Long-term continuous allopregnanolone elevation causes memory decline and hippocampus shrinkage, in female wild-type B6 mice.
Chronic stress in various forms increases the risk for cognitive dysfunction, dementia and Alzheimer's disease. While the pathogenesis behind these findings is unknown, growing evidence suggests that chronic increase in neurosteroid levels, such as allopregnanolone, is part of the mechanism. We treated wild-type C57BL/6J mice with allopregnanolone for 5months, using osmotic pumps. This treatment led to moderately increased levels of allopregnanolone, equivalent to that of mild chronic stress. After an interval of no treatment for 1month, female mice showed impaired learning and memory function in the Morris water maze (MWM) in combination with diminished hippocampus weight and increased cerebellum weight, both correlating to MWM performance. Male mice showed a minor reduction in memory function and no differences in brain structure. We conclude that chronic allopregnanolone elevation can lead to cognitive dysfunction and negative brain alterations. We suggest that allopregnanolone could play a key role in the pathogenesis of stress-induced cognitive disturbances and perhaps dementia.
Umeå Neurosteroid Research Center, Umeå University, Department of Clinical Sciences, Umeå, Sweden. Electronic address: sara.bengtsson@obgyn.umu.se.
Sara K S
SK
Bengtsson
Umeå Neurosteroid Research Center, Umeå University, Department of Clinical Sciences, Umeå, Sweden; Umecrine Cognition AB, Umeå, Sweden.
Maja
M
Johansson
Umeå Neurosteroid Research Center, Umeå University, Department of Clinical Sciences, Umeå, Sweden.
Torbjörn
T
Bäckström
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects*; D011280:Pregnanolone / Q000008:administration & dosage / Q000494:pharmacology*
D018377:Neurotransmitter Agents; D011280:Pregnanolone
Allopregnanolone; Brain tissue weight; C57BL/6J mice; Chronic stress; Dementia; GABA; Memory and learning; Mild cognitive impairment; Wild-type mice