Prognostic and symptomatic aspects of rapid eye movement sleep in a mouse model of posttraumatic stress disorder

Not every individual develops Posttraumatic Stress Disorder (PTSD) after the exposure to a potentially traumatic event. Therefore, the identification of pre-existing risk factors and early diagnostic biomarkers is of high medical relevance. However, no objective biomarker has yet progressed into clinical practice. Sleep disturbances represent commonly reported complaints in PTSD patients. In particular, changes in rapid eye movement sleep (REMS) properties are frequently observed in PTSD patients. Here, we examined in a mouse model of PTSD whether (1) mice developed REMS alterations after trauma and (2) whether REMS architecture before and/or shortly after trauma predicted the development of PTSD-like symptoms. We monitored sleep-wake behavior via combined electroencephalogram/electromyogram recordings immediately before (24 h pre), immediately after (0–48 h post) and 2 months after exposure to an electric foot shock in male C57BL/6N mice (n = 15). PTSD-like symptoms, including hyperarousal, contextual, and generalized fear, were assessed 1 month post-trauma. Shocked mice showed early onset and sustained elevation of REMS compared to non-shocked controls. In addition, REMS architecture before trauma was correlated with the intensity of acoustic startle responses, but not contextual fear, 1 month after trauma. Our data suggest REMS as prognostic (pre-trauma) and symptomatic (post-trauma) marker of PTSD-like symptoms in mice. Translated to the situation in humans, REMS may constitute a viable, objective, and non-invasive biomarker in PTSD and other trauma-related psychiatric disorders, which could guide pharmacological interventions in humans at high risk

Sleep scoring made easy Semi-automated sleep analysis software and manual rescoring tools for basic sleep research in mice

Studying sleep behavior in animal models demands clear separation of vigilance states. Pure manual scoring is time-consuming and commercial scoring software is costly. We present a LabVIEW-based, semi-automated scoring routine using recorded EEG and EMG signals. This scoring routine is • designed to reliably assign the vigilance/sleep states wakefulness (WAKE), non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS) to defined EEG/EMG episodes. • straightforward to use even for beginners in the field of sleep research. • freely available upon request. Chronic recordings from mice were used to design and evaluate the scoring routine consisting of an artifact-removal, a scoring- and a rescoring routine. The scoring routine processes EMG and different EEG frequency bands. Amplitude-based thresholds for EEG and EMG parameters trigger a decision tree assigning each EEG episode to a defined vigilance/sleep state automatically. Using the rescoring routine individual episodes or particular state transitions can be re-evaluated manually. High agreements between auto-scored and manual sleep scoring could be shown for experienced scorers and for beginners quickly and reliably. With small modifications to the software, it can be easily adapted for sleep analysis in other animal models

Altered synaptic plasticity and behavioral abnormalities in CNGA3-deficient mice

The role of the cyclic nucleotide-gated (CNG) channel CNGA3 is well established in cone photoreceptors and guanylyl cyclase-D-expressing olfactory neurons. To assess a potential function of CNGA3 in the mouse amygdala and hippocampus, we examined synaptic plasticity and performed a comparative analysis of spatial learning, fear conditioning and step-down avoidance in wild-type mice and CNGA3 null mutants (CNGA3(-/-) ). CNGA3(-/-) mice showed normal basal synaptic transmission in the amygdala and the hippocampus. However, cornu Ammonis (CA1) hippocampal long-term potentiation (LTP) induced by a strong tetanus was significantly enhanced in CNGA3(-/-) mice as compared with their wild-type littermates. Unlike in the hippocampus, LTP was not significantly altered in the amygdala of CNGA3(-/-) mice. Enhanced hippocampal LTP did not coincide with changes in hippocampus-dependent learning, as both wild-type and mutant mice showed a similar performance in water maze tasks and contextual fear conditioning, except for a trend toward higher step-down latencies in a passive avoidance task. In contrast, CNGA3(-/-) mice showed markedly reduced freezing to the conditioned tone in the amygdala-dependent cued fear conditioning task. In conclusion, our study adds a new entry on the list of physiological functions of the CNGA3 channel. Despite the dissociation between physiological and behavioral parameters, our data describe a so far unrecognized role of CNGA3 in modulation of hippocampal plasticity and amygdala-dependent fear memory

Serum MicroRNA-21 as Marker for Necroinflammation in Hepatitis C Patients with and without Hepatocellular Carcinoma

Background: MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC. Methodology/Principal Findings: 62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = −0.494, P = 0.00002), alanine aminotransferase (ALT) (r = −0.309, P = 0.007), aspartate aminotransferase (r = −0.495, P = 0.000007), bilirubin (r = −0.362, P = 0.002), international normalized ratio (r = −0.338, P = 0.034) and γ-glutamyltransferase (r = −0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dCT of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%. Conclusions/Significance: The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC