Melatonin, the major regulator of the sleep/wake cycle, also plays important physiological and pharmacological roles in the control of neuronal plasticity and neuroprotection. Accordingly, the secretion of this hormone reaches the maximal extent during brain development (childhood-adolescence) while it is greatly reduced during aging, a condition associated to altered sleep pattern and reduced neuronal plasticity. Altogether, these properties of melatonin have allowed us to demonstrate in both experimental models and clinical studies the great chronobiotic efficacy and sleep promoting effects of exogenous melatonin. Thus, the prolonged release formulation of melatonin, present as a drug in the pharmaceutical market, has been recently recommended for the treatment of insomnia in over 55 years old subjects.

Post-weaning social isolation (SI) is a model of prolonged mild stress characterized by behavioral and neurochemical alterations. We used SI in C57BL/6J mice to investigate the effects of ethanol (EtOH) in the free-choice drinking paradigm on gene expression and function of γ-aminobutyric acid type A receptors (GABA_ARs) and the role of neuroactive steroids in the actions of EtOH in the hippocampus. SI stress induced a marked reduction in hippocampal 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) and was associated with molecular and functional changes of the GABA_AR. The gene expression of the α₄ and δ subunits was increased in the hippocampus of SI C57BL/6J mice; the expression of the γ₂ subunit was decreased whereas that of the α₁ did not change. Patch-clamp recordings in dentate gyrus (DG) granule cells obtained from SI C57BL/6J mice revealed a greater enhancement of tonic currents induced by α-(4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) compared to that in control C57BL/6J mice. These neurochemical, molecular and functional changes observed in SI C57BL/6J mice were associated with an increased EtOH intake and EtOH preference. Nevertheless, the increase in EtOH consumption did not restore the reduction in hippocampal 3α,5α-TH PROG induced by SI. EtOH self-administration blocked the changes in gene expression of the α₄ subunit but not those of the δ and γ₂ subunits induced by SI. In addition, EtOH self-administration did not block the SI-induced changes in GABA_AR-mediated tonic inhibition in hippocampal granule cells but increased the frequency of basal GABAergic sIPSCs in DG granule cells. We conclude that self-administration of EtOH selectively abolishes the increase of α₄ subunit but not other neurochemical, molecular, and functional modifications induced by SI prolonged mild stress.

Neuronal plasticity is achieved by regulation of the expression of genes for neurotransmitter receptors such as the type A receptor (GABA_AR) for γ‐aminobutyric acid. We now show that two different rat neuronal populations in culture manifest distinct patterns of GABA_AR plasticity in response to identical stimuli. Whereas prolonged exposure to ethanol had no effect on expression of the δ subunit of GABA_ARs at the mRNA or protein level in cerebellar granule neurons, it increased the abundance of δ subunit mRNA and protein in hippocampal neurons. Subsequent ethanol withdrawal transiently down‐regulated δ subunit expression in cerebellar granule neurons and gradually normalized that in hippocampal neurons. These effects of ethanol exposure and withdrawal were accompanied by corresponding functional changes in GABA_ARs. GABA_ARs containing the δ subunit were also distributed differentially in the cerebellar and hippocampal neurons. These findings reveal complex and distinct mechanisms of regulation of the expression of GABA_ARs that contain the δ subunit in different neuronal types.

Probiotics are live microorganisms distributed in the gastrointestinal tract that confer health benefits to the host when administered in adequate amounts. Bifidobacteria have been widely tested as a therapeutic strategy in the prevention and treatment of a broad spectrum of gastrointestinal disorders as well as in the regulation of the “microbiota-gut-brain axis”. Metabolomic techniques can provide details in the study of molecular metabolic mechanisms involved in Bifidobacteria function through the analysis of metabolites that positively contribute to human health. This study was focused on the effects of the chronic assumption of a mixture of Bifidobacteria in adult male rats using a metabolomic approach. Plasma samples were collected at the end of treatment and analyzed with a gas chromatography-mass spectrometry (GC-MS) platform. Partial least square discriminant analysis (PLS-DA) was performed to compare the metabolic pattern in control and probiotic-treated rats. Our results show, in probiotic-treated animals, an increase in metabolites involved in the energetic cycle, such as glucose, erythrose, creatinine, taurine and glycolic acid, as well as 3-hydroxybutyric acid. This is an important metabolite of short-chain fatty acids (SCFA) with multitasking roles in energy circuit balance, and it has also been proposed to have a key role in the prevention and treatment of neurodegenerative diseases.