Stress as a modulator of motor system function and pathology

Stress is one of the most significant influences on behaviour and performance. The classical account is that stress mainly affects functions of the limbic system, such as learning, memory and emotion. Recent evidence, however, suggests that stress also modulates motor system function and influences the pathology of movement disorders. Most parts of the motor system show the presence of glucocorticoid receptors that render their circuits susceptible to the influence of stress hormones. Stress and glucocorticoids have been shown to modulate temporal and spatial aspects of motor performance. Skilled movements seem to be most prone to stress-induced disturbances, but locomotion and posture can also be affected. Stress can modulate movement through activation of the hypothalamic-pituitary-adrenal axis and via stress-associated emotional changes. The dopaminergic system seems to play a central role in mediating the effects of stress on motor function. This route might also account for the finding that stress influences the pathology of dopamine-related diseases of the motor system, such as Parkinson's disease. Clinical observations have indicated that stress might lead to the onset of Parkinsonian symptoms or accelerate their progression. Glucocorticoids are modulators of neuronal plasticity, thus determining the degree of structural and functional compensation of the damaged motor system. This may particularly affect slowly progressive neurodegenerative diseases, such as Parkinson's disease. That stress represents a significant modulator of motor system function in both the healthy and the damaged brain should be recognized when developing future therapies for neurodegenerative diseases.     

Rivastigmine as a modulator of the neuronal glutamate transporter rEAAC1 mRNA expression

Alzheimer's disease is a neurodegenerative disorder that affects the cholinergic, glutamatergic and monoaminergic systems in the neocortex and hippocampus. Today, the major pharmacological treatment involves the use of acetylcholinesterase inhibitors (AChEIs). In this study, an in situ hybridisation technique (using digoxigenin-labelled cRNA probes) was used to elucidate changes in mRNA expression of the neuronal glutamate transporter, rat excitatory amino carrier 1 (rEAAC1), after treatment with the AChEI rivastigmine. Compared with saline-treated rats, the rats subchronically (3 days) and chronically (21 days), but not acutely, treated with rivastigmine showed a significant increase in rEAAC1 mRNA expression in the hippocampal areas cornu anterior 1 (CA1), CA2, CA3 and dentate gyrus (p < 0.01), but not in the cortical areas. These results provide the first evidence that the glutamatergic system is modulated following acetylcholinesterase inhibition by rivastigmine, a finding, which is likely to be of importance for the clinical effects.     

Investigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder

Bipolar disorder (BD) is a highly heritable psychiatric disease characterized by recurrent episodes of mania and depression. To identify new BD genes and pathways, the present study employed a three-step approach. First, gene-expression profiles of BD patients were assessed during both a manic and an euthymic phase. These profiles were compared intra-individually and with the gene-expression profiles of controls. Second, those differentially expressed genes that were considered potential trait markers of BD were validated using data from the Psychiatric Genomics Consortiums'' genome-wide association study (GWAS) of BD. Third, the implicated molecular mechanisms were investigated using pathway analytical methods. In the present patients, this novel approach identified: (i) sets of differentially expressed genes specific to mania and euthymia; and (ii) a set of differentially expressed genes that were common to both mood states. In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 × 10⁻⁴) after adjustment for multiple testing. STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set. Pathway analyses in the mania versus control comparison revealed three distinct clusters of pathways tagging molecular mechanisms implicated in BD, for example, energy metabolism, inflammation and the ubiquitin proteasome system. The present findings suggest that STAB1 is a new and highly promising candidate gene in this region. The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD.     

The facial motor nucleus transcriptional program in response to peripheral nerve injury identifies Hn1 as a regeneration-associated gene

Facial nerve axotomy (FNA) is a well-established experimental model of motoneuron regeneration. After peripheral nerve axotomy, a sequence of events including glial activation and axonal regrowth leads to functional recovery of the afflicted pool of motoneurons. Using microarray analysis we identified an increase in the expression of 60 genes (at a false discovery rate of 0.1, genes were significant P < 0.004) within the facial nucleus as a consequence of nerve injury. In situ hybridization analysis validated the increased expression of many of these axotomy-induced genes. One specific gene, encoding a unique primary amino acid sequence, termed hemopoietic- and neurologic-expressed sequence-1 (Hn1), was evaluated more extensively using several additional nerve injury paradigms. Hn1 mRNA was upregulated in injured facial motoneurons in both rats and mice. Sustained upregulation of Hn1 mRNA was evident after nerve resection whereas levels of Hn1 mRNA returned to baseline in animals subjected to nerve crush or nerve transection. Hn1 was also increased in the dorsal motor nucleus and the nucleus ambiguous after vagus nerve axotomy, another regeneration model. No upregulation of Hn1 expression was observed, however, in two nonregeneration models: FNA in newborn rats and rubrospinal tractotomy. Hn1 mRNA was ubiquitous in the developing central nervous system whereas its expression in adult brain was confined to neurons of the hippocampus, cortex and cerebellum. These findings identify Hn1 as a gene associated with nervous system development and nerve regeneration.     

Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene

Background

Several proteins involved in epigenetic regulation cause syndromic neurodevelopmental disorders when human genes are mutated. More general involvement of epigenetic mechanisms in neurodevelopmental phenotypes is unclear.

Methods

In an attempt to determine whether DNA methylation differentiates clinical subgroups, profiling was performed on bisulfite converted DNA from lymphoblastoid cell lines (LCLs) in discovery (n = 20) and replication (n = 40) cohorts of females with Rett syndrome (RTT; n = 18), autism (AUT; n = 17), seizure disorder (SEZ; n = 6), and controls (CTL; n = 19) using Illumina HumanMethylation27 arrays. TAC1 CpGs were validated using a Sequenom EpiTYPER assay and expression was measured in LCLs and postmortem brain. Chromatin immunoprecipitation was performed in HEK cells. Cells were treated with valproic acid and MeCP2 binding was assessed.

Results

Two female-only cohorts were analyzed. DNA methylation profiling in a discovery cohort identified 40 CpGs that exhibited statistically significant differential methylation (≥15%) between clinical groups (P <0.01). Hierarchical clustering and principal components analysis suggested neurodevelopmental groups were distinct from CTL, but not from each other. In a larger and more heterogeneous replication cohort, these 40 CpG sites suggested no clear difference between clinical groups. Pooled analysis of DNA methylation across all 60 samples suggested only four differentially methylated CpG sites (P <0.0005), including TAC1. TAC1 promoter CpG hypermethylation was validated in AUT and SEZ (P <0.005). Analyzed for the first time in postmortem brain, TAC1 expression was reduced in cingulate cortex in RTT and AUT+SEZ (P = 0.003). However, no significant difference in TAC1 promoter CpG methylation was detected in RTT and AUT+SEZ brains. Additional molecular analyses revealed that MeCP2 binds directly to the TAC1 promoter and is sensitive to antiepileptic drug treatment.

Conclusion

These data suggest that DNA methylation is not widely altered in RTT, consistent with subtle changes in gene expression previously observed. However, TAC1 may be an important target for further functional analyses in RTT. Studies of larger sample cohorts using primary cells that also consider shared clinical features and drug treatments may be required to address apparent subtle disruptions of DNA methylation in neurodevelopmental disorders.     

CRH and the noradrenergic system mediate the antinociceptive effect of central interleukin-1α in the rat

After intracerebroventricular administration, both interleukin-1_α and corticotropin-releasing hormone increase nociceptive thresholds evaluated by the hot-plate test in the rat. Pretreatment with 6-hydroxydopamine or prazosin fully prevents the action of both substances. Moreover, the effect of interleukin-1_α is completely blocked by the intracerebroventricular administration of the corticotropin-releasing hormone antagonist α-helical CRH 9–41. Our results suggest an involvement of CRH and the noredrenergic system in the antinociceptive effect of central interleukin-1_α.     

Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression. a prospective study

The development and course of depression is causally linked to impairment of central regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Previous research documented that the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test identifies HPA dysfunction with high sensitivity. We evaluated the predictive validity for medium-term outcome of the cortisol response in the combined DEX/CRH test in 74 remitted patients previously suffering from major depressive disorder. Of the 74 patients, 61 remained in stable remission and 13 relapsed during the first 6 months after discharge from the hospital. Although the cortisol and ACTH responses in the DEX/CRH test did not differ between the two groups of patients on admission, the responses differed significantly just before discharge (P< 0.05). We defined two dichotomous variables as prediction rules indicating (1) the change between admission and discharge in the cortisol response to the DEX/CRH test, and (2) the effect of the CRH infusion on cortisol as compared to the baseline level in the DEX/CRH test prior to discharge only. An elevated cortisol response in the DEX/CRH test was correlated with a four- to six-fold higher risk for relapse than in individuals with a normal cortisol response. The two proposed rules for predicting relapse within the first 6 months after discharge could be optimized by including age and gender. Hence, an exaggerated cortisol response in the combined DEX/CRH test predicts the recurrence of depressive psychopathology. The test performance can be further optimized if gender and age are taken into account.     

Microarray analysis of gene expression in multiple sclerosis and EAE identifies 5-lipoxygenase as a component of inflammatory lesions.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by lesions that are areas of blood-brain barrier breakdown, inflammation and myelin damage. To identify genes that contribute to lesion pathology, we have compared gene expression in MS lesions and in brains of mice with experimental allergic encephalomyelitis (EAE) with that in normal white matter. Gene expression was analyzed by cDNA microarrays consisting of 2798 human genes. One of the genes found to be upregulated in both MS lesions and EAE brains was 5-lipoxygenase (5-LO), a key enzyme in the biosynthesis of the proinflammatory leukotrienes. The presence of 5-LO in MS lesions was confirmed by immunohistochemistry and indicated that 5-LO was primarily contained within macrophages. Although these findings are not specific for MS, they identify a potentially important component of pro-inflammatory activity in the demyelinating process in MS and suggest a possible target for anti-inflammatory therapy in MS.     

Genome-wide investigation of rare structural variants identifies VIPR2 as a new candidate gene for schizophrenia

Research has shown that structural variation in the human genome, including rare copy number variations (CNVs), contributes to genetic susceptibility to psychiatric diseases, such as schizophrenia, a devastating complex disorder with a high genetic load. The study by Vacic et al. applied a genome-wide approach to detect novel, rare and highly penetrant CNVs. Detailed analysis of microduplications at 7q36.3 revealed that the neuropeptide receptor gene VIPR2 confers a significant risk for schizophrenia. This suggests that altered vasoactive intestinal signaling contributes to the genetic etiology of this disorder. This article recapitulates the findings of this study within the context of current knowledge of CNVs in the field of psychiatric disease.