•Cortisol is a major mediator of maternal stress effects on fetal development.•Trans-placental transfer of maternal cortisol alone does not explain all stress effects.•Catecholamines transfer stress ...indirectly via reduced uterine perfusion.•Maternal cytokines, serotonin and oxidative stress may also play a role in stress transfer.•Stress impaired maternal microbiota may influence the early development of the gut-brain-axis.
Psychosocial maternal stress experienced during different vulnerable periods throughout gestation is thought to increase the individual’s risk to develop neuropsychiatric, cardiovascular and metabolic disease in later life. Cortisol has generally been identified as the major mediator of maternal stress transfer to the fetus. Its lipophilic nature allows a trans-placental passage and thus excessive maternal cortisol could persistently impair the development of the fetal hypothalamic-pituitary-adrenal axis (HPAA). However, cortisol alone cannot fully explain all effects of maternal stress especially during early to mid pregnancy before maturation of the fetal HPAA has even begun and expression of fetal glucocorticoid receptors is limited. This review focuses on mediators of maternal fetal stress transfer that in addition to cortisol have been proposed as transmitters of maternal stress: catecholamines, cytokines, serotonin/tryptophan, reactive-oxygen-species and the maternal microbiota. We propose that the effects of psychosocial maternal stress on fetal development and health and disease in later life are not a consequence of a single pathway but are mediated by multiple stress-transfer mechanisms acting together in a synergistic manner.
Investigations following stroke first of all require information about the spatio-temporal dimension of the ischemic core as well as of perilesional and remote affected tissue. Here we systematically ...evaluated regions differently impaired by focal ischemia.
Wistar rats underwent a transient 30 or 120 min suture-occlusion of the middle cerebral artery (MCAO) followed by various reperfusion times (2 h, 1 d, 7 d, 30 d) or a permanent MCAO (1 d survival). Brains were characterized by TTC, thionine, and immunohistochemistry using MAP2, HSP72, and HSP27. TTC staining reliably identifies the infarct core at 1 d of reperfusion after 30 min MCAO and at all investigated times following 120 min and permanent MCAO. Nissl histology denotes the infarct core from 2 h up to 30 d after transient as well as permanent MCAO. Absent and attenuated MAP2 staining clearly identifies the infarct core and perilesional affected regions at all investigated times, respectively. HSP72 denotes perilesional areas in a limited post-ischemic time (1 d). HSP27 detects perilesional and remote impaired tissue from post-ischemic day 1 on. Furthermore a simultaneous expression of HSP72 and HSP27 in perilesional neurons was revealed.
TTC and Nissl staining can be applied to designate the infarct core. MAP2, HSP72, and HSP27 are excellent markers not only to identify perilesional and remote areas but also to discriminate affected neuronal and glial populations. Moreover markers vary in their confinement to different reperfusion times. The extent and consistency of infarcts increase with prolonged occlusion of the MCA. Therefore interindividual infarct dimension should be precisely assessed by the combined use of different markers as described in this study.
Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial surface receptor involved in phagocytosis. Clearance of apoptotic debris after stroke represents an important mechanism to ...re-attain tissue homeostasis and thereby ensure functional recovery. The role of TREM2 following stroke is currently unclear.
As an experimental stroke model, the middle cerebral artery of mice was occluded for 30 minutes with a range of reperfusion times (duration of reperfusion: 6 h/12 h/24 h/2 d/7 d/28 d). Quantitative PCR (qPCR) revealed a greatly increased transcription of TREM2 after stroke. We subsequently analyzed the expression of pro-inflammatory cytokines, chemokines and their receptors in TREM2-knockout (TREM2-KO) mice via qPCR. Microglial activation (CD68, Iba1) and CD3-positive T-cell invasion were analyzed via qPCR and immunohistochemistry. Functional consequences of TREM2 knockout were assessed by infarct volumetry. The acute inflammatory response (12 h reperfusion) was very similar between TREM2-KO mice and their littermate controls. However, in the sub-acute phase (7 d reperfusion) following stroke, TREM2-KO mice showed a decreased transcription of pro-inflammatory cytokines TNFα, IL-1α and IL-1β, associated with a reduced microglial activity (CD68, Iba1). Furthermore, TREM2-KO mice showed a reduced transcription of chemokines CCL2 (MCP1), CCL3 (MIP1α) and the chemokine receptor CX3CR1, followed by a diminished invasion of CD3-positive T-cells. No effect on the lesion size was observed.
Although we initially expected an exaggerated pro-inflammatory response following ablation of TREM2, our data support a contradictory scenario that the sub-acute inflammatory reaction after stroke is attenuated in TREM2-KO mice. We therefore conclude that TREM2 appears to sustain a distinct inflammatory response after stroke.
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.
Fatigue and low sleep quality often co‐occur in multiple sclerosis. This study shows that fatigue and low sleep quality are independent at the neural level, involving sensorimotor and fronto‐parietal brain networks, respectively.
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.
A large body of evidence from in vitro studies suggests that GABA is depolarizing during early postnatal development. However, the mode of GABA action in the intact developing brain is unknown. Here ...we examine the in vivo effects of GABA in cells of the upper cortical plate using a combination of electrophysiological and Ca(2+)-imaging techniques. We report that at postnatal days (P) 3-4, GABA depolarizes the majority of immature neurons in the occipital cortex of anaesthetized mice. At the same time, GABA does not efficiently activate voltage-gated Ca(2+) channels and fails to induce action potential firing. Blocking GABA(A) receptors disinhibits spontaneous network activity, whereas allosteric activation of GABA(A) receptors has the opposite effect. In summary, our data provide evidence that in vivo GABA acts as a depolarizing neurotransmitter imposing an inhibitory control on network activity in the neonatal (P3-4) neocortex.
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.
This study aimed to explore the association between malnutrition, clinical parameters, and health-related quality of life in elderly hospitalized patients with Parkinson's disease (PD).
...Cross-sectional study of 92 hospitalized elderly patients with PD (mean age 73.6 ± 6.7 years) without dementia. The Mini Nutritional Assessment (MNA) was used to evaluate nutritional status. Motor impairment and non-motor symptoms burden (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale MDS-UPDRS, Non-Motor Symptoms Questionnaire, and Hoehn & Yahr staging), depression (Becks Depression Inventory-II), and health-related quality of life (PD quality of life Questionnaire-39) were assessed.
Every second patient was malnourished or at risk of malnutrition. In the multivariable analysis, male gender, longer disease duration, higher Hoehn & Yahr and depression were associated with total MNA score. Besides non-motor symptoms and motor impairment, malnutrition was an independent predictor of poor health-related quality of life. In the multivariate analysis, malnutrition had a statistically significant effect on emotional well-being, mobility, social support, stigmatization, and cognition. The strongest association was found between malnutrition and emotional well-being.
Elderly male persons with longer PD duration and higher disease stages are more likely to be malnourished or at risk for malnutrition. Malnutrition was mainly associated with poor emotional well-being, suggesting that treatment of depression and anxiety beside diet and physical activity can help improving nutrition status in these subjects. The MNA should not be used independent of other measures of cognition and depression in people with advanced PD.
Stroke significantly stimulates neurogenesis in the adult dentate gyrus, though the functional role of this postlesional response is mostly unclear. Recent findings suggest that newborn neurons ...generated in the context of stroke may fail to correctly integrate into pre-existing networks. We hypothesized that increased neurogenesis in the dentate gyrus following stroke is associated with aberrant neurogenesis and impairment of hippocampus-dependent memory. To address these questions we used the middle cerebral artery occlusion model (MCAO) in mice. Animals were housed either under standard conditions or with free access to running wheels. Newborn granule cells were labelled with the thymidine analoque EdU and retroviral vectors. To assess memory performance, we employed a modified version of the Morris water maze (MWM) allowing differentiation between hippocampus dependent and independent learning strategies. Newborn neurons were morphologically analyzed using confocal microscopy and Neurolucida system at 7 weeks. We found that neurogenesis was significantly increased following MCAO. Animals with MCAO needed more time to localize the platform and employed less hippocampus-dependent search strategies in MWM versus controls. Confocal studies revealed an aberrant cell morphology with basal dendrites and an ectopic location (e.g. hilus) of new granule cells born in the ischemic brain. Running increased the number of new neurons but also enhanced aberrant neurogenesis. Running, did not improve the general performance in the MWM but slightly promoted the application of precise spatial search strategies. In conclusion, ischemic insults cause hippocampal-dependent memory deficits which are associated with aberrant neurogenesis in the dentate gyrus indicating ischemia-induced maladaptive plasticity in the hippocampus.
Still unresolved is the question of how a lifetime accumulation of somatic gene copy number alterations impact organ functionality and aging and age-related pathologies. Such an issue appears ...particularly relevant in the broadly post-mitotic central nervous system (CNS), where non-replicative neurons are restricted in DNA-repair choices and are prone to accumulate DNA damage, as they remain unreplaced over a lifetime. Both DNA injuries and consecutive DNA-repair strategies are processes that can evoke extrachromosomal circular DNA species, apparently from either part of the genome. Due to their capacity to amplify gene copies and related transcripts, the individual cellular load of extrachromosomal circular DNAs will contribute to a dynamic pool of additional coding and regulatory chromatin elements. Analogous to tumor tissues, where the mosaicism of circular DNAs plays a well-characterized role in oncogene plasticity and drug resistance, we suggest involvement of the "circulome" also in the CNS. Accordingly, we summarize current knowledge on the molecular biogenesis, homeostasis and gene regulatory impacts of circular extrachromosomal DNA and propose, in light of recent discoveries, a critical role in CNS aging and neurodegeneration. Future studies will elucidate the influence of individual extrachromosomal DNA species according to their sequence complexity and regional distribution or cell-type-specific abundance.
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