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Inflammatory disorders of the central nervous system such as multiple sclerosis and acute disseminated encephalomyelitis involve an invasion of immune cells that ultimately leads to white matter demyelination, neurodegeneration and development of neurological symptoms. A clinical diagnosis is often made when neurodegenerative processes are already ongoing. In an attempt to seek early indicators of disease, we studied the temporal and spatial distribution of brain modifications in experimental autoimmune encephalomyelitis (EAE). In a thorough magnetic resonance imaging study performed with EAE mice, we observed significant enlargement of the ventricles prior to disease clinical manifestation and an increase in free water content within the cerebrospinal fluid as demonstrated by changes in T2 relaxation times. The increase in ventricle size was seen in the lateral, third and fourth ventricles. In some EAE mice the ventricle size started returning to normal values during disease remission. In parallel to this macroscopic phenomenon, we studied the temporal evolution of microscopic lesions commonly observed in the cerebellum also starting prior to disease onset. Our data suggest that changes in ventricle size during the early stages of brain inflammation could be an early indicator of the events preceding neurological disease and warrant further exploration in preclinical and clinical studies.
In spite of evidence to the contrary, concern that substances injected into the fourth ventricle (4V) reach forebrain structures challenges the validity of using these injections to evaluate the role of hindbrain structures. Injection of AngII into the lateral ventricle (LV) increases water intake, but a similar response is not observed after injection into the 4V. This alone suggests the requirement of forebrain structures, but the potential for a counteracting, anti-dipsogenic pressor response to hindbrain AngII allows for lingering concern that this competing effect of AngII, rather than lack of forebrain access, underlies the negative result. Here, we used a double cannulation approach (LV and 4V) to evaluate the effect of the AngII receptor antagonist, losartan, on the drinking response to AngII injected into the LV. Injections of losartan into the LV blocked the dipsogenic response to AngII given 5min later into the LV. There was no effect, however, when losartan was injected into 4V, even when we used a dose of losartan that was 25 times greater than needed when injected into the LV. Collectively, these experiments suggest that concerns about diffusion from hindbrain ventricles to forebrain structures are overstated and can be circumvented using proper dose and timing of injections. Moreover, these data provide additional support to the existing literature showing that forebrain structures are key sites in the stimulation of drinking behavior by AngII.
The mouse Dach1 gene, involved in the development of the neocortex and the hippocampus, is expressed by neural stem cells (NSCs) during early neurogenesis, and its expression also continues in a subpopulation of cells in the dorsal part of the lateral ventricles (LV) of the adult mouse brain. In this study we aimed to elucidate the role of Dach1-expressing cells in adult neurogenesis/gliogenesis under physiological as well as post-ischemic conditions, employing transgenic mice in which the expression of green fluorescent protein (GFP) is controlled by the D6 promotor of the mouse Dach1 gene. A neurosphere-forming assay of GFP⁺ cells isolated from the dorsal part of the LV was carried out with subsequent differentiation in vitro. To elucidate the neurogenic/gliogenic potential of GFP⁺ cells in the dorsal part of the LV, in situ immunohistochemical/electrophysiological analyses of GFP⁺ cells in adult sham-operated brains (controls) and those after middle cerebral artery occlusion (MCAo) were performed. The GFP⁺ cells isolated from the dorsal part of the LV of controls formed neurospheres and differentiated solely into a glial phenotype, while those isolated after MCAo also gave rise to cells with the properties of neuronal precursors. In situ analyses revealed that GFP⁺ cells express the phenotype of adult NSCs or neuroblasts in controls as well as following ischemia. Following MCAo we found a significantly increased number of GFP⁺ cells expressing doublecortin as well as a number of GFP⁺ cells migrating through the rostral migratory stream into the olfactory bulb, where they probably differentiated into calretinin⁺ interneurons. Collectively, our results suggest the involvement of the mouse Dach1 gene in adult neurogenesis; cells expressing this gene exhibit the properties of adult NSCs or neuroblasts and respond to MCAo by enhanced neurogenesis.
Leakage of a small amount of intravenously administered gadolinium-based contrast agents (GBCAs) into the cerebrospinal fluid (CSF) space has been reported, even in healthy subjects without blood-brain barrier disruption. Several candidates including the choroid plexus and cortical veins have been proposed as the source of the leakage. The purpose of this study was to evaluate the distribution of intravenously administered GBCA leakage into the CSF by comparing the contrast enhancement of the cerebral cisterns to the lateral ventricles (LVs).
Intracerebroventricular (icv) injections are frequently used in neuroscience research. In addition to histological verification of the injection sites, administration of angiotensin II (ANG II) is often used to verify the injection placements. ANG II is a peptide hormone exerting dipsogenic effects, i.e., it increases drinking, when administered into the cerebral ventricles. This study investigated the accuracy of ANG II-induced drinking as a method to verify icv cannula placements.
Ependymal cilia protrude into the central canal of the brain ventricles and spinal cord to circulate the cerebral spinal fluid (CSF). Ependymal cilia dysfunction can hinder the movement of CSF leading to an abnormal accumulation of CSF within the brain known as hydrocephalus. Although the etiology of hydrocephalus was studied before, the effects of ethanol ingestion on ependymal cilia function have not been investigated in vivo. Here, we report three distinct types of ependymal cilia, type-I, type-II and type-III classified based upon their beating frequency, their beating angle, and their distinct localization within the mouse brain-lateral ventricle. Our studies show for the first time that oral gavage of ethanol decreased the beating frequency of all three types of ependymal cilia in both the third and the lateral rat brain ventricles in vivo. Furthermore, we show for the first time that hydin, a hydrocephalus-inducing gene product whose mutation impairs ciliary motility, and polycystin-2, whose ablation is associated with hydrocephalus are colocalized to the ependymal cilia. Thus, our studies reinforce the presence of three types of ependymal cilia in the brain ventricles and demonstrate the involvement of ethanol as a risk factor for the impairment of ependymal cilia motility in the brain.
It is becoming increasingly evident that type 2 diabetes mellitus can have effects on global and regional brain morphology. Ventricular enlargement reflecting cerebral atrophy has been reported particularly in elderly type 2 diabetes patients. However, little is known about its timing through the disease course and morphological variability. Using the combined volumetric and advanced three-dimensional morphological approach, we identified differences in size and shape of the lateral ventricles between recent-onset type 2 diabetes patients and healthy individuals. High-resolution T1-weighted images were obtained from 23 type 2 diabetes patients whose illness duration was less than 1 year and 23 carefully matched healthy individuals. By volume measurement, we found enlarged lateral and third ventricles in type 2 diabetes patients, relative to healthy individuals (F(1,41 )= 7.96, P = 0.007; F(1,41) = 11.16, P = 0.002, respectively). Morphological analysis revealed that the expansion of lateral ventricles in the diabetic brain was prominent in the bilateral frontal horns. The current findings suggest that atrophic changes particularly of the anterior frontal lobe can occur as early as the first year after the clinical diagnosis of type 2 diabetes mellitus.
Investigating the mechanisms by which metabolic wastes are cleared from nervous tissue is important for understanding natural function and the pathophysiology of several neurological disorders including Alzheimer's disease. Recent evidence suggests clearance may be the function of annular spaces around cerebral blood vessels, called perivascular spaces (PVS), through which cerebrospinal fluid (CSF) is transported from the subarachnoid space into brain parenchyma to exchange with interstitial fluid (also known as the glymphatic system). In this work, an MRI-based methodology was developed to reconstruct the PVS network in whole rat brain to better elucidate both PVS uptake and clearance pathways. MR visible tracer (Gd-albumin) was infused in vivo into the CSF-filled lateral ventricle followed by ex vivo high-resolution MR imaging at 17.6 T with an image voxel volume two orders of magnitude smaller than previously reported. Imaged tracer distribution patterns were reconstructed to obtain a more complete brain PVS network. Several PVS connections were repeatedly highlighted across different animals, and new PVS connections between ventricles and different parts of the brain parenchyma were revealed suggesting a possible role for the ventricles as a source or sink for solutes in the brain. In the future, this methodology may be applied to understand changes in the PVS network with disease.
The choroid plexus and cerebral ventricles are critical structures for the production of cerebral spinal fluid (CSF) and play an important role in regulating ion and metal transport in the brain, however many aspects of its roles in normal physiology and disease states, such as psychiatric illness, remain unknown. The choroid plexus is difficult to examine in vivo, and in situ ex vivo, and as such has typically been examined indirectly with radiolabeled tracers or ex vivo stains, making measurements of the endogenous K+, Cl-, and Ca+ distributions unreliable. In the present study, we directly examined the distribution of endogenous ions and biologically relevant transition metals in the choroid plexus and regions surrounding the ventricles (ventricle wall, cortex, corpus callosum, striatum) using X-ray fluorescence imaging (XFI). We find that the choroid plexus was rich in Cl- and Fe while K+ levels increase further from the ventricle as Cl- levels decrease, consistent with the known role of ion transporters in the choroid plexus CSF production. A polyI:C offspring displayed enlarged ventricles, elevated Cl- surrounding the ventricles, and intraventricular calcifications. These observations fit with clinical findings in patients with schizophrenia and suggest maternal treatment with polyI:C may lead to dysfunctional ion regulation in offspring. This study demonstrates the power of XFI for examining the endogenous elemental distributions of the ventricular system in healthy brain tissue as well as disease models.
Development of multi-chambered heart is associated with spatio-temporal regulation of gene expression. A basic helix-loop-helix transcription factor Hey2 is specifically expressed in the embryonic mouse ventricles and is indispensable for ventricular myocyte differentiation, compartment identity and morphogenesis of the heart. However, how Hey2 transcription is precisely regulated in the heart remains unclear. In this study, we identified a distal Hey2 enhancer conserved in the mouse and human to possess specific transcriptional activity in ventricular free wall myocytes at the looping stage of cardiac development. Deletion of the enhancer significantly decreased endogenous Hey2 expression in the ventricular myocardium but not in other tissues of mouse embryos. Mutation/deletion of the conserved binding sites for T-box and Gata proteins, but not NK-2 proteins, abolished the enhancer activity, and Tbx20 null mice completely lost the enhancer activity in the embryonic ventricles. Luciferase reporter analysis suggested that the ventricular enhancer activity was controlled by Tbx20 through its DNA binding and cooperative function with cardiac Gata proteins. These results delineate a regulatory mechanism of ventricular Hey2 expression and help fully understand molecular cascades in myocardial cell differentiation and cardiac morphogenesis during embryonic development.
Quantitative T2'-mapping detects regional changes of the relation of oxygenated and deoxygenated hemoglobin (Hb) by using their different magnetic properties in gradient echo imaging and might therefore be a surrogate marker of increased oxygen extraction fraction (OEF) in cerebral hypoperfusion. Since elevations of cerebral blood volume (CBV) with consecutive accumulation of Hb might also increase the fraction of deoxygenated Hb and, through this, decrease the T2'-values in these patients we evaluated the relationship between T2'-values and CBV in patients with unilateral high-grade large-artery stenosis.
To explore Dawson's fingers in cerebral small vessel disease (CSVD) and factors related to the development of Dawson's finger, we collected and analyzed clinical data of 65 patients with CSVD. We found a venous abnormality feature called Dawson's fingers around the ventricles in magnetic resonance images (MRIs) of 20 out of 65 patients with CSVD (30. 8%). A significant association between Dawson's fingers and diabetes mellitus (DM) was also detected (30 vs. 8.9%, P < 0.05). CSVD patients with Dawson's fingers had significantly increased cerebral microbleeds (CMB) (44.2 vs. 75.0%, p < 0.05), lacunae (66.7 vs. 95.0%, p < 0.05), and white matter hyperintensity (WMH) (p < 0.05) damage, and these patients exhibited significant cognitive domain impairment as assessed via Montreal Cognitive Assessment (MoCA) (18.9 ± 1.8 vs. 24.0 ± 0.8, p < 0.05) and Mini-Mental State Examination (MMSE) (24.5 ± 1.1 vs. 26.6 ± 0.6, p < 0.05). Our results show a distinctly high incidence of Dawson's fingers in CSVD patients and identify a significant association with DM, thus yielding insights about the appropriate use of Dawson's fingers, a venous imaging marker, to explore the basic pathophysiology of CSVD.
Spastic paraplegia gene 11(SPG11)-linked hereditary spastic paraplegia is a complex monogenic neurodegenerative disease that in addition to spastic paraplegia is characterized by childhood onset cognitive impairment, thin corpus callosum and enlarged ventricles. We have previously shown impaired proliferation of SPG11 neural progenitor cells (NPCs). For the delineation of potential defect in SPG11 brain development we employ 2D culture systems and 3D human brain organoids derived from SPG11 patients' iPSC and controls. We reveal that an increased rate of asymmetric divisions of NPCs leads to proliferation defect, causing premature neurogenesis. Correspondingly, SPG11 organoids appeared smaller than controls and had larger ventricles as well as thinner germinal wall. Premature neurogenesis and organoid size were rescued by GSK3 inhibititors including the Food and Drug Administration-approved tideglusib. These findings shed light on the neurodevelopmental mechanisms underlying disease pathology.
Cerebral atrophy in response to traumatic brain injury is a well-documented phenomenon in both primary investigations and review articles. Recent atrophy studies focus on exploring the region-specific patterns of cerebral atrophy; yet, there is no study that analyzes and synthesizes the emerging atrophy patterns in a single comprehensive review. Here we attempt to fill this gap in our current knowledge by integrating the current literature into a cohesive theory of preferential brain tissue loss and by identifying common risk factors for accelerated atrophy progression. Our review reveals that observations for mild traumatic brain injury remain inconclusive, whereas observations for moderate-to-severe traumatic brain injury converge towards robust patterns: brain tissue loss is on the order of 5% per year, and occurs in the form of generalized atrophy, across the entire brain, or focal atrophy, in specific brain regions. The most common regions of focal atrophy are the thalamus, hippocampus, and cerebellum in gray matter and the corpus callosum, corona radiata, and brainstem in white matter. We illustrate the differences of generalized and focal gray and white matter atrophy on emerging deformation and stress profiles across the whole brain using computational simulation. The characteristic features of our atrophy simulations-a widening of the cortical sulci, a gradual enlargement of the ventricles, and a pronounced cortical thinning-agree well with clinical observations. Understanding region-specific atrophy patterns in response to traumatic brain injury has significant implications in modeling, simulating, and predicting injury outcomes. Computational modeling of brain atrophy could open new strategies for physicians to make informed decisions for whom, how, and when to administer pharmaceutical treatment to manage the chronic loss of brain structure and function.
It is poorly understood how progressive brain swelling in experimental cerebral malaria (ECM) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. We therefore monitored in the Plasmodium berghei ANKA-C57BL/6 murine ECM model, disease manifestation and progression clinically, assessed by the Rapid-Murine-Coma-and-Behavioral-Scale (RMCBS), and by high-resolution in vivo MRI, including sensitive assessment of early blood-brain-barrier-disruption (BBBD), brain edema and microvascular pathology. For histological correlation HE and immunohistochemical staining for microglia and neuroblasts were obtained. Our results demonstrate that BBBD and edema initiated in the olfactory bulb (OB) and spread along the rostral-migratory-stream (RMS) to the subventricular zone of the lateral ventricles, the dorsal-migratory-stream (DMS), and finally to the external capsule (EC) and brainstem (BS). Before clinical symptoms (mean RMCBS = 18.5±1) became evident, a slight, non-significant increase of quantitative T2 and ADC values was observed in OB+RMS. With clinical manifestation (mean RMCBS = 14.2±0.4), T2 and ADC values significantly increased along the OB+RMS (p = 0.049/p = 0.01). Severe ECM (mean RMCBS = 5±2.9) was defined by further spread into more posterior and deeper brain structures until reaching the BS (significant T2 elevation in DMS+EC+BS (p = 0.034)). Quantitative automated histological analyses confirmed microglial activation in areas of BBBD and edema. Activated microglia were closely associated with the RMS and neuroblasts within the RMS were severely misaligned with respect to their physiological linear migration pattern. Microvascular pathology and ischemic brain injury occurred only secondarily, after vasogenic edema formation and were both associated less with clinical severity and the temporal course of ECM. Altogether, we identified a distinct spatiotemporal pattern of microglial activation in ECM involving primarily the OB+RMS axis, a distinct pathway utilized by neuroblasts and immune cells. Our data suggest significant crosstalk between these two cell populations to be operative in deeper brain infiltration and further imply that the manifestation and progression of cerebral malaria may depend on brain areas otherwise serving neurogenesis.
We evaluated the protective effects of protein phosphatase 2A (PP2A)/tristetraprolin (TTP) against brain edema in a rat model of cerebral hemorrhage, bleeding in the brain that occurs in tissues and ventricles. TTP is a well-known mRNA-binding protein and essential regulatory molecule for gene expression.
Fetal cerebral ventriculomegaly is a relatively common finding, observed during approximately 1% of obstetric ultrasounds. In the second and third trimester, mild (≥10 mm) and severe ventriculomegaly (≥15 mm) are defined according to the measurement of distal lateral ventricles that is included in the routine sonographic examination of central nervous system. A detailed neurosonography and anatomy ultrasound should be performed to detect other associated anomalies in the central nervous system and in other systems, respectively. Fetal MRI might be useful when neurosonography is unavailable or suboptimal. The risk of chromosomal and non-chromosomal genetic disorders associated with ventriculomegaly is high, therefore invasive genetic testing, including microarray, is recommended. Screening for prenatal infections, in particular cytomegalovirus and toxoplasmosis, should also be carried out at diagnosis. The prognosis is determined by the severity of ventriculomegaly and/or by the presence of co-existing abnormalities. Fetal ventriculoamniotic shunting in progressive isolated severe ventriculomegaly is an experimental procedure. After delivery, ventricular-peritoneal shunting or ventriculostomy are the two available options to treat hydrocephalus in specific conditions with similar long-term outcomes. A multidisciplinary fetal neurology team, including perinatologists, geneticists, pediatric neurologists, neuroradiologists and neurosurgeons, can provide parents with the most thorough prenatal counseling. This review outlines the latest evidence on diagnosis and management of pregnancies complicated by fetal cerebral ventriculomegaly.
The immature brains of newborns often respond differently from the brains of adults when exposed to similar insults. Previous studies have indicated that although hypoxia-ischemia (HI) induces persistent thrombosis in adult brains, it only modestly impairs blood perfusion in newborn brains. Here, we used the Vannucci model of HI encephalopathy to study age-related responses to cerebral HI in rat pups. We found that HI triggered fibrin deposition and impaired blood perfusion in both neonatal and adult brains. However, these effects were only transient in neonatal brains (<4 hours) and were accompanied by acute induction of both tissue-type and urinary-type plasminogen activators (tPA and uPA), which was not observed in adult brains subjected to the same insult. Interestingly, activation of the plasminogen system persisted up to 24 hours in neonatal brains, long after the clearance of fibrin-rich thrombi. Furthermore, astrocytes and macrophages outside blood vessels expressed tPA after HI, suggesting the possibility of tPA/plasmin-mediated cytotoxicity. Consistent with this hypothesis, injection of alpha2-antiplasmin into cerebral ventricles markedly ameliorated HI-induced damage to neurofilaments and white matter oligodendrocytes, providing a dose-response reduction of brain injury after 7 days of recovery. Conversely, ventricular injection of tPA increased HI-induced brain damage. Together, these results suggest that tPA/plasmin induction, which may contribute to acute fibrinolysis, is a critical component of extravascular proteolytic damage in immature brains, representing a new therapeutic target for the treatment of HI encephalopathy.
The major neural stem cell population in the developing cerebral cortex is composed of the radial glial cells, which generate glial cells and neurons. The mechanisms that modulate the maintenance of the radial glia (RG) stem cell phenotype, or its differentiation, are not yet completely understood. We previously demonstrated that the transforming growth factor-β1 (TGF-β1) promotes RG differentiation into astrocytes in vitro (Glia 2007; 55:1023-33) through activation of multiple canonical and non-canonical signaling pathways (Dev Neurosci 2012; 34:68-81). However, it remains unknown if TGF-β1 acts in RG-astrocyte differentiation in vivo. Here, we addressed the astrogliogenesis induced by TGF-β1 by using the intraventricular in utero injection in vivo approach. We show that injection of TGF-β1 in the lateral ventricles of E14,5 mice embryos resulted in RG fibers disorganization and premature gliogenesis, evidenced by appearance of GFAP positive cells in the cortical wall. These events were followed by decreased numbers of neurons in the cortical plate (CP). Together, we also described that TGF-β1 actions are region-dependent, once RG cells from dorsal region of the cerebral cortex demonstrated to be more responsive to this cytokine compared with RG from lateral cortex either in vitro as well as in vivo. Our work demonstrated that TGF-β1 is a critical cytokine that regulates RG fate decision and differentiation into astrocytes in vitro and in vivo. We also suggest that RG cells are heterogeneous population that acts as distinct targets of TGF-β1 during cerebral cortex development.
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