Examining Hippocampal Reelin Expression and Neural Plasticity in an Animal Model of Depression

Stress is an important risk factor for the development of clinical depression, yet little is known about the neurobiological mechanisms by which stress might promote depressive symptomatology. The brain is particularly susceptible to the negative effects of stress, as high levels of stress hormones result in decreased hippocampal neurogenesis, slowed cell maturation, and decreased cell complexity. Although we already know that these neurobiological changes are associated with significant impairments in important psychological functions such as learning, memory and motivation, we know little about the molecular details of this stress-induced remodeling and how it contributes to the development of depression. Currently, one candidate molecule of particular interest is reelin, an extracellular matrix protein responsible for regulating neuronal maturation and synaptic plasticity in the adult brain. Interestingly, recent post- mortem analyses indicate that reelin expression is decreased in depressed patients. Similarly, preclinical research has shown that repeated glucocorticoid administration significantly reduces reelin expression in the adult hippocampus. Combined, these results suggest that reelin may be an important protein to examine in regards to the pathogenesis of depression as well as a potential therapeutic target for the treatment of this disorder. The goal of this dissertation is to provide a comprehensive examination of the influence repeated glucocorticoid administration has on reelin expression in the rat hippocampus, and how this relates to the pathogenesis of depression. In chapter 2 we examined how co-treatment with the stress hormone corticosterone (CORT), and the antidepressant imipramine, influence reelin expression in the proliferative region of the hippocampus. In addition we determined whether changes in reelin expression are associated with alterations in neurogenesis and behavioral measures of depression. Results revealed that imipramine prevents CORT-induced downregulation of reelin in the hippocampus, and that these changes parallel improvements in FST behavior, increased neurogenesis and enhanced maturation of immature granule cells. Importantly, these data provide further evidence of reelin’s role in depression and establish this protein as a target of antidepressant treatment. In chapter 3 we examined the effect of CORT on a number of interneuron markers that co-localize with reelin throughout the hippocampus to determine whether the populations of neurons that express reelin are lost or are no longer expressing this protein. Results of this study indicate that CORT influences a number of interneuron markers in a region-specific manner in the hippocampus, but does not cause these cell populations to die, suggesting that CORT exploits an intracellular mechanism to regulate reelin expression in the hippocampus. Finally, in chapter 4, the influence of CORT on MeCP2 and DNMT1, two markers associated with DNA methylation, was examined in the hippocampus to elucidate a potential intracellular mechanism for CORT-induced reelin deficits. Results of this study indicate that CORT has no influence on global protein levels of these markers, but significantly increases the number of MeCP2-expressing cells in the proliferative subgranular zone of the hippocampus, suggesting that there is an increase in the number of methylated cells in this region. While it cannot be conclude from this study that increased methylation causes reelin deficits, the fact that an increase in MeCP2 is seen in the exact region where reelin deficits are most pronounced suggest it is possible. Moreover, these findings are novel, and suggest a role for MeCP2, and more generally, DNA methylation, in the neurobiology of depression. Collectively, the results of this dissertation enhance our understanding of the functional consequences of altered hippocampal neuroplasticity on the development of depressive symptomatology, and the role that reelin may play in this process. They also provide further support for reelin as a novel therapeutic target for the treatment of major depression

The Effects of the COVID-19 Pandemic on Maine’s Labor Market and Workforce

This article uses a variety of data sources to examine the pandemic’s impact on the labor market in Maine, first by putting it in the context of past recessions, then by assessing telework suitability across occupations, and finally by exploring the differential job losses that occurred during the pandemic by sector and by gender and educational attainment

Risk, nostalgia, and the production of the ideal childhood in online commentary on children’s outdoor play

We use Foucauldian discourse analysis to examine comments posted online in response to news articles that reported on one Canadian neighbourhood’s ‘ban’ on children’s outdoor play. Our analysis showed that reader comments, both for and against the ban on street play, accessed discourses of risk that produced an idealized childhood based on close parental supervision. Additionally, nostalgic discourse, the feeling that unfettered, wholesome outdoor play has been lost and cannot be reclaimed, also made claims about who the ideal childhood is for. While marginalized children continue to experience disadvantage that inherently exposes them to risks daily, White, middle class children already have access to safer streets, both parent presence or unquestioned but appropriate parental absence, and play in the streets can be part of their everyday lives. We consider how the idealized childhoods produced by discourses of risk and nostalgia influence the materiality of children’s outdoor play, including how children’s time is organized and who gets to organize it, how play is experienced and who gets to experience it; in ideal ways, in ideal spaces, and for the ideal child

Gestational and Chronic Low-Dose PFOA Exposures and Mammary Gland Growth and Differentiation in Three Generations of CD-1 Mice

Background: Prenatal exposure to perfluorooctanoic acid (PFOA), a ubiquitous industrial surfactant, has been reported to delay mammary gland development in female mouse offspring (F1) and the treated lactating dam (P0) after gestational treatments at 3 and 5 mg PFOA/kg/day

Hepatic Mitochondrial Alteration in CD-1 Mice Associated with Prenatal Exposures to Low Doses of Perfluorooctanoic Acid (PFOA)

Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3 and 1 mg/kg of PFOA from gestation days (GD) 1 through 17. On postnatal day (PND) 21, histopathologic changes in the livers of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND 91 in an apparent dose-dependent response. Transmission electron microscopy (TEM) of selected liver sections from PND 91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. Within hypertrophied hepatocytes, mitochondria were not only increased in number, but also exhibited altered morphologies suggestive of increased and/or uncontrolled fission and fusion reactions. These findings suggest that peroxisome proliferation is not a component of PFOA-induced hepatic toxicity in animals that are prenatally exposed to low doses of PFOA

Perfluorooctanoic Acid (PFOA)–induced Liver Lesions in Two Strains of Mice Following Developmental Exposures: PPARα Is Not Required

Perfluorooctanoate acid (PFOA) is a ubiquitous pollutant that causes liver toxicity in rodents, a process believed to be dependent on peroxisome proliferation activated receptor alpha (PPARα) activation. Differences between humans and rodents have made the human relevance of some health effects caused by PFOA controversial. We analyzed liver toxicity at 18 months following gestational PFOA exposure in CD-1 and 129/Sv strains of mice and compared PFOA-induced effects between strains and in wild type (WT) and PPARα-knockout (KO) 129/Sv mice. Pregnant mice were exposed daily to doses (0.01–5mg/kg/BW) of PFOA from gestation days 1–17. The female offspring were necropsied at 18 months and liver sections underwent a full pathology review. Hepatocellular adenomas formed in PFOA-exposed PPARα-KO 129/Sv and CD-1 mice, and were absent in untreated controls from those groups and WT 129/Sv. Hepatocellular hypertrophy was significantly increased by PFOA exposure in CD-1 and an increased severity was found in WT 129/Sv mice. PFOA significantly increased non-neoplastic liver lesions in PPARα-KO mice (hepatocyte hypertrophy, bile duct hyperplasia and hematopoietic cell proliferation). Low dose gestational exposures to PFOA induced latent PPARα independent liver toxicity that was observed in aged mice. Evidence of liver toxicity in PPARα-KO mice warrants further investigation into PPARα independent pathways

Effects of perfluorooctanoic acid on mouse mammary gland development and differentiation resulting from cross-foster and restricted gestational exposures

The adverse consequences of developmental exposures to perfluorooctanoic acid (PFOA) are established in mice, and include impaired development of the mammary gland (MG). However, the relationships between timing or route of exposure, and consequences in the MG have not been characterized. To address the effects of these variables on the onset and persistence of MG effects in female offspring, timed pregnant CD-1 dams received PFOA by oral gavage over various gestational durations. Cross-fostering studies identified the 5 mg/kg dose, under either lactational- or intrauterine-only exposures, to delay MG development as early as postnatal day (PND) 1, persisting beyond PND 63. Intrauterine exposure during the final days of pregnancy caused adverse MG developmental effects similar to that of extended gestational exposures. These studies confirm a window of MG sensitivity in late fetal and early neonatal life, and demonstrate developmental PFOA exposure results in early and persistent MG effects, suggesting permanent consequences

Analysis of PFOA in dosed CD-1 mice. Part 2: Disposition of PFOA in tissues and fluids from pregnant and lactating mice and their pups

Previous studies in mice with multiple gestational exposures to perfluorooctanoic acid (PFOA) demonstrate numerous dose dependent growth and developmental effects which appeared to worsen if offspring exposed in utero nursed from PFOA-exposed dams. To evaluate the disposition of PFOA in the pregnant and lactating dam and her offspring, time-pregnant CD-1 mice received a single 0, 0.1, 1, or 5 mg PFOA/kg BW dose (n = 25/dose group) by gavage on gestation day 17. Maternal and pup fluids and tissues were collected over time. Pups exhibited significantly higher serum PFOA concentrations than their respective dams, and their body burden increased after birth until at least postnatal day 8, regardless of dose. The distribution of milk:serum PFOA varied by dose and time, but was typically in excess of 0.20. These data suggest that milk is a substantial PFOA exposure route in mice and should be considered in risk assessment modeling designs for this compound