Altered brain functional connectivity and behaviour in a mouse model of maternal alcohol binge-drinking

Abstract

Prenatal and perinatal alcohol exposure caused by maternal alcohol intake during gestation and lactation periods can have long-lasting detrimental effects on the brain development and behaviour of offspring. Children diagnosed with Foetal Alcohol Spectrum Disorders (FASD) display a wide range of cognitive, emotional and motor deficits, together with characteristic morphological abnormalities. Maternal alcohol binge drinking is particularly harmful for foetal and early postnatal brain development, as it involves exposure to high levels of alcohol over short periods of time. However, little is known about the long-term effects of maternal alcohol binge drinking on brain function and behaviour. To address this issue, we used pregnant C57BL/6 female mice with time-limited access to a 20% v/v alcohol solution as a procedure to model alcohol binge drinking during gestation and lactational periods. Male offspring were behaviourally tested during adolescence (30 days) and adulthood (60 days), and baseline neural metabolic capacity of brain regions sensitive to alcohol effects were also evaluated in adult animals from both groups. Our results show that prenatal and postnatal alcohol exposure caused age-dependent changes in spontaneous locomotor activity, increased anxiety-like behaviour and attenuated alcohol-induced conditioned place preference in adults. Also, significant changes in neural metabolic capacity using cytochrome c oxidase (CCO) quantitative histochemistry were found in the hippocampal dentate gyrus, the mammillary bodies, the ventral tegmental area, the lateral habenula and the central lobules of the cerebellum in adult mice with prenatal and postnatal alcohol exposure. In addition, the analysis of interregional CCO activity correlations in alcohol-exposed adult mice showed disrupted functional brain connectivity involving the limbic, brainstem, and cerebellar regions. Finally, increased neurogenesis was found in the dentate gyrus of the hippocampus of alcohol-exposed offspring, suggesting neuroadaptive effects due to early alcohol exposure. Our results demonstrate that maternal binge-like alcohol drinking causes long-lasting effects on motor and emotional-related behaviours associated with impaired neuronal metabolic capacity and altered functional brain connectivity.This study was supported by grants from the EuropeanUnion's Horizon 2020 research and innovation programme 2014-2020under Grant Agreement No 634143, the Spanish Ministry of Economy,Innovation and Competitiveness (SAF2016-75966-R), the SpanishMinistryof Education and Science and Innovation and EuropeanRegional Development Fund (PSI2013-45924-P, PSI2015-73111-EXP, PSI2017-83038-P, PSI2017-83893-R, the Plan Nacional sobre Drogas(#2014/020), and the Plan de Ciencia, Tecnología e Innovación delPrincipado de Asturias (FC-15-GRUPIN14-088). Department ofExperimental and Health Sciences is a“Unidad de Excelencia María deMaeztu”funded by the MINECO (MDM-2014-0370). The authors de-clare no potential conflicts of interest