- Author
-
F. CorrĂȘa da Silva
- Title
- Hypothalamic cellular changes in neuroendocrine disorders
- Subtitle
- Human postmortem studies
- Supervisors
-
E. Fliers
D.F. Swaab - Co-supervisors
- Award date
- 4 March 2024
- Number of pages
- 335
- ISBN
- 9789493330634
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
The hypothalamus is one of the key brain regions involved in energy homeostasis, circadian rhythm, and behavioral outputs coordination. Solid evidence from murine models show that development and progression of metabolic disorders are rooted in neuronal and glial dysfunctions in the hypothalamus. While spatial and temporal changes in neurons and non-neuronal cells are well understood in animal models, little is known how translational those findings are in human with metabolic disorders. We profiled cellular and molecular changes in the hypothalamus of type 2 diabetes mellitus (T2DM) and Prader-Willi Syndrome (PWS) individuals. In the first section of this thesis, we evaluated the molecular and cellular signatures of hypothalamic dysfunction in PWS using state-of-art molecular techniques and histopathological profiling of human hypothalamic postmortem tissue. We dissected the neuroanatomic basis of circadian misalignments experienced by PWS individuals. Moreover, we characterized a pronounced glial dysfunction in hypothalamic area that controls energy metabolism and behavioral outputs; and different PWS subgenotypes present specific glial signatures leading to potential personalized medicine strategies in a genotype-dependent manner. Next, we explored the neuronal and glial hypothalamic profiles of T2DM individuals, especially focused on the hypothalamic paraventricular nucleus. Our data show that T2DM pathophysiology is connected to loss of oxytocinergic neurons, parallel to defective gliovascular coupling, and altered tanycytic lipid metabolism. In summary, we provide the cellular basis for hypothalamic dysfunction in different neuroendocrine disorders in humans.
- Persistent Identifier
- https://hdl.handle.net/11245.1/0d6548b0-feb0-4856-bff9-6be2d1f6f177
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: Introduction: The role of glia in eating disorders
Chapter 2: Hypothalamic neuropeptides and neurocircuitries in Prader Willi syndrome
Chapter 3: Selective changes in vasopressin neurons and astrocytes within the suprachiasmatic nucleus of Prader-Willi Syndrome subjects
Chapter 4: Reduced perineuronal nets in the hypothalamus of Prader-Willi syndrome patients
Chapter 5: Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion
Chapter 6: Lipid droplets accumulate in the hypothalamus of mice and humans with and without metabolic diseases
Chapter 7: Reduction of oxytocin-containing neurons and enhanced glymphatic activity in the hypothalamic paraventricular nucleus of patients with type 2 diabetes mellitus
Chapter 8: General discussion
English summary; Nederlandse samenvatting; List of publications; PhD portifolio; About the author; Acknowledgements
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library, or send a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.