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Neurobiol Aging. 2015 Jul;36(7):2282-2295. doi: 10.1016/j.neurobiolaging.2015.03.013. Epub 2015 Apr 1.

The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity.

Author information

1
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
2
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
3
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
4
Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
5
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: rbrinton@usc.edu.

Abstract

The perimenopause is an aging transition unique to the female that leads to reproductive senescence which can be characterized by multiple neurological symptoms. To better understand potential underlying mechanisms of neurological symptoms of perimenopause, the present study determined genomic, biochemical, brain metabolic, and electrophysiological transformations that occur during this transition using a rat model recapitulating fundamental characteristics of the human perimenopause. Gene expression analyses indicated two distinct aging programs: chronological and endocrine. A critical period emerged during the endocrine transition from regular to irregular cycling characterized by decline in bioenergetic gene expression, confirmed by deficits in fluorodeoxyglucose-positron emission tomography (FDG-PET) brain metabolism, mitochondrial function, and long-term potentiation. Bioinformatic analysis predicted insulin/insulin-like growth factor 1 and adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK/PGC1α) signaling pathways as upstream regulators. Onset of acyclicity was accompanied by a rise in genes required for fatty acid metabolism, inflammation, and mitochondrial function. Subsequent chronological aging resulted in decline of genes required for mitochondrial function and β-amyloid degradation. Emergence of glucose hypometabolism and impaired synaptic function in brain provide plausible mechanisms of neurological symptoms of perimenopause and may be predictive of later-life vulnerability to hypometabolic conditions such as Alzheimer's.

KEYWORDS:

Fatty acid metabolism; Female brain aging; Glucose metabolism; Hypometabolism; Long-term potentiation; Mitochondria; Perimenopause; Synaptic plasticity

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