The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity.
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.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
Fei
F
Yin
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
Jia
J
Yao
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
Harsh
H
Sancheti
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Tao
T
Feng
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
Roberto C
RC
Melcangi
Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
Todd E
TE
Morgan
Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
Caleb E
CE
Finch
Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
Christian J
CJ
Pike
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Wendy J
WJ
Mack
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
Enrique
E
Cadenas
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.
Roberta D
RD
Brinton
D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology*; D004734:Energy Metabolism / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics; D017774:Long-Term Potentiation / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000502:physiology; D023421:Models, Animal; D009473:Neuronal Plasticity / Q000502:physiology*; D047648:Perimenopause / Q000235:genetics / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000502:physiology
D016229:Amyloid beta-Peptides; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I; D055372:AMP-Activated Protein Kinases; D005947:Glucose
Fatty acid metabolism; Female brain aging; Glucose metabolism; Hypometabolism; Long-term potentiation; Mitochondria; Perimenopause; Synaptic plasticity