 5.7% at the surface (i.e

Symbols of Resilience and Contested Place Identity in the Coastal Fishing Towns of Cromer and Sheringham, Norfolk, UK: Implications for Social Wellbeing

Fishing has been a core part of the identities of Cromer and Sheringham, rural coastal communities with a long tradition of inshore crab fishing in the East of England. However, given the decline in the number of fishing boats and wider demographic, economic and social change, the fishing identity of these towns is perceived as threatened. Drawing on qualitative research, this chapter develops a conceptual approach drawing on perspectives from place research and social wellbeing to explore the different place meanings held by coastal residents, visitors and fishermen. A focus on how different people relate to place and with each other provides a more nuanced understanding of social wellbeing. Tensions over place identity are exposed particularly between ‘newcomers’ and local residents, and over aspirations for economic development. Cromer and Sheringham’s fishing identity is being defended by the fishermen and those who value the fishery. This case study reveals the political nature of how different understandings of place, development and wellbeing are constructed and contested. The future of the fishery and the town will depend on whose values and place meanings are privileged and represented in governance processes