The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder

Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either 'reactive' or 'endogenous' subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of 'reactive' or 'endogenous' subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of 'reactive' and 'endogenous' depression. We then translated these findings to clinical samples using a human post-mortem mRNA study

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Pluripotent Embryonic Stem Cells Development and Differentiation under Altered Gravity Conditions

Murine embryonic stem cells (ESCs) were exposed to simulated microgravity using the principle of a fast 2D clinostat and hypergravity (1.8 g) to investigate the effects of (altered) gravity on cell differentiation. In this context, gravity-induced changes in the cell cycle distribution, the gene expression, the cytoskeleton, the embryoid body morphology and the differentiation potential have been investigated. Changes in the gene expression and embryoid body morphology as well as reduced beating patterns (correlated with a lower expression of Myh 7) of ESCs after exposure demonstrated the impact of simulated microgravity. The analysis showed changes in the actin framework of the cytoskeleton on day 6 of clinorotation as compared with the corresponding 1 g controls; the actin framework was less pronounced under simulated microgravity conditions. Cell cycle analysis of clinorotated ESCs revealed significant changes in the G1-phase: the number of cells in the 1 g control group was significant higher as compared with the clinostat group. ESCs exposed to hypergravity revealed changes in the actin framework after 24 hours; the microfilaments were denser and tightly arranged than under 1 g conditions. Furthermore, hypergravity induced significant differences in the morphology of embryoid bodies regarding area and diameter and resulted in an increased size compared with the 1 g control, whereas the cell cycle seemed to be unaffected by hypergravity. Location of the 1 g control near to the centrifuge versus location of the 1 g control on the bottom of a clinostat revealed different numbers of cells in the SubG1-phase. This result indicates a potential device-specific side effect of vibration and in turn a combined effect of hypergravity and vibration on the running centrifuge. As a result of the insufficient RNA quality and the fluctuating expression values of the investigated genes (Oct 4, Nanog, CDH 1, Myh 6, cardiac Troponin and Klf 4), there were no consistent results obtained in this study. However, increased beating activities in EBs may indicate changes in the expression of differentiation markers and in genes, which are involved in the process of cardiomyogenesis. The handling procedures of embryonic stem cells used in this study, have to be revised for further studies since standard laboratory procedures include e.g. centrifugation steps in order to concentrate cells, which might interfere with the gravity-related experimental set-up. Overall, the results of this study suggest that embryonic stem cells are sensitive to altered gravity conditions and respond to gravity changes by e.g. forming a more/less powerful actin framework. Further investigations are necessary for understanding the effects of gravity and its effects on the actin cytoskeleton for the differentiation of ESCs and for understanding the development under altered gravity conditions

Modulation of Differentiation Processes in Murine Embryonic Stem Cells Exposed to Parabolic Flight-Induced Acute Hypergravity and Microgravity

Embryonic developmental studies under microgravity conditions in space are very limited. To study the effects of short-term altered gravity on embryonic development processes, we exposed mouse embryonic stem cells (mESCs) to phases of hypergravity and microgravity and studied the differentiation potential of the cells using wide-genome microarray analysis. During the 64th European Space Agency's parabolic flight campaign, mESCs were exposed to 31 parabolas. Each parabola comprised phases lasting 22 s of hypergravity, microgravity, and a repeat of hypergravity. On different parabolas, RNA was isolated for microarray analysis. After exposure to 31 parabolas, mESCs (P31 mESCs) were further differentiated under normal gravity (1 g) conditions for 12 days, producing P31 12-day embryoid bodies (EBs). After analysis of the microarrays, the differentially expressed genes were analyzed using different bioinformatic tools to identify developmental and nondevelopmental biological processes affected by conditions on the parabolic flight experiment. Our results demonstrated that several genes belonging to GOs associated with cell cycle and proliferation were downregulated in undifferentiated mESCs exposed to gravity changes. However, several genes belonging to developmental processes, such as vasculature development, kidney development, skin development, and to the TGF-β signaling pathway, were upregulated. Interestingly, similar enriched and suppressed GOs were obtained in P31 12-day EBs compared with ground control 12-day EBs. Our results show that undifferentiated mESCs exposed to alternate hypergravity and microgravity phases expressed several genes associated with developmental/differentiation and cell cycle processes, suggesting a transition from the undifferentiated pluripotent to a more differentiated stage of mESCs

Simulated Microgravity Modulates Differentiation Processes of Embryonic Stem Cells

Background/Aims: Embryonic developmental studies under microgravity conditions in space are very limited. To study the effects of altered gravity on the embryonic development processes we established an in vitro methodology allowing differentiation of mouse embryonic stem cells (mESCs) under simulated microgravity within a fast-rotating clinostat (clinorotation) and capture of microarray-based gene signatures. Methods: The differentiating mESCs were cultured in a 2D pipette clinostat. The microarray and bioinformatics tools were used to capture genes that are deregulated by simulated microgravity and their impact on developmental biological processes. Results: The data analysis demonstrated that differentiation of mESCs in pipettes for 3 days resultet to early germ layer differentiation and then to the different somatic cell types after further 7 days of differentiation in the Petri dishes. Clinorotation influences differentiation as well as non-differentiation related biological processes like cytoskeleton related 19 genes were modulated. Notably, simulated microgravity deregulated genes Cyr61, Thbs1, Parva, Dhrs3, Jun, Tpm1, Fzd2 and Dll1 are involved in heart morphogenesis as an acute response on day 3. If the stem cells were further cultivated under normal gravity conditions (1 g) after clinorotation, the expression of cardiomyocytes specific genes such as Tnnt2, Rbp4, Tnni1, Csrp3, Nppb and Mybpc3 on day 10 was inhibited. This correlated well with a decreasing beating activity of the 10-days old embryoid bodies (EBs). Finally, we captured Gadd45g, Jun, Thbs1, Cyr61and Dll1 genes whose expressions were modulated by simulated microgravity and by real microgravity in various reported studies. Simulated microgravity also deregulated genes belonging to the MAP kinase and focal dhesion signal transduction pathways. Conclusion: One of the most prominent biological processes affected by simulated microgravity was the process of cardiomyogenesis. The most significant simulated microgravity-affected genes, signal transduction pathways, and biological processes which are relevant for mESCs differentiation have been identified and discussed below