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AnxBio Proteomics

ABSTRACT: Anxiety disorders are the most common mental disorders within the EU and cause considerable disability due to high prevalence (14%), early onset and chronic nature. The currently used, poorly targeted drugs are ineffective because of addiction, tolerance, and poor efficacy. Consequently, better anxiolytics are needed, and their development requires understanding of the molecular mechanisms of anxiety, which currently remain largely unknown. Our goal was to identify the major biological pathways and biomarkers for anxiety disorders using a well-established mouse model and a human patient sample. Our mouse model, the social defeat, allows investigation of gene-environment interactions, known to be important in anxiety disorders. Using the most current proteomics methods we analyzed protein expression related to increased anxiety in brain and blood cells in the mouse. This multidisciplinary project was designed to increase the understanding of the neurobiological basis of anxiety, and provided targets for the development of improved anxiolytics and biomarkers for anxiety disorders.

INSTRUMENT(S): Bruker Impact II

ORGANISM(S): Mus Muculus

SUBMITTER: Chris Turck

PROVIDER: MSV000083001 | MassIVE | Thu Oct 04 23:57:00 BST 2018

REPOSITORIES: MassIVE

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Project description:Brain structure and function are sexually dimorphic. As neuroscience research has largely focused on the male brain and behavior, the female brain and, in particular, its inherent dynamics have been left underexplored. During the mammalian reproductive period, the female brain is exposed to fluctuating hormone levels over the cycles known as menstrual (in humans) or estrous (in rodents). Variation in estradiol levels has been shown to affect synaptic plasticity in the female brain, including changes in dendritic spine density systematically across the estrous cycle. Female emotionality and cognitive function vary with physiologically fluctuating sex hormone levels. However, the molecular mechanisms underlying the dynamic nature of the female brain structure and function are currently unknown. Here we show that neuronal chromatin organization in the female ventral hippocampus of mouse is dynamic and fluctuates across the estrous cycle. We find changes in chromatin organization associated with the transcriptional activity of nearby genes important for neuronal function, neurotransmission, synapse formation, and behavior. We also link these chromatin dynamics to variation in anxiety-like behavior and to fluctuations in dendritic spine and synaptic density in the ventral hippocampus. In terms of chromatin structure, within-female and between-sex variation are of similar magnitudes, emphasizing the importance of accounting for fluctuating sex-hormone levels in females in the studies of the brain epigenome and behavior. These results provide critical insights into the mechanisms underlying sex-hormone and sex-dependent variation in adult brain structure and function. The study also has implications for better understanding of sex-biased disorders such as depression and anxiety which are strongly associated with sex-hormone status in females and are twice as prevalent in women than in men. This study establishes a foundation for the development of sex-specific approaches to treat sex-biased neuropsychiatric disorders including depression and anxiety disorders.

Project description:A group of postnatal neurodevelopmental disorders collectively referred to as MeCP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MeCP2 function causes Rett syndrome (RTT), whereas increased MeCP2 dosage causes MECP2 duplication or triplication syndromes. MeCP2 acts as a transcriptional repressor, however, the gene expression changes observed in the hypothalamus and cerebellum of MeCP2 disorder mouse models suggest that MeCP2 can also upregulate gene expression. In this study, we compared gene expression changes in the amygdalae of mice lacking MeCP2 (Mecp2-null) and mice overexpressing MeCP2 (MECP2-TG). We chose the amygdala because it is a neuroanatomical region implicated in the control of anxiety and social behavior, two prominent phenotypes in MECP2-TG mice, and hypothesized that transcriptional profiling of this particular brain region may reveal expression changes relevant to heightened anxiety-like behavior and abnormal social behavior. A total of 1,060 genes were altered in opposite directions in both MeCP2 mouse models compared with wild-type littermates, with ~60% up-regulated and ~40% down-regulated. Interestingly, we found a significant enrichment of anxiety- and/or social behavior-related genes among the differentially expressed genes. To determine whether these genes contribute to the anxiety and social behavior phenotypes in MECP2-TG mice, we performed genetic and pharmacologic studies and found that a reduction in Crh suppresses anxiety-like behavior, and a reduction in Oprm1 improves social approach behavior. These studies suggest that MeCP2 impacts molecular pathways involved in anxiety and social behavior, and provide insight into potential therapies for MeCP2 disorders. This study is published in Nature Genetics http://dx.doi.org/10.1038/ng.1066. Total amygdala RNA samples were collected from Mecp2-null male mice (n=4), MECP2-transgenic male mice (n=5), and their wild type male littermates at 6 weeks of age (n=4, n=5 for each group respectively).

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AnxBio Proteomics

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