Epigenetic Dysregulation of Dopaminergic System by Maternal Cafeteria Diet During Early Postnatal Development.

Dopamine is a neurotransmitter crucial for motor, motivational, and reward-related functions. Our aim was to determine the effect of a palatable maternal diet on the transcriptional regulation of dopaminergic-related genes during perinatal development of rat offspring. For that, female offspring from dams fed with a control (CON) or a cafeteria (CAF) diet were sacrificed on embryonic day 21 (E21) and postnatal day 10 (PND10). Using micropunch techniques, ventral tegmental area (VTA) and nucleus accumbens (NAc) were isolated from brain's offspring. Bioinformatic analysis of the promoter regions, mRNA quantification and methylation studies were done. The increase in tyroxine hidroxylase (TH), dopamine receptor (DRD) 1 and ghrelin receptor (GHSR) expression in VTA and NAc from E21 to PND10 was correlated with changes in DNA methylation of their promoter regions. Maternal diet did not affect the expressionpatternsin E21. At PND10, maternal CAF diet decreased the transcription of TH, GHSR, DRD2 and dopamine transporter (DAT) in VTA. Interestingly, the changes in TH, DRD2 and DAT expression were related to the methylation status of their promoters. In NAc, maternal CAF diet reduced DRD1, DRD2 and DAT expression in the offspring at PND10, although alternations in the methylation patterns were only detected in DAT promoter. These results show the importance of maternal nutrition and provide novel insights into the mechanisms through which maternal junk-food feeding can affect reward system during development and early postnatal life. Particularly important is the expression decline of DRD2 given its physiological implication in obesity and addiction.

Oestrogens and Progestagens: Synthesis and Action in the Brain.

When steroids, such as pregnenolone, progesterone and oestrogen, are synthesised de novo in neural tissues, they are more specifically referred to as neurosteroids. These neurosteroids bind specific receptors to promote essential brain functions. Pregnenolone supports cognition and protects mouse hippocampal cells against glutamate and amyloid peptide-induced cell death. Progesterone promotes myelination, spinogenesis, synaptogenesis, neuronal survival and dendritic growth. Allopregnanolone increases hippocampal neurogenesis, neuronal survival and cognitive functions. Oestrogens, such as oestradiol, regulate synaptic plasticity, reproductive behaviour, aggressive behaviour and learning. In addition, neurosteroids are neuroprotective in animal models of Alzheimer's disease, Parkinson's disease, brain injury and ageing. Using in situ hybridisation and/or immunohistochemistry, steroidogenic enzymes, including cytochrome P450 side-chain cleavage, 3ß-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase, cytochrome P450arom, steroid 5α-reductase and 3α-hydroxysteroid dehydrogenase, have been detected in numerous brain regions, including the hippocampus, hypothalamus and cerebral cortex. In the present review, we summarise some of the studies related to the synthesis and function of oestrogens and progestagens in the central nervous system.

Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus.

Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of ~20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a 15N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated 15N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration.