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Around 3-8% of all women in reproductive age suffer from premenstrual dysphoric disorder (PMDD) which disenables them to live an ordinary life during the luteal phase (premenstrual phase) of the menstrual cycle. Throughout the premenstrual phase these women experience emotional, cognitive and physiological changes. Hitherto, the etiology of this disorder is unknown. Some consider the source of this state as non-biological, claiming that PMDD is a social construction imbedded in gender roles, that suggests that women should not show aggressive behavior or depressive mood unless it is during the premenstrual stage. Contradictory, research made in cognitive neuroscience claim that the origin is biological. It is assumed that the increased symptoms in women with PMDD is a result from dysfunctional sensitivity for the progesterone metabolite allopregnanolone that has a receptor in the GABAA system, hence, producing an anxious effect from high levels of allopregnanolone instead of the expected sedative, soothing effects. Research suggest that structural and functional changes occur in brain areas such as the hippocampus, parahippocampus, amygdala, cerebellum as well as in brainderived neurotrophic factor which is important for brain plasticity, growth and survival of neurons. Cognitive behaviors such as anticipation for negative stimuli, working memory and lack of cognitive control also seem to be affected by PMDD. Nonetheless, the evidence is inconsistent, the area of research face multiple issues in regards to study designs, hence making generalization at this point difficult. In sum, this essay reviews recent studies conducted in neuroscience of cognitive changes in women with PMDD, with focus on functional, structural and behavioral changes between the phases of the cycle.

Around 3-8% of all women in reproductive age suffer from premenstrual dysphoric disorder (PMDD) which disenables them to live an ordinary life during the luteal phase (premenstrual phase) of the menstrual cycle. Throughout the premenstrual phase these women experience emotional, cognitive and physiological changes. Hitherto, the etiology of this disorder is unknown. Some consider the source of this state as non-biological, claiming that PMDD is a social construction imbedded in gender roles, that suggests that women should not show aggressive behavior or depressive mood unless it is during the premenstrual stage. Contradictory, research made in cognitive neuroscience claim that the origin is biological. It is assumed that the increased symptoms in women with PMDD is a result from dysfunctional sensitivity for the progesterone metabolite allopregnanolone that has a receptor in the GABAA system, hence, producing an anxious effect from high levels of allopregnanolone instead of the expected sedative, soothing effects. Research suggest that structural and functional changes occur in brain areas such as the hippocampus, parahippocampus, amygdala, cerebellum as well as in brainderived neurotrophic factor which is important for brain plasticity, growth and survival of neurons. Cognitive behaviors such as anticipation for negative stimuli, working memory and lack of cognitive control also seem to be affected by PMDD. Nonetheless, the evidence is inconsistent, the area of research face multiple issues in regards to study designs, hence making generalization at this point difficult. In sum, this essay reviews recent studies conducted in neuroscience of cognitive changes in women with PMDD, with focus on functional, structural and behavioral changes between the phases of the cycle.

STUDY QUESTION: Does repeat-associated non-AUG (RAN) translation play a role in fragile X-associated primary ovarian insufficiency (FXPOI), leading to the presence of polyglycine containing protein (FMRpolyG)-positive inclusions in ovarian tissue? SUMMARY ANSWER: Ovaries of a woman with FXPOI and of an Fmr1 premutation (PM) mouse model (exCGG-KI) contain intranuclear inclusions that stain positive for both FMRpolyG and ubiquitin. WHAT IS KNOWN ALREADY: Women who carry the FMR1 PM are at 20-fold increased risk to develop primary ovarian insufficiency (FXPOI). A toxic RNA gain-of-function has been suggested as the underlying mechanism since the PM results in increased levels of mRNA containing an expanded repeat, but reduced protein levels of fragile X mental retardation protein (FMRP). Recently, RAN translation has been shown to occur from FMR1 mRNA that contains PM repeat expansions, leading to FMRpolyG inclusions in brain and non-CNS tissues of fragile X-associated tremor/ataxia syndrome (FXTAS) patients. STUDY DESIGN, SIZE, DURATION: Ovaries of a woman with FXPOI and women without PM (controls), and ovaries from wild-type and exCGG-KI mice were analyzed by immunohistochemistry for the presence of inclusions that stained for ubiquitin and FMRpolyG. The ovaries from wild-type and exCGG-KI mice were further characterized for the number of follicles, Fmr1 mRNA levels and FMRP protein expression. The presence of inclusions was also analyzed in pituitaries of a man with FXTAS and the exCGG-KI mice. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human ovaries from a woman with FXPOI and two control subjects and

Study questionDoes repeat-associated non-AUG (RAN) translation play a role in fragile X-associated primary ovarian insufficiency (FXPOI), leading to the presence of polyglycine containing protein (FMRpolyG)-positive inclusions in ovarian tissue?Summary answerOvaries of a woman with FXPOI and of an Fmr1 premutation (PM) mouse model (exCGG-KI) contain intranuclear inclusions that stain positive for both FMRpolyG and ubiquitin.What is known alreadyWomen who carry the FMR1 PM are at 20-fold increased risk to develop primary ovarian insufficiency (FXPOI). A toxic RNA gain-of-function has been suggested as the underlying mechanism since the PM results in increased levels of mRNA containing an expanded repeat, but reduced protein levels of fragile X mental retardation protein (FMRP). Recently, RAN translation has been shown to occur from FMR1 mRNA that contains PM repeat expansions, leading to FMRpolyG inclusions in brain and non-CNS tissues of fragile X-associated tremor/ataxia syndrome (FXTAS) patients.Study design, size, durationOvaries of a woman with FXPOI and women without PM (controls), and ovaries from wild-type and exCGG-KI mice were analyzed by immunohistochemistry for the presence of inclusions that stained for ubiquitin and FMRpolyG . The ovaries from wild-type and exCGG-KI mice were further characterized for the number of follicles, Fmr1 mRNA levels and FMRP protein expression. The presence of inclusions was also analyzed in pituitaries of a man with FXTAS and the exCGG-KI mice.Participants/materials, setting, methodsHuman ovaries from a woman with FXPOI and two control subjects and pituitaries from a man with FXTAS and a control subjects were fixed in 4% formalin. Ovaries and pituitaries of wild-type and exCGG mice were fixed in Bouin's fluid or 4% paraformaldehyde. Immunohistochemistry was performed on the human and mouse samples using FMRpolyG, ubiquitin and Fmrp antibodies. Fmr1 mRNA and protein expression were determined in mouse ovaries by quantitative R

Of the plethora of symptoms that arise in HD, depression is the most diagnosed psychiatric symptom, with 30-50% of patients developing depression. This makes depression far more prevalent in the HD population than in the general populace and indeed, significantly more conspicuous compared to other neurodegenerative diseases such as Parkinson’s or Alzheimer’s disease. Due to depression’s ubiquity, impact and also the fact that it can appear decades before crippling motor symptoms, treatment and management of depression would significantly prolong the symptom-free period of patients’ lives. The overrepresentation of depression is most likely an endemic reflection of pathophysiology caused by the HD mutation. However, the aetiology of depression in the context of HD has not been well understood. The hypothalamic-pituitary-adrenal (HPA) axis is the major endocrine system responsible for stress adaptation and its dysfunction has been implicated in clinical depression. Few studies have examined the HPA-axis in HD to date. Our group has previously found, using the R6/1 mouse model of HD, a female-specific depression-like behavioural phenotype. In this thesis, examining the HPA-axis in these animals, it was found that female, but not male, R6/1 mice displayed a hyperactive HPA-axis in response to stressors. Further pharmacological challenges, gene expression analyses and in vitro studies discerned the source of the abnormality to a hypersensitive adrenal gland; a novel finding of a peripheral source for what has been largely seen as a centrally mediated pathology. Environmental factors have been found to produce significant modulation to the progression of HD. Previously, our lab has shown that environmental enrichment is able to delay the onset of various symptoms in the R6/1 mice, including depression-like behavioural phenotype in the female mice. In this thesis, environmental enrichment was also found to be able to rescue the abnormalities of the HPA-axis both in vivo an