Aging-Related Behavioral, Adiposity, and Glucose Impairments and Their Association following Prenatal Alcohol Exposure in the C57BL/6J Mouse

Abstract

People that experience prenatal alcohol exposure (PAE) may have behavioral and metabolic impairments, and it is unclear whether these remain stable or change with age. We assessed behavioral and metabolic endpoints across the lifespan in a mouse model of fetal alcohol spectrum disorder (FASD). Pregnant C57BL/6J mice received alcohol (ALC; 3 g/kg) or maltose-dextrin (control, CON) daily from embryonic day 8.5 to 17.5. Offspring were tested on accelerating rotarod, Y-maze, novel object recognition, and fear conditioning at 6 weeks and 10 and 17 months; females were also tested at 24 months. Body composition, fasting glucose, and glucose clearance were assessed at 18 months. Female but not male ALC mice had greater adiposity than age-matched CON from 7 months onward. At 18 months, male but not female ALC mice had reduced glucose clearance and ALC mice were more likely to have elevated fasting glucose. In the rotarod training session, ALC females performed worse than CON. In the Y-maze, significant exposure-age interactions affected ALC performance in both sexes versus age-match CON. For fear conditioning, all animals acquired the task and froze more at older ages. In both the context and cued tasks, there were exposure-age interactions and ALC animals frozen less than CON at 10 months. Correlation analysis revealed that fasting glucose and glucose clearance correlated with % of body fat in ALC but not in CON mice. Additionally, glucose intolerance and % body fat negatively correlated with performance in the rotarod, context learning, and novel object recognition tasks in ALC but not CON mice. All mice exhibit worsening of behavioral performance as they age, and PAE did not further exacerbate this. ALC but not CON mice displayed adiposity and glucose intolerance that correlate with their cognitive impairments, suggesting that these may be mechanistically related in PAE. Findings emphasize that FASD should be considered a whole-body disorder.

GABAergic LRP1 is a key link between obesity and memory function

“…This is consistent with previous studies using targeted deletion of LRP1 in the forebrain of mice, suggesting an important role for LRP1 in GABAergic neurons in motor function [30,31]. However, previous studies demonstrated that reduction in motor coordination is also accompanied by increased adiposity, increased circulating insulin and leptin levels, and glucose intolerance [32,33], and crosstalk between leptin and insulin signaling [34][35][36]. Moreover, while GABAergic LRP1 deleted mice were hypoactive and obese, non-obese mice with panneuronal LRP1 deletion exhibited hyperactive characteristics [31].…”

LRP1 in GABAergic neurons is a key link between obesity and memory function

“…This is consistent with previous studies where LRP1 was generally deleted from the forebrain of mice, indicating the significant role of LRP1 in GABAergic neurons in motor function [ 36 , 37 ]. However, experimental evidence demonstrated that reduction in motor coordination is also accompanied by increased adiposity, increased circulating insulin and leptin levels, glucose intolerance [ 38 , 39 ], and crosstalk between leptin and insulin signaling [ [40] , [41] , [42] ]. Moreover, while GABAergic LRP1 deleted mice were hypoactive and obese, non-obese mice with pan-neuronal LRP1 deletion exhibited hyperactive characteristics [ 37 ].…”

Traditional Chinese medicine formula Xiaoyaosan alleviates autistic behaviors and anxiety behaviors in valproic acid-induced autistic rats

“…TST is widely used to assess the social behavior of animals in studies [23] , and the results of our experiments showed that autistic rats exhibited signi cant social impairment. The cognitive functions of animals are generally evaluated by learning and memory abilities, which became signi cantly worse in autistic rats in the NOR task [24] . All of the above ndings indicate that the autistic rats were successfully modeled in this study.…”

“…Learning memory impairment in autism was evaluated using the novel object recognition (NOR) task [24] .…”