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Linking Early Life Hypothalamic-Pituitary-Adrenal Axis Functioning, Brain Asymmetries, and Personality Traits in Dyslexia: An Informative Case Study

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Linking Early Life Hypothalamic-Pituitary-Adrenal Axis Functioning, Brain Asymmetries, and Personality Traits in Dyslexia: An Informative Case Study

Victoria Zakopoulou et al. Front Hum Neurosci.

Abstract

Developmental dyslexia (DD) is a multi-system disorder, combining influences of susceptibility genes and environmental factors. The causative interaction between specific genetic factors, brain regions, and personality/mental disorders, as well as specific learning disabilities, has been thoroughly investigated with regard to the approach of developing a multifaceted diagnostic procedure with an intervention strategy potential. In an attempt to add new translational evidence to the interconnection of the above factors in the occurrence of DD, we performed a combinatorial analysis of brain asymmetries, personality traits, cognitive and learning skills, and expression profiles of selected genes in an adult, early diagnosed with DD, and in his son of typical development. We focused on the expression of genes, based on the assumption that the regulation of transcription may be affected by genetic and epigenetic factors. The results highlighted a potential chain link between neuroplasticity-related as well as stress-related genes, such as BDNF, Sox4, mineralocorticoid receptor (MR), and GILZ, leftward asymmetries in the amygdala and selective cerebellum lobules, and tendencies for personality disorders and dyslexia. This correlation may reflect the presence of a specific neuro-epigenetic component of DD, ensuing from the continuous, multifaceted difficulties in the acquisition of cognitive and learning skills, which in turn may act as a fostering mechanism for the onset of long-term disorders. This is in line with recent findings demonstrating a dysfunction in processes supported by rapid neural adaptation in children and adults with dyslexia. Accordingly, the co-evaluation of all the above parameters may indicate a stress-related dyslexia endophenotype that should be carefully considered for a more integrated diagnosis and effective intervention.

Keywords: BDNF; MR; brain asymmetries; dyslexia; hypothalamic–pituitary–adrenal (HPA) axis; neuroplasticity genes; stress.

Figures

Figure 1
Figure 1
(A) Voxel-based morphometry (VMB) analysis of the cerebrum. (B) VBM lobular analysis of the cerebellum. The location of lobule V is shown (arrow).
Figure 2
Figure 2
Relative expression of selected neuroplasticity and stress-related genes between father and son. Gene expression was compared in whole blood RNA samples collected from the patient and his son. Relative gene expression levels were determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The levels of GAPDH and β-actin were used as controls for cDNA normalization. Photographs provide one representative example of at least three different experiments that yielded consistent results. The mRNA levels of the genes encoding MR, Ube3A, GILZ, and Sox4 were lower in the sample from the father (F) compared to the son (S). In contrast, the expression of BDNF was significantly higher in the father whereas glucocorticoid receptor (GR) showed no difference.
Figure 3
Figure 3
Chain link of brain asymmetries, specific learning disabilities, neurogenesis, hypothalamic–pituitary–adrenal (HPA) axis, and psycho-emotional disorders. The proposed translational mechanism highlights the complex roles that specific brain and genetic asymmetries in constant interaction with the HPA axis may play in the expression and the management of learning disabilities. It also indicates the longitudinal potential consequences in cognitive and emotional development and in the behavioral adaptation of the individual from early childhood to adulthood (Hoeft et al., 2011). In essence, this chain link underscores the core roles of multifaceted associations between neurophysiological and epigenetic development, as well as the adaptation of cognitive and learning mechanisms.

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