Histone deacetylases inhibitor trichostatin A reverses anxiety-like symptoms and memory impairments induced by maternal binge alcohol drinking in mice

Background: Alcohol exposure during development has detrimental effects, including a wide range of physical, cognitive and neurobehavioural anomalies known as foetal alcohol spectrum disorders. However, alcohol consumption among pregnant woman is an ongoing latent health problem. Aim: In the present study, the effects of trichostatin A (TSA) on emotional and cognitive impairments caused by prenatal and lactational alcohol exposure were assessed. TSA is an inhibitor of class I and II histone deacetylases enzymes (HDAC), and for that, HDAC4 activity was determined. We also evaluated mechanisms underlying the behavioural effects observed, including the expression of brain-derived neurotrophic factor (BDNF) in discrete brain regions and newly differentiated neurons in the dentate gyrus (DG). Methods: C57BL/6 female pregnant mice were used, with limited access to a 20% v/v alcohol solution as a procedure to model binge alcohol drinking during gestation and lactation. Male offspring were treated with TSA during the postnatal days (PD28-35) and behaviourally evaluated (PD36-55). Results: Early alcohol exposure mice presented increased anxiogenic-like responses and memory deterioration - effects that were partially reversed with TSA. Early alcohol exposure produces a decrease in BDNF levels in the hippocampus (HPC) and prefrontal cortex, a reduction of neurogenesis in the DG and increased activity levels of the HDAC4 in the HPC. Conclusions: Such findings support the participation of HDAC enzymes in cognitive and emotional alterations induced by binge alcohol consumption during gestation and lactation and would indicate potential benefits of HDAC inhibitors for some aspects of foetal alcohol spectrum disorders.The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by the Ministerio de Economía y Competitividad (Spanish Ministry of Economy and Competitiveness – grant number SAF2016-75966-R-FEDER), and the Spanish Ministry of Health (Retic-ISCIII-RD16/0017/0010 and PNSD 2018/007). SM-R received a postdoctoral fellowship from the Conselleria d’Educació, Investigació, Cultura i Esport (APOSTD/2017/102), Generalitat Valenciana, Spain. LC received an FPI grant (BES-2014-070657) from the Ministerio de Economía y Competitividad, The Department of Experimental and Health Sciences (UPF), ‘Unidad de Excelencia María de Maeztu’ funded by the MINECO (ref. MDM-2014-0370)

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

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