There are robust sex differences in brain anatomy, function, as well as neuropsychiatric and neurodegenerative disease risk (1-6), with women approximately twice as likely to suffer from a depressive illness as well as Alzheimer’s Disease. Disruptions in ovarian hormones likely play a role in such disproportionate disease prevalence, given that ovarian hormones serve as key regulators of brain functional and structural plasticity and undergo major fluctuations across the female lifespan (7-9). From a clinical perspective, there is a wellreported increase in depression susceptibility and initial evidence for cognitive impairment or decline during hormonal transition states, such as the postpartum period and perimenopause (9-14). What remains unknown, however, is the underlying mechanism of how fluctuations in ovarian hormones interact with other biological factors to influence brain structure, function, and chemistry. While this line of research has translational relevance for over half the population, neuroscience is notably guilty of female participant exclusion in research studies, with the male brain implicitly treated as the default model and only a minority of basic and clinical neuroscience studies including a female sample (15-18). Female underrepresentation in neuroscience directly limits opportunities for basic scientific discovery; and without basic knowledge of the biological underpinnings of sex differences, we cannot address critical sexdriven differences in pathology. Thus, my doctoral thesis aims to deliberately investigate the influence of sex and ovarian hormones on brain states in health as well as in vulnerability to depression and cognitive impairment:Table of Contents
List of Abbreviations ..................................................................................................................... i
List of Figures .............................................................................................................................. ii
Acknowledgements .....................................................................................................................iii
1 INTRODUCTION .....................................................................................................................1
1.1 Lifespan approach: Sex, hormones, and metabolic risk factors for cognitive health .......3
1.2 Reproductive years: Healthy models of ovarian hormones, serotonin, and the brain ......4
1.2.1 Ovarian hormones and brain structure across the menstrual cycle ........................4
1.2.2 Serotonergic modulation and brain function in oral contraceptive users .................6
1.3 Neuropsychiatric risk models: Reproductive subtypes of depression ...............................8
1.3.1 Hormonal transition states and brain chemistry measured by PET imaging ...........8
1.3.2 Serotonin transporter binding across the menstrual cycle in PMDD patients .......10
2 PUBLICATIONS ....................................................................................................................12
2.1 Publication 1: Association of estradiol and visceral fat with structural brain networks
and memory performance in adults .................................................................................13
2.2 Publication 2: Longitudinal 7T MRI reveals volumetric changes in subregions of
human medial temporal lobe to sex hormone fluctuations ..............................................28
2.3 Publication 3: One-week escitalopram intake alters the excitation-inhibition balance
in the healthy female brain ...............................................................................................51
2.4 Publication 4: Using positron emission tomography to investigate hormone-mediated
neurochemical changes across the female lifespan: implications for depression ..........65
2.5 Publication 5: Increase in serotonin transporter binding across the menstrual cycle in
patients with premenstrual dysphoric disorder: a case-control longitudinal neuro-
receptor ligand PET imaging study ..................................................................................82
3 SUMMARY ...........................................................................................................................100
References ..............................................................................................................................107
Supplementary Publications ...................................................................................................114
Author Contributions to Publication 1 .....................................................................................184
Author Contributions to Publication 2 .....................................................................................186
Author Contributions to Publication 3 .....................................................................................188
Author Contributions to Publication 4 .....................................................................................190
Author Contributions to Publication 5 .....................................................................................191
Declaration of Authenticity ......................................................................................................193
Curriculum Vitae ......................................................................................................................194
List of Publications ................................................................................................................195
List of Talks and Posters ......................................................................................................19
