The ageing hypothalamus: impact on neuronal and glial cells that control energy homeostasis

Perez Santamarina, Estela (2020) The ageing hypothalamus: impact on neuronal and glial cells that control energy homeostasis. Doctoral thesis, University of East Anglia.

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Abstract

The hypothalamus regulates key endocrine, homeostatic and adaptive functions, ranging from energy uptake and expenditure to circadian rhythm and reproductive functions through the coordinated activity of neuronal and glial cells. There are complex but integrated interconnections between the hypothalamic nuclei that maintain energy homeostasis through regulation of food intake and energy expenditure. Critically, the Arcuate nucleus (Arc) and the circumventricular termed the median eminence (ME) lay at the core of the energy regulation. Assumedly, age-related changes in the hypothalamic circuitry could underlie the decline in metabolism and energy homeostasis observed during ageing. Therefore, the present study is focused on elucidating the effects of ageing in the Arc-ME.

First, age-related changes in the hypothalamic neurons controlling energy balance, POMC and AgRP/NPY, were examined using immunohistochemistry and reporter mice. A reduction in the number of anorexigenic POMC neurons, but not orexigenic NPY, was associated with age. Cell death studies confirmed that programmed cell death events are not responsible for POMC decline. Second, RNA-seq analysis identified four biological processes affected in the ageing hypothalamus, including upregulation of neuroinflammation and myelin-related genes; and downregulation of genes involved in the neuronal cytoskeleton, intracellular transport and axonal growth. Third, age-related changes in the microglia (Iba1+) and astrocytes (GFAP+) suggested that reactive gliosis involving both populations develop gradually in the hypothalamus with age. Also, aged hypothalamic microglia adopt a neurotoxic/pro-inflammatory (M1) activated phenotype. Fourth, in vivo adult neurogenesis in the hypothalamus was assessed by cumulative BrdU labelling. The majority of proliferating cells in the ME belonged to the oligodendrocyte and microglia lineage, but a numeric decline is observed with age. Fifth, characterisation of the hypothalamic myelin pattern using immunohistochemistry revealed that myelin microstructure in the Arc-ME is impaired with age. The number and differentiation program of the oligodendrocytes was then investigated using lineage-specific markers, and an increase in number but not differences in oligodendrocyte maturation was observed. However, western blot results supported that inhibition of the intracellular trafficking of myelin components, rather than oligodendrocyte dysfunction, could underlie the defective myelin pattern observed with age.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Biological Sciences
Depositing User:	Chris White
Date Deposited:	09 May 2022 09:49
Last Modified:	31 Dec 2023 01:38
URI:	https://ueaeprints.uea.ac.uk/id/eprint/84966
DOI:

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