Moritz D. Brandt

Physical exercise increases Notch activity, proliferation and cell cycle exit of type-3 progenitor cells in adult hippocampal neurogenesis.

In adult hippocampal neurogenesis of mice, the proliferation of precursor cells can be stimulated by voluntary exercise (wheel‐running). Physical activity has an additional effect on late progenitor cells (type‐3) by promoting cell survival and further maturation. Notch1 is a key regulator of various steps in neuronal development, including the inhibition of cell cycle exit and neuronal differentiation of neural stem cells, as well as promoting the survival and dendritic branching of newborn neurons. We here report that physical activity increased the proportion and absolute number of doublecortin+ (DCX) type‐2b and type‐3 progenitor cells that showed an activated Notch1 pathway. In contrast, the fraction of dividing cells with nuclear Notch intracellular domain expression indicating an activated Notch pathway was not affected by physical exercise. We used double labeling with two halogenated thymidine analogs, iododeoxyuridine and chlorodeoxyuridine, to distinguish between cell cycle exit and continued division at the progenitor cell level. After 7 days of physical exercise, the proliferative activity of precursor cells was increased, whereas the proportion of type‐2b/3 cells re‐entering S‐phase was reduced. Consistent with this observation, the proportion of DCX+ cells that expressed the marker of postmitotic immature granule cells (calretinin) was enhanced. Running promotes both the proliferation and cell cycle exit of DCX+ type‐3 precursors, possibly by preferentially stimulating a last neurogenic cell division. These pro‐proliferative effects are independent of Notch1, whereas the running‐induced survival and cell cycle exit of type‐3 progenitor cells might by mediated by Notch1 activity.

Brief Report: Adult Hippocampal Precursor Cells Shorten S‐Phase and Total Cell Cycle Length During Neuronal Differentiation

Cell cycle analyses of adult hippocampal neural stem and precursor cells in vivo are challenging, as there is no temporal or local discrimination of different precursor cell populations. All commonly used techniques to determine the cell cycle length of proliferating cells in the adult hippocampus do not allow discrimination between different cell types. Here, we introduce a novel procedure to precisely calculate cell cycle phase lengths of distinct precursor cell populations in vivo and thereby demonstrate a large heterogeneity of cell cycle kinetics within the pool of adult hippocampal precursor cells. Proliferating NeuroD1+ cells exhibited a significantly faster S‐phase progression (Ts = 10.1 ± 0.6 hours) and shorter total cell cycle length (Tc = 22.6 ± 0.1 hours) than NeuroD1− cells (Ts = 13.5 ± 0.8 hours, Tc = 27.0 ± 0.5 hours; p < .05). Dividing glial fibrillary acidic protein (GFAP+) cells also showed significantly shorter mean Ts of 9.7 ± 0.6 hours and Tc of 22.8 ± 0.5 hours compared to the rest of uncommitted NeuroD1− precursors (p < .01). Together, NeuroD1+ neuronal progenitors and mitotic GFAP+ radial glia‐like cells divide significantly faster than amplifying neural progenitor cells by accelerating their S‐phase. S‐phase duration seems to determine cell cycle length in the adult hippocampus. STEM CELLS 2012;30:2843–2847

Sleep disorders in Parkinson's disease.

Sleep disorders in patients with Parkinsons disease (PD) are very common and have an immense negative impact on their quality of life. Insomnia, daytime sleepiness with sleep attacks, restless-legs syndrome (RLS) and REM-sleep behaviour disorder (RBD) are the most frequent sleep disorders in PD. Neurodegenerative processes within sleep regulatory brain circuitries, antiparkinsonian (e.g., levodopa and dopamine agonists) and concomitant medication (e.g., antidepressants) as well as comorbidities or other non-motor symptoms (such as depression) are discussed as causative factors. For the diagnosis of sleep disturbances we recommend regular screening using validated questionnaires such as the Pittsburgh Sleep Quality Index (PSQI) or the Medical Outcomes Study Sleep Scale (MOS), for evaluating daytime sleepiness we would suggest to use the Epworth Sleepiness Scale (ESS), the inappropriate sleep composite score (ISCS) or the Stanford sleepiness scale (SSS). All of these questionnaires should be used in combination with a detailed medical history focusing on common sleep disorders and medication. If necessary, patients should be referred to sleep specialists or sleep laboratories for further investigations. Management of sleep disorders in PD patients usually starts with optimization of (dopaminergic) antiparkinsonian therapy followed by specific treatment of the sleep disturbances. Aside from these clinical issues of sleep disorders in PD, the concept of REM-sleep behaviour disorder (RBD) as an early sign for emerging neurodegenerative diseases is of pivotal interest for future research on biomarkers and neuroprotective treatment strategies of neurodegenerative diseases, and particularly PD.

Acute effects of wheel running on adult hippocampal precursor cells in mice are not caused by changes in cell cycle length or S phase length

Exercise stimulates cellular brain plasticity by extending the pool of proliferating neural precursor cells in the adult hippocampus. This effect has been investigated extensively, but the most immediate cellular effect induced by exercise that results in this acute increase in the number of cycling cells remained unclear. In the developing brain as well as adult pathological models, cell cycle alterations have a major influence on the balance between proliferative and neurogenic divisions. In this study we investigated whether this might also apply to the acute physiological pro-neurogenic stimulus of physical exercise in adulthood. Do changes in cell cycle precede the measurable increase in proliferation? After 5 days of voluntary wheel running, however, we measured only a very small, statistically not significant acceleration in cell cycle, which could not quantitatively explain the observed increase in proliferating cells after exercise. Thus, at this acute stage, changes at the level of cell cycle control is not the primary causal mechanism for the expansion of the precursor cell population, although with time after the stimulus changes in cell cycle of the entire population of labeled cells might be the result of the expanded pool of cells that have progressed to the advanced neurogenic stages with shorter cell cycle length.

Different Mechanisms Must Be Considered to Explain the Increase in Hippocampal Neural Precursor Cell Proliferation by Physical Activity

The number of proliferating neural precursor cells in the adult hippocampus is strongly increased by physical activity. The mechanisms through which this behavioral stimulus induces cell proliferation, however, are not yet understood. In fact, even the mode of proliferation of the stem and progenitor cells is not exactly known. Evidence exists for several mechanisms including cell cycle shortening, reduced cell death and stem cell recruitment, but as yet no model can account for all observations. An appreciation of how the cells proliferate, however, is crucial to our ability to model the neurogenic process and predict its behavior in response to pro-neurogenic stimuli. In a recent study, we addressed modulation of the cell cycle length as one possible mode of regulation of precursor cell proliferation in running mice. Our results indicated that the observed increase in number of proliferating cells could not be explained through a shortening of the cell cycle. We must therefore consider other mechanisms by which physical activity leads to enhanced precursor cell proliferation. Here we review the evidence for and against several different hypotheses and discuss the implications for future research in the field.

Proton MR Spectroscopy of Neural Stem Cells: Does the Proton-NMR Peak at 1.28 ppm Function As a Biomarker for Cell Type or State?

Recently, a peak at 1.28 ppm in proton magnetic resonance spectroscopy ((1)H-MRS) of neural stem cells (NSCs) was introduced as a noninterventional biomarker for neurogenesis in vivo. This would be an urgently needed requisite for translational studies in humans regarding the beneficial role of adult neurogenesis for the structural and functional integrity of the brain. However, many concerns have risen about the validity of the proposed signal as a specific marker for NSCs. The peak has also been related to cell-type-independent phenomena such as apoptosis or necrosis. Thus, we compared the 1.28-ppm peak in various immature stem cell populations, including embryonic stem cells, mouse embryonic fibroblasts, embryonic stem cell- and induced pluripotent stem cell-derived NSCs, ex vivo isolated embryonic NSCs, as well as mature and tumor cell types from different germ layers. To correlate the integral peak intensity with cell death, we induced both apoptosis with camptothecin and necrosis with sodium azide. A peak at 1.28 ppm was found in most cell types, and in most, but not all, NSCH cultures, demonstrating no specificity for NSCs. The intensities of the 1.28-ppm resonance significantly correlated with the rate of apoptosis, but not with the rate of necrosis, cell cycle phase distribution, cell size, or type. Multiple regression analysis displayed a significant predictive value of the peak intensity for apoptosis only. In this context, its specificity for apoptosis as a major selection process during neurogenesis may suggest this resonance as an indirect marker for neurogenesis in vivo.

“Silenced” polydendrocytes: a new cell type within the oligodendrocyte progenitor cell population?

Oligodendrocyte progenitor cells (OPCs) were first described more than two decades ago. Novel labeling techniques have shown them to be cells with more than just progenitor functions, with their classification as a fourth glial cell type in addition to astrocytes, oligodendrocytes, and microglial cells. Another term used for this cell type is polydendrocytes, owing to both their morphology and to the evolving knowledge about their diverse functions. Recently, an exclusive hallmark of neurons—the generation of action potentials—became debatable, because a subset of polydendrocytes was reported to generate action potentials in response to adequate stimuli. The new technique of inducible reporter gene expression has brought new insights into the fate and function of polydendrocytes. In recent studies, so-called “silenced” OPCs were detected in cortical tissue, and which underwent proliferation with subsequent cell cycle exit, but without any signs of differentiation. Within this review, we focus on the identification of this new subset of polydendrocytes and their possible functions within cortical networks.

Early Postnatal but Not Late Adult Neurogenesis Is Impaired in the Pitx3-Mutant Animal Model of Parkinson's Disease

The generation of new neurons in the adult dentate gyrus has functional implications for hippocampal formation. Reduced hippocampal neurogenesis has been described in various animal models of hippocampal dysfunction such as dementia and depression, which are both common non-motor-symptoms of Parkinsons disease (PD). As dopamine plays an important role in regulating precursor cell proliferation, the loss of dopaminergic neurons in the substantia nigra (SN) in PD may be related to the reduced neurogenesis observed in the neurogenic regions of the adult brain: subventricular zone (SVZ) and dentate gyrus (DG). Here we examined adult hippocampal neurogenesis in the Pitx3-mutant mouse model of PD (aphakia mice), which phenotypically shows a selective embryonic degeneration of dopamine neurons within the SN and to a smaller extent in the ventral tegmental area (VTA). Proliferating cells were labeled with BrdU in aphakia mice and healthy controls from 3 to 42 weeks of age. Three weeks old mutant mice showed an 18% reduction of proliferating cells in the DG and of 26% in the SVZ. Not only proliferation but also the number of new neurons was impaired in young aphakia mice resulting in 33% less newborn cells 4 weeks after BrdU-labeling. Remarkably, however, the decline in the number of proliferating cells in the neurogenic regions vanished in older animals (8–42 weeks) indicating that aging masks the effect of dopamine depletion on adult neurogenesis. Region specific reduction in precursor cells proliferation correlated with the extent of dopaminergic degeneration in mesencephalic subregions (VTA and SN), which supports the theory of age- and region-dependent regulatory effects of dopaminergic projections. Physiological stimulation of adult neurogenesis by physical activity (wheel running) almost doubled the number of proliferating cells in the dentate gyrus of 8 weeks old aphakia mice to a number comparable to that of wild-type mice, abolishing the slight reduction of baseline neurogenesis at this age. The described age-dependent susceptibility of adult neurogenesis to PD-like dopaminergic degeneration and its responsiveness to physical activity might have implications for the understanding of the pathophysiology and treatment of non-motor symptoms in PD.

RLS patients show better nocturnal performance in the Simon task due to diminished visuo-motor priming

OBJECTIVE The restless legs syndrome (RLS) is characterized by sensory-motor symptoms which usually occur predominantly at rest in the evening and at night. It is assumed that this circadian rhythm is caused by low dopamine levels in the evening. Yet, it has never been investigated whether RLS patients show diurnal variations in cognitive functions modulated by dopamine and what neurophysiological and functional neuroanatomical processes underlie such modulations. METHODS We used a Simon task combined with EEG and source localization to investigate whether top-down response selection and/or automatic visuo-motor priming are subject to diurnal changes in RLS patients, as compared to matched healthy controls. RESULTS We found that RLS patients showed better task performance due to reduced visuo-motor priming in the evening, as reflected by smaller early lateralized readiness potential (e-LRP) amplitudes and decreased activation of the superior parietal cortex and premotor cortex. Top-down response selection and early attentional processing were unaffected by RLS. CONCLUSIONS Counterintuitively, RLS patients show enhanced task performance in the evening, i.e. when experiencing dopaminergic deficiency. Yet, this may be explained by deficits in visuo-motor priming that lead to reduced false response tendencies. SIGNIFICANCE This study reveals a counterintuitive circadian variation of cognitive functions in RLS patients.

Role of the IL-6-Receptor expression in CD14+ monocytes in modulating sleep in patients with bipolar disorder

OBJECTIVE Bipolar disorder is a severe mental disorder associated with persistent sleep disturbances and elevated levels of mRNA coding for pro-inflammatory cytokines within peripheral monocytes. The mechanisms causing and sustaining a reduced sleep quality remain elusive. The pro-inflammatory cytokine receptor IL-6R is known to negatively affect sleep quality and architecture. Since elevations in IL-6R have repeatedly been demonstrated in bipolar disorder the association of sleep quality and architecture with levels of mRNA coding for IL-6R in monocytes was to be tested. METHODS Euthymic patients with bipolar disorder (n = 24) and healthy control subjects (n = 25) were assessed using all night polysomnography (PSG) and six day actigraphy. CD14+ monocytes were isolated on the evening of PSG assessment and levels of mRNA coding for IL-6R and other cytokines were determined using hybridization based assays. Interactions between IL-6R and sleep measures were calculated using linear regression models, adjusting for potential confounders. RESULTS Patients with bipolar disorder were found to have a reduced subjective sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) and more frequent arousals and short changes to wake during sleep. Both PSQI and the frequency of arousals were significantly predicted by levels of IL-6R. Contrary to previous publications, elevated levels of mRNA coding for pro-inflammatory cytokines in peripheral CD14+ monocytes of patients with bipolar disorder could not be replicated. LIMITATIONS Participants were only investigated with one night of PSG which may have given rise to first night effects. CONCLUSIONS Reduced sleep quality in euthymic patients with bipolar disorder may be related to an increased expression of IL-6R by peripheral monocytes.