E.A.J.F. Lakke

Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent findings in major depressive disorder (MDD). Impaired HPA feedback may be due to the lower glucocorticoid receptor (GR) or mineralocorticoid receptor (MR) levels in the forebrain. GR levels are transcriptionally controlled by multiple untranslated alternative first exons, each with its own promoter providing a mechanism for tissue-specific fine-tuning of GR levels. Recently epigenetic methylation of these GR promoters was shown to modulate hippocampal GR levels. Here we investigate in post-mortem brain tissues whether in MDD HPA axis hyperactivity may be due to epigenetic modulation of GR transcript variants. Levels of GRalpha, GRbeta and GR-P transcripts were homogeneous throughout the limbic system, with GRalpha being the most abundant (83%), followed by GR-P (5-6%) while GRbeta was barely detectable (0.02%). Among the alternative first exons, 1B and 1C were the most active, while 1E and 1J showed the lowest expression and transcript 1F expressed intermediate levels of about 1%. In MDD, total GR levels were unaltered, although GRalpha was decreased in the amygdala and cingulate gyrus (p<0.05); transcripts containing exons 1B, 1C and 1F were lower, and 1D and1J were increased in some regions. NGFI-A, a transcription factor of exon 1F was down-regulated in the hippocampus of MDD patients; concomitantly exon 1F expression was reduced. Bisulphite sequencing of the alternative promoters showed low methylation levels in both MDD and control brains. Promoter 1F was uniformly unmethylated, suggesting that reduced 1F transcript levels are not linked to promoter methylation but to the observed dearth of NGFI-A. Previous studies showed high methylation levels in the 1F promoter, associated with childhood abuse. Provided our donors were not abused, our results suggest that the pathomechanism of MDD is similar but nevertheless distinct from that of abuse victims, explaining the clinical similarity of both conditions and that susceptibility to depression may be either predisposed by early trauma or developed independent of such a condition. However, this should be further confirmed in dedicated studies in larger cohorts.

Decreased expression of mineralocorticoid receptor mRNA and its splice variants in postmortem brain regions of patients with major depressive disorder

Appropriate signaling in the brain by the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) is critical in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, emotional arousal and cognitive performance. To date, few data exist on MR (and GR) expression in the brain of patients suffering from major depressive disorder (MDD). With the help of quantitative PCR we assessed MR and GR mRNA expression, including the splice variants MRα and MRβ, in tissue samples from the hippocampus, amygdala, inferior frontal gyrus, cingulate gyrus and nucleus accumbens. Expression levels were compared between tissue samples from six MDD patients and six non-depressed subjects. Relative to total GR, total MR mRNA expression was higher in hippocampus and lower in the amygdala, inferior frontal gyrus and nucleus accumbens. Both MRα and MRβ could be detected in all brain regions that were analyzed, although MRβ expression was low. Significantly lower expression levels (30-50%) were detected for MR or GR in hippocampal, inferior frontal gyrus and cingulate gyrus tissue from MDD patients (pxa0<xa0.05), while no differences were found in the amygdala or nucleus accumbens. The data show that both MRα and MRβ mRNA are expressed throughout the human limbic brain with highest expressions in the hippocampus. A decreased expression of corticosteroid receptors in specific brain regions of MDD patients could underlie HPA hyperactivity, mood and cognitive disturbances often observed in patients suffering from stress-related psychopathologies.

Repair of ventral root avulsions of the brachial plexus: a review.

Abstractu2003 Traumatic root avulsions of the brachial plexus constitute a devastating lesion resulting in loss of function of the upper limb and carry a large emotional and socioeconomic impact. In this literature survey, the different factors involved in root avulsion are discussed in combination with various surgical techniques for repair of experimental ventral root avulsion. Until now repair of root avulsions did not generate unequivocal proof of recovery of limb function, particularly of the hand. More experimental studies are needed to assess the efficacy of several repair techniques, the optimal timing for surgery, and the complications associated with spinal cord manipulation.

New insights in the neuroanatomy of the human adult superior hypogastric plexus and hypogastric nerves.

BACKGROUNDnThe superior hypogastric plexus (SHP) is an autonomic plexus, located ventrally to the abdominal aorta and its bifurcation, innervating pelvic viscera. It is classically described as being composed of merely sympathetic fibres. However, post-operative complications after surgery damaging the peri-aortic retroperitoneal compartment suggest the existence of parasympathetic fibres. This immunohistochemical study describes the neuroanatomical composition of the human mature SHP.nnnMATERIAL AND METHODSnEight pre-determined retroperitoneal localizations including the lumbar splanchnic nerves, the SHP and the HN were studied in four human cadavers. Control tissues (white rami, grey rami, vagus nerve, splanchnic nerves, sympathetic ganglia, sympathetic chain and spinal nerve) were collected to verify the results. All tissues were stained with haematoxylin and eosin and antibodies S100, tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP) and myelin basic protein (MBP) to identify pre- and postganglionic parasympathetic and sympathetic nerve fibres.nnnRESULTSnAll tissues comprising the SHP and hypogastric nerves (HN) showed isolated expression of TH, VIP and MBP, revealing the presence of three types of fibres: postganglionic adrenergic sympathetic fibres marked by TH, unmyelinated VIP-positive fibres and myelinated preganglionic fibres marked by MBP. Analysis of control tissues confirmed that TH, VIP and MBP were well usable to interpret the neurochemical composition of the SHP and HN.nnnCONCLUSIONnThe human SHP and HN contain sympathetic and most likely postganglionic parasympathetic fibres. The origin of these fibres is still to be elucidated, however surgical damage in the peri-aortic retroperitoneal compartment may cause pelvic organ dysfunction related to both parasympathetic and sympathetic denervation.

Three-dimensional inversion recovery manganese-enhanced MRI of mouse brain using super-resolution reconstruction to visualize nuclei involved in higher brain function

The visualization of activity in mouse brain using inversion recovery spin echo (IR‐SE) manganese‐enhanced MRI (MEMRI) provides unique contrast, but suffers from poor resolution in the slice‐encoding direction. Super‐resolution reconstruction (SRR) is a resolution‐enhancing post‐processing technique in which multiple low‐resolution slice stacks are combined into a single volume of high isotropic resolution using computational methods. In this study, we investigated, first, whether SRR can improve the three‐dimensional resolution of IR‐SE MEMRI in the slice selection direction, whilst maintaining or improving the contrast‐to‐noise ratio of the two‐dimensional slice stacks. Second, the contrast‐to‐noise ratio of SRR IR‐SE MEMRI was compared with a conventional three‐dimensional gradient echo (GE) acquisition. Quantitative experiments were performed on a phantom containing compartments of various manganese concentrations. The results showed that, with comparable scan times, the signal‐to‐noise ratio of three‐dimensional GE acquisition is higher than that of SRR IR‐SE MEMRI. However, the contrast‐to‐noise ratio between different compartments can be superior with SRR IR‐SE MEMRI, depending on the chosen inversion time. In vivo experiments were performed in mice receiving manganese using an implanted osmotic pump. The results showed that SRR works well as a resolution‐enhancing technique in IR‐SE MEMRI experiments. In addition, the SRR image also shows a number of brain structures that are more clearly discernible from the surrounding tissues than in three‐dimensional GE acquisition, including a number of nuclei with specific higher brain functions, such as memory, stress, anxiety and reward behavior. Copyright

The perisylvian language network and language analytical abilities

Aiming at exploring the brains structural organisation underlying successful second language learning, we investigate the anatomy of the perisylvian language network in a group of healthy adults, consisting of participants with high and average language analytical abilities. Utilising deterministic tractography, six tracts per participant (left and right long direct segment, left and right indirect anterior segment and left and right indirect posterior segment) were virtually dissected and measurements pertaining to their microstructural organisation were collected. Our results obtained by means of linear discriminant analysis pointed to mean diffusivity (MD) values of three tracts (right anterior, left long and left anterior segments) as best discriminating between the two groups. By far the highest coefficient was obtained for the MD values of the right anterior segment, pointing to the role of the right white matter fronto-parietal connectivity for superior language learning abilities. The results imply the importance of attentional processes and reasoning abilities for successful L2 acquisition, and support previous findings concerning right-hemispheric involvement in language learning.

The visual cortex and visual cognition in Huntington’s disease: An overview of current literature

ABSTRACT The processing of visual stimuli from retina to higher cortical areas has been extensively studied in the human brain. In Huntingtons disease (HD), an inherited neurodegenerative disorder, it is suggested that visual processing deficits are present in addition to more characteristic signs such as motor disturbances, cognitive dysfunction, and behavioral changes. Visual deficits are clinically important because they influence overall cognitive performance and have implications for daily functioning. The aim of this review is to summarize current literature on clinical visual deficits, visual cognitive impairment, and underlying visual cortical changes in HD patients. A literature search was conducted using the electronic database of PubMed/Medline. This review shows that changes of the visual system in patients with HD were not the primary focus of currently published studies. Still, early atrophy and alterations of the posterior cerebral cortex was frequently observed, primarily in the associative visual cortical areas such as the lingual and fusiform gyri, and lateral occipital cortex. Changes were even present in the premanifest phase, before clinical onset of motor symptoms, suggesting a primary region for cortical degeneration in HD. Although impairments in visuospatial processing and visual perception were reported in early disease stages, heterogeneous cognitive batteries were used, making a direct comparison between studies difficult. The use of a standardized battery of visual cognitive tasks might therefore provide more detailed information regarding the extent of impairments in specific visual domains. Further research could provide more insight into clinical, functional, and pathophysiological changes of the visual pathway in HD.