Downregulation of the Vitamin D Receptor Regulated Gene Set in the Hippocampus After MDMA Treatment

The active ingredient of ecstasy, ±3,4-methylenedioxymethamphetamine (MDMA), in addition to its initial reinforcing effects, induces selective and non-selective brain damage. Evidences suggest that the hippocampus (HC), a central region for cognition, may be especially vulnerable to impairments on the long-run, nevertheless, transcription factors that may precede and regulate such chronic changes remained uninvestigated in this region. In the current study, we used gene-set enrichment analysis (GSEA) to reveal possible transcription factor candidates responsible for enhanced vulnerability of HC after MDMA administration. Dark Agouti rats were intraperitoneally injected with saline or 15 mg/kg MDMA. Three weeks later HC gene expression was measured by Illumina whole-genome beadarrays and GSEA was performed with MSigDB transcription factor sets. The number of significantly altered genes on the genome level (significance < 0.001) in up/downregulated sets was also counted. MDMA upregulated one, and downregulated 13 gene sets in the HC of rats, compared to controls, including Pax4, Pitx2, FoxJ2, FoxO1, Oct1, Sp3, AP3, FoxO4, and vitamin D receptor (VDR)-regulated sets (q-value <0.05). VDR-regulated set contained the second highest number of significantly altered genes, including among others, Camk2n2, Gria3, and Grin2a. Most identified transcription factors are implicated in the response to ischemia confirming that serious hypoxia/ischemia occurs in the HC after MDMA administration, which may contribute to the selective vulnerability of this brain region. Moreover, our results also raise the possibility that vitamin D supplementation, in addition to the commonly used antioxidants, could be a potential alternative method to attenuate MDMA-induced chronic hippocampal impairments

Increased activation of the pregenual anterior cingulate cortex to citalopram challenge in migraine: an fMRI study

Background The anterior cingulate cortex (ACC) is a key structure of the pain processing network. Several structural and functional alterations of this brain area have been found in migraine. In addition, altered serotonergic neurotransmission has been repeatedly implicated in the pathophysiology of migraine, although the exact mechanism is not known. Thus, our aim was to investigate the relationship between acute increase of brain serotonin (5-HT) level and the activation changes of the ACC using pharmacological challenge MRI (phMRI) in migraine patients and healthy controls. Methods Twenty-seven pain-free healthy controls and six migraine without aura patients participated in the study. All participant attended to two phMRI sessions during which intravenous citalopram, a selective serotonin reuptake inhibitor (SSRI), or placebo (normal saline) was administered. We used region of interest analysis of ACC to compere the citalopram evoked activation changes of this area between patients and healthy participants. Results Significant difference in ACC activation was found between control and patient groups in the right pregenual ACC (pgACC) during and after citalopram infusion compared to placebo. The extracted time-series showed that pgACC activation increased in migraine patients compared to controls, especially in the first 8-10 min of citalopram infusion. Conclusions Our results demonstrate that a small increase in 5-HT levels can lead to increased phMRI signal in the pregenual part of the ACC that is involved in processing emotional aspects of pain. This increased sensitivity of the pgACC to increased 5-HT in migraine may contribute to recurring headache attacks and increased stress-sensitivity in migraine

Financial Stress Interacts With CLOCK Gene to Affect Migraine.

Previous studies suggested that both maladaptive stress response and circadian dysregulation might have a role in the background of migraine. However, effects of circadian genes on migraine have not been tested yet. In the present study, we investigated the main effect of rs10462028 of the circadian locomotor output cycles kaput (CLOCK) gene and its interaction with different stress factors on migraine. In our cross-sectional study 2,157 subjects recruited from Manchester and Budapest completed the ID-Migraine questionnaire to detect migraine type headaches (migraineID). Additional stress factors were assessed by a shortened version of the Childhood Trauma Questionnaire, the List of Threatening Experiences questionnaire, and a validated questionnaire to identify financial difficulties. Rs10462028 showed no main genetic effect on migraineID. However, chronic stress indexed by financial difficulties showed a significant interaction effect with rs10462028 (p = 0.006 in recessive model) on migraineID. This result remained significant after correction for lifetime bipolar and unipolar depression and was replicated in both subsamples, although only a trend effect was reached after Bonferroni-correction, which is the strictest correction not considering interdependences. Childhood adversity (CHA) and Recent negative life events (RLE) showed no significant gene × stress interaction with rs10462028. In addition, in silico analysis demonstrated that the genetic region tagged by rs10462028 alters the binding of several miRNAs. Our exploratory study suggests that variations in the CLOCK gene, with moderating effect on gene function through miRNA binding, in interaction with financial difficulties might influence the risk of migraine-type headaches. Thus, financial hardship as a chronic stress factor may affect migraine through altering circadian rhythms

A replication study separates polymorphisms behind migraine with and without depression

The largest migraine genome-wide association study identified 38 candidate loci. In this study we assessed whether these results replicate on a gene level in our European cohort and whether effects are altered by lifetime depression. We tested SNPs of the loci and their vicinity with or without interaction with depression in regression models. Advanced analysis methods such as Bayesian relevance analysis and a neural network based classifier were used to confirm findings. Main effects were found for rs2455107 of PRDM16 (OR = 1.304, p = 0.007) and five intergenic polymorphisms in 1p31.1 region: two of them showed risk effect (OR = 1.277, p = 0.003 for both rs11209657 and rs6686879), while the other three variants were protective factors (OR = 0.4956, p = 0.006 for both rs12090642 and rs72948266; OR = 0.4756, p = 0.005 for rs77864828). Additionally, 26 polymorphisms within ADGRL2, 2 in REST, 1 in HPSE2 and 33 mostly intergenic SNPs from 1p31.1 showed interaction effects. Among clumped results representing these significant regions, only rs11163394 of ADGRL2 showed a protective effect (OR = 0.607, p = 0.002), all other variants were risk factors (rs1043215 of REST with the strongest effect: OR = 6.596, p = 0.003). Bayesian relevance analysis confirmed the relevance of intergenic rs6660757 and rs12128399 (p31.1), rs1043215 (REST), rs1889974 (HPSE2) and rs11163394 (ADGRL2) from depression interaction results, and the moderate relevance of rs77864828 and rs2455107 of PRDM16 from main effect analysis. Both main and interaction effect SNPs could enhance predictive power with the neural network based classifier. In summary, we replicated p31.1, PRDM16, REST, HPSE2 and ADGRL2 genes with classic genetic and advanced analysis methods. While the p31.1 region and PRDM16 are worthy of further investigations in migraine in general, REST, HPSE2 and ADGRL2 may be prime candidates behind migraine pathophysiology in patients with comorbid depression

Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness

Neuropeptides are auxiliary messenger molecules that always co-exist in nerve cells with one or more small molecule (classic) neurotransmitters. Neuropeptides act both as transmitters and trophic factors, and play a role particularly when the nervous system is challenged, as by injury, pain or stress. Here neuropeptides and coexistence in mammals are reviewed, but with special focus on the 29/30 amino acid galanin and its three receptors GalR1, -R2 and -R3. In particular, galanin’s role as a co-transmitter in both rodent and human noradrenergic locus coeruleus (LC) neurons is addressed. Extensive experimental animal data strongly suggest a role for the galanin system in depression–like behavior. The translational potential of these results was tested by studying the galanin system in postmortem human brains, first in normal brains, and then in a comparison of five regions of brains obtained from depressed people who committed suicide, and from matched controls. The distribution of galanin and the four galanin system transcripts in the normal human brain was determined, and selective and parallel changes in levels of transcripts and DNA methylation for galanin and its three receptors were assessed in depressed patients who committed suicide: upregulation of transcripts, e.g., for galanin and GalR3 in LC, paralleled by a decrease in DNA methylation, suggesting involvement of epigenetic mechanisms. It is hypothesized that, when exposed to severe stress, the noradrenergic LC neurons fire in bursts and release galanin from their soma/dendrites. Galanin then acts on somato-dendritic, inhibitory galanin autoreceptors, opening potassium channels and inhibiting firing. The purpose of these autoreceptors is to act as a ‘brake’ to prevent overexcitation, a brake that is also part of resilience to stress that protects against depression. Depression then arises when the inhibition is too strong and long lasting – a maladaption, allostatic load, leading to depletion of NA levels in the forebrain. It is suggested that disinhibition by a galanin antagonist may have antidepressant activity by restoring forebrain NA levels. A role of galanin in depression is also supported by a recent candidate gene study, showing that variants in genes for galanin and its three receptors confer increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events. In summary, galanin, a neuropeptide coexisting in LC neurons, may participate in the mechanism underlying resilience against a serious and common disorder, MDD. Existing and further results may lead to an increased understanding of how this illness develops, which in turn could provide a basis for its treatment

Decrease in REM latency and changes in sleep quality parallel serotonergic damage and recovery after MDMA: a longitudinal study over 180 days

The recreational drug ecstasy [3,4-methylenedioxymethamphetamine (MDMA)], has been found to selectively damage brain serotonin neurons in experimental animals, and probably in human MDMA users, but detailed morphometric analyses and parallel functional measures during damage and recovery are missing. Since there is evidence that serotonin regulates sleep, we have compared serotonergic markers parallel with detailed analysis of sleep patterns at three time-points within 180 d after a single dose of 15 mg/kg MDMA in male Dark Agouti rats. At 7 d and 21 d after MDMA treatment, significant (30-40%), widespread reductions in serotonin transporter (5-HTT) density were detected in the cerebral cortex, hippocampus, most parts of the hypothalamus, and some of the brainstem nuclei. With the exception of the hippocampus, general recovery was observed in the brain 180 d after treatment. Transient increases followed by decreases were detected in 5-HTT mRNA expression of dorsal and median raphe nuclei at 7 d and 21 d after the treatment. Significant reductions in rapid eye movement (REM) sleep latency, increases in delta power spectra in non-rapid eye movement sleep and increased fragmentation of sleep were also detected, but all these alterations disappeared by the 180th day. The present data provide evidence for long-term, albeit, except for the hippocampus, transient changes in the terminal and cellular regions of the serotonergic system after this drug. Reduced REM latency and increased sleep fragmentation are the most characteristic alterations of sleep consistently described in depression using EEG sleep polygraphy