an experimental approach with a trauma film paradigm

Background Intrusive memories of traumatic events are a core feature of post- traumatic stress disorder but little is known about the neurobiological formation of intrusions. The aim of this study was to determine whether the activity of the noradrenergic system during an intrusion-inducing stressor would influence subsequent intrusive memories. Method We conducted an experimental, double-blind, placebo-controlled study in 118 healthy women. Participants received a single dose of either 10 mg yohimbine, stimulating noradrenergic activity, or 0.15 mg clonidine, inhibiting noradrenergic activity, or placebo. Subsequently, they watched an established trauma film which induced intrusions. The number of consecutive intrusions resulting from the trauma film, the vividness of the intrusions, and the degree of distress evoked by the intrusions were assessed during the following 4 days. Salivary cortisol and α-amylase were collected before and after the trauma film. Results A significant time × treatment interaction for the number of intrusions and the vividness of intrusions indicated a different time course of intrusions depending on treatment. Post-hoc tests revealed a delayed decrease of intrusions and a delayed decrease of intrusion vividness after the trauma film in the yohimbine group compared with the clonidine and placebo groups. Furthermore, after yohimbine administration, a significant increase in salivary cortisol levels was observed during the trauma film. Conclusions Our findings indicate that pharmacological activation of the noradrenergic system during an emotionally negative event makes an impact on consecutive intrusive memories and their vividness in healthy women. The noradrenergic system seems to be involved in the formation of intrusive memories

Expression of the retinoic acid catabolic enzyme CYP26B1 in the human brain to maintain signaling homeostasis

Date of Acceptance: 27/08/2015 Funding was provided by the Wellcome Trust grant WT081633MA-NCE and Biological Sciences Research Council Grant BB/K001043/1. Prof Fragoso is the recipient of a Post Doctoral Science without Borders grant from the Brazilian National Council for Scientific and Technological Development (CNPq, 237450/2012-7).Peer reviewedPublisher PD

Inferior frontal sulcal hyperintensities on brain MRI are associated with amyloid positivity beyond Age—results from the multicentre observational DELCODE study

Inferior frontal sulcal hyperintensities (IFSHs) on fluid-attenuated inversion recovery (FLAIR) sequences have been proposed to be indicative of glymphatic dysfunction. Replication studies in large and diverse samples are nonetheless needed to confirm them as an imaging biomarker. We investigated whether IFSHs were tied to Alzheimer’s disease (AD) pathology and cognitive performance. We used data from 361 participants along the AD continuum, who were enrolled in the multicentre DELCODE study. The IFSHs were rated visually based on FLAIR magnetic resonance imaging. We performed ordinal regression to examine the relationship between the IFSHs and cerebrospinal fluid-derived amyloid positivity and tau positivity (Aβ42/40 ratio ≤ 0.08; pTau181 ≥ 73.65 pg/mL) and linear regression to examine the relationship between cognitive performance (i.e., Mini-Mental State Examination and global cognitive and domain-specific performance) and the IFSHs. We controlled the models for age, sex, years of education, and history of hypertension. The IFSH scores were higher in those participants with amyloid positivity (OR: 1.95, 95% CI: 1.05–3.59) but not tau positivity (OR: 1.12, 95% CI: 0.57–2.18). The IFSH scores were higher in older participants (OR: 1.05, 95% CI: 1.00–1.10) and lower in males compared to females (OR: 0.44, 95% CI: 0.26–0.76). We did not find sufficient evidence linking the IFSH scores with cognitive performance after correcting for demographics and AD biomarker positivity. IFSHs may reflect the aberrant accumulation of amyloid β beyond age

Direct inhibition of retinoic acid catabolism by fluoxetine

Recent evidence from animal and human studies suggests neuroprotective effects of the SSRI fluoxetine, e.g., in the aftermath of stroke. The underlying molecular mechanisms remain to be fully defined. Because of its effects on the cytochrome P450 system (CYP450), we hypothesized that neuroprotection by fluoxetine is related to altered metabolism of retinoic acid (RA), whose CYP450-mediated degradation in brain tissue constitutes an important step in the regulation of its site-specific auto- and paracrine actions. Using traditional pharmacological in vitro assays, the effects of fluoxetine on RA degradation were probed in crude synaptosomes from rat brain and human-derived SH-SY5Y cells, and in cultures of neuron-like SH-SY5Y cells. Furthermore, retinoid-dependent effects of fluoxetine on neuronal survival following glutamate exposure were investigated in rat primary neurons cells using specific retinoid receptor antagonists. Experiments revealed dose-dependent inhibition of synaptosomal RA degradation by fluoxetine along with dose-dependent increases in RA levels in cell cultures. Furthermore, fluoxetine's neuroprotective effects against glutamate excitotoxicity in rat primary neurons were demonstrated to partially depend on RA signaling. Taken together, these findings demonstrate for the first time that the potent, pleiotropic antidepressant fluoxetine directly interacts with RA homeostasis in brain tissue, thereby exerting its neuroprotective effects

Retinoic acid as target for local pharmacokinetic interaction with modafinil in neural cells

While the biological importance of the cytochrome P450 system in the liver is well established, much less is known about its role in the brain and drug interactions at the level of brain cells have hardly been investigated. Here, we show that modafinil, a well-known inducer of hepatic CYP enzymes, also increases CYP3A4 expression in human-derived neuron-like SH-SY5Y cells. Upregulation of CYP3A4 by modafinil was associated with increased retinoic acid (RA) degradation, which could be blocked by specific CYP3A4 inhibitor erythromycin. In turn, reduced RA levels in culture medium during modafinil treatment resulted in decreased neuronal differentiation of SH-SY5Y cells as assessed by intracellular neurotransmitter concentrations and proliferative activity. Again, this differentiation-impeding effect of modafinil on SH-SY5Y cells was antagonized by erythromycin. Similarly, modafinil treatment of the murine GL261 glioma cell line resulted in increased proliferative activity. This was associated with upregulation of RA-degrading CYP26A1 in GL261 cells. Taken together, our results indicate that psychopharmacological agents such as modafinil may directly act on CYP enzymes in neural tissue. These kinds of drug effects may become highly relevant especially in the context of biomolecules such as RA whose local metabolism in brain is under tight spatial and temporal control

Does cortisol modulate emotion recognition and empathy?

INTRODUCTION: Emotion recognition and empathy are important aspects in the interaction and understanding of other people's behaviors and feelings. The Human environment comprises of stressful situations that impact social interactions on a daily basis. Aim of the study was to examine the effects of the stress hormone cortisol on emotion recognition and empathy. METHODS: In this placebo-controlled study, 40 healthy men and 40 healthy women (mean age 24.5 years) received either 10mg of hydrocortisone or placebo. We used the Multifaceted Empathy Test to measure emotional and cognitive empathy. Furthermore, we examined emotion recognition from facial expressions, which contained two emotions (anger and sadness) and two emotion intensities (40% and 80%). RESULTS: We did not find a main effect for treatment or sex on either empathy or emotion recognition but a sexxemotion interaction on emotion recognition. The main result was a four-way-interaction on emotion recognition including treatment, sex, emotion and task difficulty. At 40% task difficulty, women recognized angry faces better than men in the placebo condition. Furthermore, in the placebo condition, men recognized sadness better than anger. At 80% task difficulty, men and women performed equally well in recognizing sad faces but men performed worse compared to women with regard to angry faces. CONCLUSION: Apparently, our results did not support the hypothesis that increases in cortisol concentration alone influence empathy and emotion recognition in healthy young individuals. However, sex and task difficulty appear to be important variables in emotion recognition from facial expressions

Essential role of interleukin-6 in post-stroke angiogenesis

Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6(-/-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of interleukin-6 competent bone marrow into IL-6(-/-) mice (IL-6(chi)) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection

Exofocal dopaminergic degeneration as antidepressant target in mouse model of poststroke depression

BACKGROUND: Although poststroke depression (PSD) is a frequent chronic complication of stroke with high relevance for outcome and survival, underlying pathomechanisms remain inadequately understood. This may be because suitable animal models are largely lacking and existing models are poorly characterized. METHODS: Male 129/SV mice were subjected to 30-min middle cerebral artery occlusion (MCAo)/reperfusion and serial magnetic resonance imaging scans. A subset of animals received selective serotonin reuptake inhibitor citalopram starting 7 days after MCAo. Behavioral assessment was performed at 14 weeks. To identify biological correlates of PSD, we quantified corticosterone levels in serum and brain-derived neurotrophic factor levels in brain. The integrity of the mesolimbic dopaminergic system was assessed using tyrosine hydroxylase and dynorphin in situ hybridizations as well as dopamine transporter autoradiography. RESULTS: Left, but not right, MCAo, elicited anhedonia and increased anxiety and despair. This depression-like syndrome was associated with alterations in the mesolimbic reward system. MCAo resulted in delayed degeneration of dopaminergic neurons in ipsilateral midbrain, which was accompanied by reduced dopamine concentrations and decreased levels of dopamine transporter density along with increased brain-derived neurotrophic factor protein levels in ischemic striatum and increased dynorphin messenger RNA expression in nucleus accumbens. Chronic antidepressant treatment initiated as late as 7 days after stroke reversed the behavioral phenotype, prevented degeneration of dopaminergic midbrain neurons, and attenuated striatal atrophy at 4 months. CONCLUSIONS: Our results highlight the importance of the dopaminergic system for the development of PSD. Prevention of secondary neurodegeneration by antidepressants may provide a novel target for subacute stroke therapy