The role of oxidative stress, DNA damage and DNA repair in stress-mediated depression.
Our lab focuses on the role of oxidative DNA damage and repair in neurodegeneration. Specifically, we look at the role of DNA glycosylases OGG1 and MUTYH that repair oxidative lesions that accumulate on the DNA and how the actions of these glycosylases are involved in neurodegenerative diseases. Previous work from our lab has shown that transgenic knockdown of Ogg1 and Mutyh genes resulted in decreased anxiety-like behaviors and other studies have shown that the 8-oxoguanine oxidative lesion and its repair may alter transcriptional states.
This project aims to examine how chronic stress relates to OS and how this may mediate the physiological dysregulation in neuronal systems during depression and anxiety which lead to neuronal and glial atrophy. Here we use a chronic unpredictable mild stress paradigm to induce depression- and anxiety-like behaviors in mice so we can examine how the accumulation of OS alters the neuroepigenome. We expect our study will contribute to a better understanding of the pathophisiology of mood disorders to provide new insights for biomarkers and treatment targets including possibilities for early intervention that may prevent the pathological changes that develop in the brain in depression.
This project requires a certain level of distress in the experimental animals. Here we have chosen a chronic unpredictable mild stress paradigm which has been used extensively in depression research. This paradigm utilizes mild environmental changes that persist over the course of weeks. This paradigm is known to induce anxiety- and depressive-like behaviors such as decreased reward seeking, decreased exploratory behaviors and abnormal social behaviors, as well as some physical symptoms like decreased weight gain. Overall, we do not expect to see dramatic changes in the normal behavior of the mice within their home cages. Unfortunately since this study requires the assessment of behavioral traits we need to utilize mice as opposed to other options, like cell cultures or organoids (replacement). For this project we would like to apply for 664 mice, a number calculated based on previous experience with these analysis techniques and previous studies utilizing stress paradigms, but have designed the study in such a way that it can be halted should we obtain the necessary number of samples earlier (reduction). We have worked to minimize the level of distress by utilizing mild environmental stressors as opposed to other trauma based paradigms, like social defeat, and by implementing less distressing handling procedures and less invasive sample collections (refinement). To protect the welfare of the animals included in this study we have consistent monitoring of both distress symptoms (behaviors) and biological markers of stress (corticosterone levels and body weight) with defined endpoints.
This project aims to examine how chronic stress relates to OS and how this may mediate the physiological dysregulation in neuronal systems during depression and anxiety which lead to neuronal and glial atrophy. Here we use a chronic unpredictable mild stress paradigm to induce depression- and anxiety-like behaviors in mice so we can examine how the accumulation of OS alters the neuroepigenome. We expect our study will contribute to a better understanding of the pathophisiology of mood disorders to provide new insights for biomarkers and treatment targets including possibilities for early intervention that may prevent the pathological changes that develop in the brain in depression.
This project requires a certain level of distress in the experimental animals. Here we have chosen a chronic unpredictable mild stress paradigm which has been used extensively in depression research. This paradigm utilizes mild environmental changes that persist over the course of weeks. This paradigm is known to induce anxiety- and depressive-like behaviors such as decreased reward seeking, decreased exploratory behaviors and abnormal social behaviors, as well as some physical symptoms like decreased weight gain. Overall, we do not expect to see dramatic changes in the normal behavior of the mice within their home cages. Unfortunately since this study requires the assessment of behavioral traits we need to utilize mice as opposed to other options, like cell cultures or organoids (replacement). For this project we would like to apply for 664 mice, a number calculated based on previous experience with these analysis techniques and previous studies utilizing stress paradigms, but have designed the study in such a way that it can be halted should we obtain the necessary number of samples earlier (reduction). We have worked to minimize the level of distress by utilizing mild environmental stressors as opposed to other trauma based paradigms, like social defeat, and by implementing less distressing handling procedures and less invasive sample collections (refinement). To protect the welfare of the animals included in this study we have consistent monitoring of both distress symptoms (behaviors) and biological markers of stress (corticosterone levels and body weight) with defined endpoints.