| The early life environment is an important influence on development in all mammalian species. The consequence of exposure to certain key, chronic environmental stimuli is the programming of gene expression to influence the development of a phenotype that is adaptive to the prevailing environment, a phenomenon described as phenotypic plasticity. One example of such environmental programming is the lifelong increase in hippocampal glucocorticoid receptor (GR) expression observed in rats that are reared by high compared to low licking/grooming (LG) mothers. For such an effect to occur, information from the environment must be transduced into signals that reach specific genomic sites. This project addresses mechanisms by which a signal from the early life environment, in this case maternal LG, affects genomic targets associated with the regulation of genes known to be modulated by maternal LG.;The studies described in this thesis show that the offspring of High-LG mothers have increased levels of key proteins for the modulation of gene expression in the hippocampal region compared to the offspring of Low-LG offspring at postnatal day 4 (P4), a time point corresponding with the programming process. These proteins include the transcription factors NGFI-A, Sp1, and Sp4; as well as the transcriptional co-activators NAB1, NAB2, CBP, and MBD2. Additionally, it is demonstrated that maternal LG behaviour dynamically regulates the binding of NGFI-A and Sp1 to specific target regions of the genome including the GAD1 and GR exon 17 promoter regions. LG behaviour is also shown to induce increases in plasma levels of the active thyroid hormone T3 in High-LG offspring, and chronic T4 treatment is shown to be sufficient to induce NGFI-A binding to the GR exon 17 promoter. Experiments in primary dissociated hippocampal cultures show that NGFI-A overexpression is sufficient to induce GR expression, while the knockdown of NGFI-A or MBD2 by siRNA eliminates the ability of 5-HT treatments to induce GR expression. Finally, tactile stimulation is demonstrated to be the critical component of the LG stimulus transmitting information to the offspring, in that the dynamic changes in plasma T3 and NGFI-A binding to the GR 17 promoter can be mimicked by this manipulation. Furthermore, the NGFI-A binding to the GR exon 17 induced by tactile stimulation in the offspring of High-LG mothers is shown to be dependent on 5-HT.;These experiments demonstrate that the environmental cue of maternal LG is transduced by offspring through a series of steps into a specific signal targeting discrete parts of the genome, in this case the NGFI-A binding to response elements within the GAD1 and GR exon 17 promoters of cells in the hippocampus. The regulation of these genes in this area is influenced by maternal LG, and the simple overexpression of NGFI-A is shown to be sufficient to induce their expression in hippocampal neurons. These events delineate a concrete pathway by which a gross environmental signal is transduced into information programming gene expression. |
