Generation of adult hippocampal neural stem cells occurs in the early postnatal dentate gyrus and depends on cyclin D2.

Lifelong hippocampal neurogenesis is maintained by a pool of multipotent adult neural stem cells (aNSCs) residing in the subgranular zone of the dentate gyrus (DG). The mechanisms guiding transition of NSCs from the developmental to the adult state remain unclear. We show here, by using nestin-based reporter mice deficient for cyclin D2, that the aNSC pool is established through cyclin D2-dependent proliferation during the first two weeks of life. The absence of cyclin D2 does not affect normal development of the dentate gyrus until birth but prevents postnatal formation of radial glia-like aNSCs. Furthermore, retroviral fate mapping reveals that aNSCs are born on-site from precursors located in the dentate gyrus shortly after birth. Taken together, our data identify the critical time window and the spatial location of the precursor divisions that generate the persistent population of aNSCs and demonstrate the central role of cyclin D2 in this process.

Poststroke dendritic arbor regrowth requires the actin nucleator Cobl.

Ischemic stroke is a major cause of death and long-term disability. We demonstrate that middle cerebral artery occlusion (MCAO) in mice leads to a strong decline in dendritic arborization of penumbral neurons. These defects were subsequently repaired by an ipsilateral recovery process requiring the actin nucleator Cobl. Ischemic stroke and excitotoxicity, caused by calpain-mediated proteolysis, significantly reduced Cobl levels. In an apparently unique manner among excitotoxicity-affected proteins, this Cobl decline was rapidly restored by increased mRNA expression and Cobl then played a pivotal role in poststroke dendritic arbor repair in peri-infarct areas. In Cobl knockout (KO) mice, the dendritic repair window determined to span day 2 to 4 poststroke in wild-type (WT) strikingly passed without any dendritic regrowth. Instead, Cobl KO penumbral neurons of the primary motor cortex continued to show the dendritic impairments caused by stroke. Our results thereby highlight a powerful poststroke recovery process and identified causal molecular mechanisms critical during poststroke repair.

A limited role of NKCC1 in telencephalic glutamatergic neurons for developing hippocampal network dynamics and behavior.

NKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical, and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in vitro excitatory actions of γ-aminobutyric acid (GABA) and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics, and behavioral performance are subtle. Our data reveal a neural network function of NKCC1 in hippocampal glutamatergic neurons in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development.

Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis.

BACKGROUND: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. METHODS: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE). RESULTS: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome. CONCLUSIONS: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.

Systematic quantitative assessment of motor function in clinically isolated REM sleep behaviour disorder: A diagnostic window into early alpha-synucleinopathies.

Mild motor abnormalities can herald the beginning of Parkinson´s disease but their diagnostic value is limited by multifactorial ageing-related influences on motor function. We characterized mild motor abnormalities in different motor domains by conducting a systematic motor assessment in 20 patients with clinically isolated REM sleep behaviour disorder (iRBD) without parkinsonian motor signs and 20 healthy controls. We addressed the influence of lifestyle factors and age on motor function, which needs to be distinguished from neurodegenerative motor features, and assessed the diagnostic value of innovative and established quantitative motor tests in iRBD. Patients with iRBD showed abnormalities in perceptual motor speed (falling stick test), trunk movement coordination (bend, twist and touch test) and dynamic balance (line walk test) without alterations in simple motor speed (alternate tap test), dexterity (grooved pegboard), static balance (force plate) and gait (timed up and go test). The falling stick test showed the highest diagnostic accuracy in identifying subjects with RBD (ROC-AUC 0.85, p ≤ 0.001). Multivariate analysis revealed physical activity and age as additional determinants of motor test performance. iRBD comprises a wide spectrum of mild motor abnormalities which cannot be verified by established tests for motor speed, gait and balance. The falling stick test, an innovative screening test for perceptual motor speed, provides high diagnostic potential in identifying subjects with subclinical neurodegenerative symptoms before parkinsonian motor signs become apparent. Normative data for physical activity and age need to be obtained to ensure correct interpretation of motor test results in prodromal Parkinson-related disease.

Neural distinctiveness of fatigue and low sleep quality in multiple sclerosis.

BACKGROUND AND PURPOSE: Fatigue and low sleep quality in multiple sclerosis (MS) are closely related symptoms. Here, the associations between the brain's functional connectivity (FC) and fatigue and low sleep quality were investigated to determine the degree of neural distinctiveness of these symptoms. METHOD: A hundred and four patients with relapsing-remitting MS (age 38.9 ± 10.2 years, 66 females) completed the Modified Fatigue Impact Scale and the Pittsburgh Sleep Quality Index and underwent resting-state functional magnetic resonance imaging. FC was analyzed using independent-component analysis in sensorimotor, default-mode, fronto-parietal and basal-ganglia networks. Multiple linear regression models allowed us to test the association between FC and fatigue and sleep quality whilst controlling for one another as well as for demographic, disease-related and imaging variables. RESULTS: Higher fatigue correlated with lower sleep quality (r = 0.54, p < 0.0001). Higher fatigue was associated with lower FC of the precentral gyrus in the sensorimotor network, the precuneus in the posterior default-mode network and the superior frontal gyrus in the left fronto-parietal network, independently of sleep quality. Lower sleep quality was associated with lower FC of the left intraparietal sulcus in the left fronto-parietal network, independently of fatigue. Specific associations were found between fatigue and the sensorimotor network's global FC and between low sleep quality and the left fronto-parietal network's global FC. CONCLUSION: Despite the high correlation between fatigue and low sleep quality in the clinical picture, our findings clearly indicate that, on the neural level, fatigue and low sleep quality in MS are associated with decreased FC in distinct functional brain networks.

Optimized Protocol for Proportionate CNS Cell Retrieval as a Versatile Platform for Cellular and Molecular Phenomapping in Aging and Neurodegeneration.

Efficient purification of viable neural cells from the mature CNS has been historically challenging due to the heterogeneity of the inherent cell populations. Moreover, changes in cellular interconnections, membrane lipid and cholesterol compositions, compartment-specific biophysical properties, and intercellular space constituents demand technical adjustments for cell isolation at different stages of maturation and aging. Though such obstacles are addressed and partially overcome for embryonic premature and mature CNS tissues, procedural adaptations to an aged, progeroid, and degenerative CNS environment are underrepresented. Here, we describe a practical workflow for the acquisition and phenomapping of CNS neural cells at states of health, physiological and precocious aging, and genetically provoked neurodegeneration. Following recent, unprecedented evidence of post-mitotic cellular senescence (PoMiCS), the protocol appears suitable for such de novo characterization and phenotypic opposition to classical senescence. Technically, the protocol is rapid, efficient as for cellular yield and well preserves physiological cell proportions. It is suitable for a variety of downstream applications aiming at cell type-specific interrogations, including cell culture systems, Flow-FISH, flow cytometry/FACS, senescence studies, and retrieval of omic-scale DNA, RNA, and protein profiles. We expect suitability for transfer to other CNS targets and to a broad spectrum of engineered systems addressing aging, neurodegeneration, progeria, and senescence.

Microglia-mediated phagocytosis of apoptotic nuclei is impaired in the adult murine hippocampus after stroke.

Following stroke, neuronal death takes place both in the infarct region and in brain areas distal to the lesion site including the hippocampus. The hippocampus is critically involved in learning and memory processes and continuously generates new neurons. Dysregulation of adult neurogenesis may be associated with cognitive decline after a stroke lesion. In particular, proliferation of precursor cells and the formation of new neurons are increased after lesion. Within the first week, many new precursor cells die during development. How dying precursors are removed from the hippocampus and to what extent phagocytosis takes place after stroke is still not clear. Here, we evaluated the effect of a prefrontal stroke lesion on the phagocytic activity of microglia in the dentate gyrus (DG) of the hippocampus. Three-months-old C57BL/6J mice were injected once with the proliferation marker BrdU (250 mg/kg) 6 hr after a middle cerebral artery occlusion or sham surgery. The number of apoptotic cells and the phagocytic capacity of the microglia were evaluated by means of immunohistochemistry, confocal microscopy, and 3D-reconstructions. We found a transient but significant increase in the number of apoptotic cells in the DG early after stroke, associated with impaired removal by microglia. Interestingly, phagocytosis of newly generated precursor cells was not affected. Our study shows that a prefrontal stroke lesion affects phagocytosis of apoptotic cells in the DG, a region distal to the lesion core. Whether disturbed phagocytosis might contribute to inflammatory- and maladaptive processes including cognitive impairment following stroke needs to be further investigated.

Experience-dependent structural plasticity in the adult brain: How the learning brain grows.

Volumetric magnetic resonance imaging studies have shown that intense learning can be associated with grey matter volume increases in the adult brain. The underlying mechanisms are poorly understood. Here we used monocular deprivation in rats to analyze the mechanisms underlying use-dependent grey matter increases. Optometry for quantification of visual acuity was combined with volumetric magnetic resonance imaging and microscopic techniques in longitudinal and cross-sectional studies. We found an increased spatial vision of the open eye which was associated with a transient increase in the volumes of the contralateral visual and lateral entorhinal cortex. In these brain areas dendrites of neurons elongated, and there was a strong increase in the number of spines, the targets of synapses, which was followed by spine maturation and partial pruning. Astrocytes displayed a transient pronounced swelling and underwent a reorganization of their processes. The use-dependent increase in grey matter corresponded predominantly to the swelling of the astrocytes. Experience-dependent increase in brain grey matter volume indicates a gain of structure plasticity with both synaptic and astrocyte remodeling.

Disease aggressiveness signatures of amyotrophic lateral sclerosis in white matter tracts revealed by the D50 disease progression model.

Numerous neuroimaging studies in amyotrophic lateral sclerosis (ALS) have reported links between structural changes and clinical data; however phenotypic and disease course heterogeneity have occluded robust associations. The present study used the novel D50 model, which distinguishes between disease accumulation and aggressiveness, to probe correlations with measures of diffusion tensor imaging (DTI). DTI scans of 145 ALS patients and 69 controls were analyzed using tract-based-spatial-statistics of fractional anisotropy (FA), mean- (MD), radial (RD), and axial diffusivity (AD) maps. Intergroup contrasts were calculated between patients and controls, and between ALS subgroups: based on (a) the individual disease covered (Phase I vs. II) or b) patients' disease aggressiveness (D50 value). Regression analyses were used to probe correlations with model-derived parameters. Case-control comparisons revealed widespread ALS-related white matter pathology with decreased FA and increased MD/RD. These affected pathways showed also correlations with the accumulated disease for increased MD/RD, driven by the subgroup of Phase I patients. No significant differences were noted between patients in Phase I and II for any of the contrasts. Patients with high disease aggressiveness (D50 < 30 months) displayed increased AD/MD in bifrontal and biparietal pathways, which was corroborated by significant voxel-wise regressions with D50. Application of the D50 model revealed associations between DTI measures and ALS pathology in Phase I, representing individual disease accumulation early in disease. Patients' overall disease aggressiveness correlated robustly with the extent of DTI changes. We recommend the D50 model for studies developing/validating neuroimaging or other biomarkers for ALS.

Microbiota profiling in aging-associated inflammation and liver degeneration.

BACKGROUND: The number of people above the age of 60 years is raising world-wide being associated with an increase in the prevalence of aging-associated impairments and even diseases. Recent studies suggest that aging is associated with alterations in bacterial endotoxin levels and that these changes may add to low-grade inflammation, the so-called 'inflammaging', and aging-associated liver degeneration. However, mechanisms involved, and especially, the interaction of intestinal microbiota and barrier in the development of aging-associated inflammation and liver degeneration have not been fully understood. OBJECTIVE: The aim of the present study was to determine if intestinal microbiota composition changes with age and if these alterations are associated with changes of markers of intestinal barrier function and the development of inflammation and liver degeneration. METHODS: Blood, liver, small and large intestinal tissue of male 2-, 15-, 24- and 30-months old C57BL/6 mice fed standard chow were obtained. Intestinal microbiota composition, expression levels of antimicrobial peptides in small intestine and markers of intestinal barrier function were measured. Furthermore, indices of liver damage, inflammation and expression levels of lipopolysaccharide binding protein (Lbp) as well as of toll-like receptors (Tlr) 1-9 in liver tissue were assessed. RESULTS: Pairwise comparisons of the microbial community in the small intestine showed differences between 2- and 24-, 15- and 24-, as well as 15- and 30-months old animals while Shannon's diversity, species richness and evenness indexes did not differ in both small and large intestine, respectively, between age groups. Concentrations of nitric oxide were significantly lower in small intestine of 15-, 24- and 30-months old mice compared to 2-months old mice while mRNA expression of the antimicrobial peptides defensin alpha 1 and lysozyme 1 was unchanged. In contrast, in liver tissue, older age of animals was associated with increasing inflammation and the development of fibrosis in 24- and 30-months old mice. Numbers of inflammatory foci and neutrophils in livers of 24- and 30-months old mice were significantly higher compared to 2-months old mice. These alterations were also associated with higher endotoxin levels in plasma as well as an increased mRNA expression of Lbp and Tlr1, Tlr2, Tlr4, Tlr6 and Tlr9 in livers in older mice. CONCLUSION: Despite no consistent and robust changes of microbiota composition in small and/or large intestine of mice of different age were observed, our data suggest that alterations of markers of intestinal barrier function in small intestine are associated with an induction of several Tlrs and beginning hepatic inflammation in older mice and increase with age.

Propentdyopents as Heme Degradation Intermediates Constrict Mouse Cerebral Arterioles and Are Present in the Cerebrospinal Fluid of Patients With Subarachnoid Hemorrhage.

RATIONALE: Delayed ischemic neurological deficit is the most common cause of neurological impairment and unfavorable prognosis in patients with subarachnoid hemorrhage (SAH). Despite the existence of neuroimaging modalities that depict the onset of the accompanying cerebral vasospasm, preventive and therapeutic options are limited and fail to improve outcome owing to an insufficient pathomechanistic understanding of the delayed perfusion deficit. Previous studies have suggested that BOXes (bilirubin oxidation end products), originating from released heme surrounding ruptured blood vessels, are involved in arterial vasoconstriction. Recently, isolated intermediates of oxidative bilirubin degradation, known as PDPs (propentdyopents), have been considered as potential additional effectors in the development of arterial vasoconstriction. OBJECTIVE: To investigate whether PDPs and BOXes are present in hemorrhagic cerebrospinal fluid and involved in the vasoconstriction of cerebral arterioles. METHODS AND RESULTS: Via liquid chromatography/mass spectrometry, we measured increased PDP and BOX concentrations in cerebrospinal fluid of SAH patients compared with control subjects. Using differential interference contrast microscopy, we analyzed the vasoactivity of PDP isomers in vitro by monitoring the arteriolar diameter in mouse acute brain slices. We found an arteriolar constriction on application of PDPs in the concentration range that occurs in the cerebrospinal fluid of patients with SAH. By imaging arteriolar diameter changes using 2-photon microscopy in vivo, we demonstrated a short-onset vasoconstriction after intrathecal injection of either PDPs or BOXes. Using magnetic resonance imaging, we observed a long-term PDP-induced delay in cerebral perfusion. For all conditions, the arteriolar narrowing was dependent on functional big conductance potassium channels and was absent in big conductance potassium channels knockout mice. CONCLUSIONS: For the first time, we have quantified significantly higher concentrations of PDP and BOX isomers in the cerebrospinal fluid of patients with SAH compared to controls. The vasoconstrictive effect caused by PDPs in vitro and in vivo suggests a hitherto unrecognized pathway contributing to the pathogenesis of delayed ischemic deficit in patients with SAH.

Weather conditions associated with subarachnoid hemorrhage: a multicenter case-crossover study.

BACKGROUND: Most spontaneous subarachnoid hemorrhages (SAH) occur unexpectedly and independently of classical risk factors. In the light of increasing climate variability and change, we investigated weather and rapid weather changes as possible short-term risk factors for SAH. METHODS: Seven hundred ninety one patients admitted to three major hospitals in Germany for non-traumatic SAH with a determinable onset of SAH symptoms were included in this hospital-based, case-crossover study. The effects of atmospheric pressure, relative air humidity, and ambient temperature and their 24 h changes on the onset of SAH under temperate climate conditions were estimated. RESULTS: There was no association between the risk of SAH and 24 h weather changes, mean daily temperature or mean relative air humidity in the overall population. For every 11.5 hPa higher mean daily atmospheric pressure, the risk of SAH increased by 15% (OR 1.15, 95% confidence interval (CI) 1.01-1.30) in the entire study population with a lag time of three days. CONCLUSION: Our results suggest no relevant association between 24 h-weather changes or absolute values of ambient temperature and relative humidity and the risk of SAH. The medical significance of the statistically weak increase in SAH risk three days after exposure to high atmospheric pressure is unclear. However, as the occurrence of stable high-pressure systems will increase with global warming and potentially affect SAH risk, we call for confirming studies in different geographical regions to verify our observations.

Impact of subthreshold depression on health-related quality of life in patients with Parkinson's disease based on cognitive status.

BACKGROUND: In patients with Parkinson's disease (PD), depression has a strong impact on quality of life (QoL). However, little is known about the influence of subthreshold depression (STD) on QoL in PD patients. METHODS: A total of 230 hospitalized PD patients with normal and impaired cognitive status were included in this observational study. We collected the following data for analysis: Beck Depression Inventory level, Montreal Cognitive Assessment (MOCA) score, non-motor symptoms questionnaire score, PD questionnaire-39 (PDQ-39) score, Hoehn-Yahr stage, and Movement Disorder Society-sponsored revision of the unified PD rating scale III (MDS-UPDRS III) score. To study the impact of STD on the PDQ-39 summary index (SI) and its domains, we used multivariate analysis of variance and multivariate analysis of covariance. RESULTS: In this cohort, 80 (34.8%) patients had STD [44 (32.3%) with high MOCA score (> 21) and 36 (38.3%) with low MOCA score (< 21)]. In PDQ-39 SI, there was a significant effect on depression level. In patients with higher MOCA score, STD was associated with worse PDQ-39 domains emotional well-being and cognition, whereas in patients with lower MOCA score, STD had no significant effect on PDQ-39 SI or its subdomains. CONCLUSION: In PD patients, QoL is significantly affected by STD, and thus, more attention in medical care should be focused on treating STD. However, the impact is only observable in PD patients with normal cognitive function. STD patients show more reduced QoL than non-depressed patients, indicating that STD should be treated as a transition zone between normal mood and depression.

Non-idiopathic peripheral facial palsy: prognostic factors for outcome.

OBJECTIVES: There is a lack of data on patients' and diagnostic factors for prognostication of complete recovery in patients with non-idiopathic peripheral facial palsy (FP). METHODS: Cohort register-based study of 264 patients with non-idiopathic peripheral FP and uniform diagnostics and standardized treatment in a university hospital from 2007 to 2017 (47% female, median age: 57 years). Clinical data, facial grading, electrodiagnostics, motor function tests, non-motor function tests, and onset of prednisolone therapy were assessed for their impact on the probability of complete recovery using univariable and multivariable statistics. RESULTS: The most frequent reason for a non-idiopathic peripheral FP was a reactivation of Varicella Zoster Virus (VZV; 36.4%). Traumatic origin had a higher proportion of complete FP (52.9%). Furthermore, in traumatic FP, the mean interval between onset and start of prednisolone therapy was longer than in other cases (5.6 ± 6.2 days). Patients with reactivation of VZV, Lyme disease or otogenic FP had a significant higher recovery rate (p = 0.002, p < 0.0001, p = 0.018, respectively), whereas patients with post-surgery FP and other reasons had a significant lower recovery rate (p < 0.0001). After multivariate analyses voluntary activity in first EMG, Lyme disease and post-surgery cause were identified as independent diagnostic and prognostic factors on the probability of complete recovery (all p < 0.05). CONCLUSION: Infectious causes for non-idiopathic FP like VZV reactivation and Lyme disease had best probability for complete recovery. Post-surgery FP had a worse prognosis. LEVEL OF EVIDENCE: 2.

Ratings of Emotional Expressions in Static and Dynamic Facial Recordings Before and After Upper Face Botulinum Injections-An Observational Prospective Study.

BACKGROUND: Botulinum toxin A (BTX), a neurotoxin widely used for facial aesthetics, causes dose-dependent muscle paralysis. It was hypothesized that treatment of mimic muscles with BTX might have a positive impact on emotional expression in static images (photographs), but a negative impact in dynamic recordings (videos). OBJECTIVES: The aim of this study was to compare of emotional expression recorded in photographs and videos before and after treatment with BTX. METHODS: Twenty healthy women (mean age, 45 years) received a dose of 19 mouse units of XEOMIN (Merz, Frankfurt am Main, Germany) into the procerus, occipitofrontalis, and orbicularis oculi muscles. Photographs and videos of the participants' faces with neutral and happy expressions were recorded before treatment and 2 weeks later. Recordings were rated by naive raters blind to the conditions and in balanced order. RESULTS: Videos were generally rated as more pleasant, arousing, attractive, and genuine than photographs (all Ps > 0.001). This was especially the case for videos with neutral expression (P = 0.003). Independent of presentation mode and facial expression, women were rated as more attractive after BTX treatment (P = 0.03). CONCLUSIONS: In contrast to the hypothesis, the reduced mobility had no detectable negative impact on dynamic emotional expression, but videos received more positive ratings, particularly for neutral expressions. It is thus recommended to assess emotional expression with dynamic recordings to evaluate the effects of treatment with BTX. BTX seems to improve perceived attractiveness, although the cause of this effect remains unclear.

Stroke Accelerates and Uncouples Intrinsic and Synaptic Excitability Maturation of Mouse Hippocampal DCX+ Adult-Born Granule Cells.

Stroke robustly stimulates adult neurogenesis in the hippocampal dentate gyrus. It is currently unknown whether this process induces beneficial or maladaptive effects, but morphological and behavioral studies have reported aberrant neurogenesis and impaired hippocampal-dependent memory following stroke. However, the intrinsic function and network incorporation of adult-born granule cells (ABGCs) after ischemia is unclear. Using patch-clamp electrophysiology, we evaluated doublecortin-positive (DCX+) ABGCs as well as DCX- dentate gyrus granule cells 2 weeks after a stroke or sham operation in DCX/DsRed transgenic mice of either sex. The developmental status, intrinsic excitability, and synaptic excitability of ABGCs were accelerated following stroke, while dendritic morphology was not aberrant. Regression analysis revealed uncoupled development of intrinsic and network excitability, resulting in young, intrinsically hyperexcitable ABGCs receiving disproportionately large glutamatergic inputs. This aberrant functional maturation in the subgroup of ABGCs in the hippocampus may contribute to defective hippocampal function and increased seizure susceptibility following stroke.SIGNIFICANCE STATEMENT Stroke increases hippocampal neurogenesis but the functional consequences of the postlesional response is mostly unclear. Our findings provide novel evidence of aberrant functional maturation of newly generated neurons following stroke. We demonstrate that stroke not only causes an accelerated maturation of the intrinsic and synaptic parameters of doublecortin-positive, new granule cells in the hippocampus, but that this accelerated development does not follow physiological dynamics due to uncoupled intrinsic and synaptic maturation. Hyperexcitable immature neurons may contribute to disrupted network integration following stroke.

Aging-related liver degeneration is associated with increased bacterial endotoxin and lipopolysaccharide binding protein levels.

Aging is a risk factor in the development of many diseases, including liver-related diseases. The two aims of the present study were 1) to determine how aging affects liver health in mice in the absence of any interventions and 2) if degenerations observed in relation to blood endotoxin levels are critical in aging-associated liver degeneration. Endotoxin levels and markers of liver damage, mitochondrial dysfunction, insulin resistance, and apoptosis as well as the Toll-like receptor 4 (Tlr-4) signaling cascade were studied in liver tissue and blood, respectively, of 3- and 24-mo-old male C57BL/6J mice. In a second set of experiments, 3- to 4-mo-old and 14-mo-old female lipopolysaccharide-binding protein (LBP)-/- mice and littermates fed standard chow, markers of liver damage, insulin resistance, and mitochondrial dysfunction were assessed. Plasma activity of aspartate aminotransferase and histological signs of hepatic inflammation and fibrosis were significantly higher in old C57BL/6J mice than in young animals. The number of neutrophils, CD8α-positive cells, and mRNA expression of markers of apoptosis were also significantly higher in livers of old C57BL/6J mice compared with young animals, being also associated with a significant induction of hepatic Tlr-4 and LBP expression as well as higher endotoxin levels in peripheral blood. Compared with age-matched littermates, LBP-/- mice display less signs of senescence in liver. Taken together, our data suggest that, despite being fed standard chow, old mice developed liver inflammation and beginning fibrosis and that bacterial endotoxin may play a critical role herein.NEW & NOTEWORTHY Old age in mice is associated with marked signs of liver degeneration, hepatic inflammation, and fibrosis. Aging-associated liver degeneration is associated with elevated bacterial endotoxin levels and an induction of lipopolysaccharide-binding protein (LBP) and Toll-like receptor 4-dependent signaling cascades in liver tissue. Furthermore, in old aged LBP-/- mice, markers of senescence seem to be lessened, supporting the hypothesis that bacterial endotoxin levels might be critical in aging-associated decline of liver.

The importance of different learning stages for motor sequence learning after stroke.

The task of learning predefined sequences of interrelated motor actions is of everyday importance and has also strong clinical importance for regaining motor function after brain lesions. A solid understanding of sequence learning in stroke patients can help clinicians to optimize and individualize rehabilitation strategies. Moreover, to investigate the impact of a focal lesion on the ability to successfully perform motor sequence learning can enhance our comprehension of the underlying physiological principles of motor sequence learning. In this article, we will first provide an overview of current concepts related to motor sequence learning in healthy subjects with focus on the involved brain areas and their assumed functions according to the temporal stage model. Subsequently, we will consider the question of what we can learn from studies investigating motor sequence learning in stroke patients. We will first focus on the implications of lesion location. Then, we will analyze whether distinct lesion locations affect specific learning stages. Finally, we will discuss the implications for clinical rehabilitation and suggest directions for further research.

Maternal psychosocial stress during early gestation impairs fetal structural brain development in sheep.

Maternal stress, especially during early pregnancy, predisposes offspring to neuropsychiatric disorders. We hypothesized that maternal psychosocial stress (MPS) during pregnancy affects fetal structural neurodevelopment depending on the gestational age of exposure. Fetal sheep brains were harvested at 130 days gestation (dG, term 150 dG) from ewes frequently isolated from flock-mates during early gestation (first and second trimester; n = 10) or late gestation (third trimester; n = 10), or from control flock-mates (n = 8). Immunohistochemistry for formation of neuronal processes, myelination, synaptic density, cell proliferation and programed cell death was performed on brain tissue sections. Sections of the cortical gray matter, the hippocampal CA3 region and the superficial, subcortical and deep white matter were examined morphometrically. Stress effects depended on the brain region and time of exposure. Stress during early gestation but not during late gestation reduced the amount of neuronal processes in the cerebral cortex and hippocampus by 36.9 ± 10.1% (p < 0.05, mean ± SEM) and 36.9 ± 15.8% (p < 0.05), respectively, accompanied by a decrease in synaptic density in the cerebral cortex and hippocampus by 39.8 ± 23.1% (p < 0.05) and 32.9 ± 13.4% (p < 0.01). Myelination was decreased in white matter layers on average by 44.8 ± 11.7% (p < 0.05) accompanied by reduced (glial) cell proliferation in the deep white matter by 83.6 ± 12.4% (p < 0.05). In contrast, stress during the third trimester had no effect in any brain region. Chronic MPS during the first and second trimester induced prolonged effects on neuronal network and myelin formation which might contribute to disturbed neurobehavioral, cognitive and motor development in offspring of stressed mothers.Lay summaryMany women are exposed to stressful events during pregnancy. Maternal stress especially during early pregnancy predisposes for offspring's neuropsychiatric disorders. In our sheep study, we show that disturbance of fetal brain development is a potential mechanism and is worst during 1st and 2nd trimester.