Periventricular Zone Research Articles

The expansion and severity of chronic MS lesions follows a periventricular gradient

Background and Objectives: Expansion of chronic lesions in multiple sclerosis (MS) patients and recently described cerebrospinal fluid (CSF)-related gradient of tissue damage are linked to microglial activation. The aim of this study was to investigate whether lesion expansion is associated with proximity to ventricular CSF spaces. Methods: Pre- and post-gadolinium three-dimensional (3D)-T1, 3D FLAIR and diffusion tensor images were acquired from 36 relapsing-remitting MS (RRMS) patients. Lesional activity was analysed between baseline and 48 months at different distances from the CSF using successive 1 mm thick concentric bands radiating from the ventricles. Results: Voxel-based analysis of the rate of lesion expansion demonstrated a clear periventricular gradient decreasing away from the ventricles. This was particularly apparent when lesions of equal diameter were analysed. Periventricular lesional tissue showed higher degree of tissue destruction at baseline that significantly increased during follow-up in bands close to CSF. This longitudinal change was proportional to degree of lesion expansion. Lesion-wise analysis revealed a gradual, centrifugal decrease in the proportion of expanding lesions from the immediate periventricular zone. Discussion: Our data suggest that chronic white matter lesions in close proximity to the ventricles are more destructive, show a higher degree of expansion at the lesion border and accelerated tissue loss in the lesion core.

Expression of Doublecortin, Glial Fibrillar Acidic Protein, and Vimentin in the Intact Subpallium and after Traumatic Injury to the Pallium in Juvenile Salmon, Oncorhynchus masou.

Fetalization associated with a delay in development and the preservation of the features of the embryonic structure of the brain dominates the ontogeny of salmonids. The aim of the present study was to comparatively analyze the distribution of the glial-type aNSC markers such as vimentin and glial fibrillar acidic protein (GFAP) and the migratory neuronal precursors such as doublecortin in the telencephalon subpallium of juvenile masu salmon, Oncorhynchus masou, in normal conditions and at 1 week after an injury to the dorsal pallium. Immunohistochemical labeling of vimentin, GFAP, and doublecortin in the pallium of intact juvenile masu salmon revealed single cells with similar morphologies corresponding to a persistent pool of neuronal and/or glial progenitors. The study of the posttraumatic process showed the presence of intensely GFAP-labeled cells of the neuroepithelial type that form reactive neurogenic zones in all areas of the subpallial zone of juvenile masu salmon. A comparative analysis of the distribution of radial glia in the dorsal, ventral, and lateral zones of the subpallium showed a maximum concentration of cells in the dorsal part of subpallium (VD) and a minimum concentration in the lateral part of subpallium VL. An essential feature of posttraumatic immunolabeling in the masu salmon subpallium is the GFAP distribution patterns that are granular intracellular in the apical periventricular zone (PVZ) and fibrillar extracellular in the subventricular (SVZ) and parenchymal zones (PZ). In contrast to those in intact animals, most of the GFAP+ granules and constitutive neurogenic niches in injured fish were localized in the basal part of the PVZ. With the traumatic injury to the subpallium, the number of Vim+ cells in the lateral and ventral regions significantly increased. At 1 week post-injury, the total immunolabeling of vimentin cells in the PVZ was replaced by the granular pattern of Vim immunodistribution spreading from the PVZ to the SVZ and deeper parenchymal layers of the brain in all areas of the subpallium. A significant increase in the number of DC+ cells was observed also in all areas of the subpallium. The number of cells increased both in the PVZ and in the SVZ, as well as in the deeper PZ. Thus, at 1 week after the injury to the dorsal pallium, the number of DC, Vim, and GFAP expressing cells of the neuroepithelial type in the subpallium of juvenile masu salmon increased, and additionally GFAP+ radial glia appeared in VD, which was absent from intact animals.

Molecular Markers of Adult Neurogenesis in the Telencephalon and Tectum of Rainbow Trout, Oncorhynchus mykiss.

In the brain of teleost fish, radial glial cells are the major type of astroglial cells. To answer the question as to how radial glia structures adapt to the continuous growth of the brain, which is characteristic of salmonids, it is necessary to study various types of cells (neuronal precursors, astroglial cells, and cells in a state of neuronal differentiation) in the major integrative centers of the salmon brain (telencephalon and tectum opticum), using rainbow trout, Oncorhynchus mykiss, as a model. A study of the distribution of several molecular markers in the telencephalon and tectum with the identification of neural stem/progenitor cells, neuroblasts, and radial glia was carried out on juvenile (three-year-old) O. mykiss. The presence of all of these cell types provides specific conditions for the adult neurogenesis processes in the trout telencephalon and tectum. The distribution of glutamine synthetase, a molecular marker of neural stem cells, in the trout telencephalon revealed a large population of radial glia (RG) corresponding to adult-type neural stem cells (NSCs). RG dominated the pallial region of the telencephalon, while, in the subpallial region, RG was found in the lateral and ventral zones. In the optic tectum, RG fibers were widespread and localized both in the marginal layer and in the periventricular gray layer. Doublecortin (DC) immunolabeling revealed a large population of neuroblasts formed in the postembryonic period, which is indicative of intense adult neurogenesis in the trout brain. The pallial and subpallial regions of the telencephalon contained numerous DC+ cells and their clusters. In the tectum, DC+ cells were found not only in the stratum griseum periventriculare (SGP) and longitudinal torus (TL) containing proliferating cells, but also in the layers containing differentiated neurons: the central gray layer, the periventricular gray and white layers, and the superficial white layer. A study of the localization patterns of vimentin and nestin in the trout telencephalon and tectum showed the presence of neuroepithelial neural stem cells (eNSCs) and ependymoglial cells in the periventricular matrix zones of the brain. The presence of vimentin and nestin in the functionally heterogeneous cell types of adult trout indicates new functional properties of these proteins and their heterogeneous involvement in intracellular motility and adult neurogenesis. Investigation into the later stages of neuronal development in various regions of the fish brain can substantially elucidate the major mechanisms of adult neurogenesis, but it can also contribute to understanding the patterns of formation of certain brain regions and the involvement of RG in the construction of the definite brain structure.

Features of the formation of interzonal connections of the brain according to quantitative electroencephalography in full-term and premature infants

To study the features of functional interzonal integration and its dynamics in infants from 0 to 9 months during prospective observation, taking into account the timing gestation, clinical picture and morphological changes on neurosonography (NSG). A comprehensive unified examination was carried out in dynamics in 89 infants three times at the age of 3, 6, 9 months and included, in addition to assessing the neurological status, the Denver Developmental Screening Test (DDST), transfontanellar ultrasonography with a vector sensor according to the generally accepted method. We also evaluated the parameters of electroencephalography (EEG) recorded in the waking state with an analysis of background parameters, zonal differences, and the identification of pathological types of activity and calculation of the average coherence power (ACP). In accordance with the gestational age, infants are divided into two groups of full-term and premature babies. In the group of premature babies, the clinical picture in the neonatal period was dominated by cerebral ischemia of I and II degrees. The DDST parameters throughout the entire observation period did not reveal any deviations from the optimal development in all children. There were significant changes in functional connectivity (FC) in premature infants, which were more pronounced by 9 months. Functional hyperintegration was recorded in the intrahemispheric occipital-temporal and occipital-central regions bilaterally, in the anterofrontal-temporal leads on the left and in the interhemispheric anterofrontal regions. The ACP indicators were affected by changes in the NSG. An increase in ACP values in the occipitotemporal leads was associated with the presence of subependymal cysts in both preterm and full-term infants. Intraventricular hemorrhages and increased echogenicity in the periventricular zones in preterm infants were associated with an increase in coherence in the anterior frontal, left occipito-central, and temporo-anterofrontal leads. Thus, in preterm infants with cerebral ischemia of grades I and II, as well as in children with subependymal cysts, ACP indicators indicate hyperintegration of brain areas that are of fundamental importance for speech development and the formation of cognitive functions. Changes in the level of FC in the areas of the cerebral cortex in children with low gestational age, cerebral ischemia I and II, even at the optimal rate of motor and preverbal development, require further study, as it can reflect both the physiological processes of maturation in the postnatal period with transient deviations, and act as the role of possible early markers of future variants of deviant development.

Neuroprotective Role of Curcumin Against Benzo[a]pyrene-Induced Neurodegeneration in Zebrafish

Curcuma longa L. has been shown to exhibit neuroprotection in the brain. Curcuma longa L. has been used for its neuroprotective effect in humans of neurological disorders. The present study is aimed to evaluate the neuroprotective role of curcumin, a key component of Curcuma longa L., following exposure to waterborne B[a]P. Wild-type adult zebrafish (Danio rerio) were assigned as naïve, control (dimethyl sulfoxide), curcumin, B[a]P (Benzo[a]pyrene) and B[a]P+ curcumin group. B[a]P-induced altered antioxidant levels were enhanced by curcumin in the B[a]P+curcumin group. Findings showed that B[a]P induced anti-anxiety behavioral response and altered antioxidant activity in zebrafish is reduced by curcumin. The periventricular grey zone (PGZ) located on the optic tectum (TeO) in the zebrafish brain regulates anxiety-like behavior. Our histological study showed a significant increase in pyknotic neuronal counts in PGZ of TeO in adult zebrafish brain following B[a]P exposure and was improved by curcumin co-supplementation. Recent findings showed that curcumin improves glutathione production, an antioxidant necessary for maintaining redox homeostasis and shows a neuroprotective role in brain cells. The present study's findings address the potential role of curcumin co-supplementation as a herbal therapeutic against B[a]P-induced neurotoxicity in zebrafish.

Temporal exposure to chronic unpredictable stress induces precocious neurobehavioral deficits by distorting neuromorphology and glutathione biosynthesis in zebrafish brain

Modelling of chronic stress conditions in experimental animals and its neuropsychiatric outcomes has been well documented in literature. Zebrafish (Danio rerio) by exhibiting significant genetic and epidemiological similarities with human beings, has now emerged as a promising animal model of translational research. In this line, risk assessment following exposure to chronic unpredictable stress (CUS) towards neurobehavioral response and neuromorphology of sensitive brain region in zebrafish is the prime objective of the present study. With the existing knowledge on CUS in affecting diverse neurobehavioral aspects, we were primarily interested in whether this neurobehavioral transformation is an outcome of altered glutathione biosynthesis in zebrafish. We were also concerned about whether the precocious neurobehavioral transformation has been linked to altered neuromorphology in the periventricular grey zone (PGZ) of the zebrafish brain. Our basic findings showed that CUS itself represented as a universal factor in altering native bottom-dwelling and scototaxis behaviour of zebrafish. Our findings also backing the argument that CUS itself represented a collective stress regimen by altering the brain glutathione biosynthesis in zebrafish. Correspondingly, a temporal transformation in CUS instigated augmentation in neuronal pyknosis and chromatin condensation were observed in PGZ of the zebrafish brain. Collectively, these findings designate that CUS induced temporal neurobehavioral transformation is an outcome of augmented oxidative stress and neuromorphological alteration in the zebrafish brain. However, the underlying mechanism of such neuropathological manifestation associated with CUS might provide novel insight towards the development of prophylactic/therapeutic intervention to counter such co-morbid behavioral alteration.

Peak ependymal cell stretch overlaps with the onset locations of periventricular white matter lesions

Deep and periventricular white matter hyperintensities (dWMH/pvWMH) are bright appearing white matter tissue lesions in T2-weighted fluid attenuated inversion recovery magnetic resonance images and are frequent observations in the aging human brain. While early stages of these white matter lesions are only weakly associated with cognitive impairment, their progressive growth is a strong indicator for long-term functional decline. DWMHs are typically associated with vascular degeneration in diffuse white matter locations; for pvWMHs, however, no unifying theory exists to explain their consistent onset around the horns of the lateral ventricles. We use patient imaging data to create anatomically accurate finite element models of the lateral ventricles, white and gray matter, and cerebrospinal fluid, as well as to reconstruct their WMH volumes. We simulated the mechanical loading of the ependymal cells forming the primary brain-fluid interface, the ventricular wall, and its surrounding tissues at peak ventricular pressure during the hemodynamic cycle. We observe that both the maximum principal tissue strain and the largest ependymal cell stretch consistently localize in the anterior and posterior horns. Our simulations show that ependymal cells experience a loading state that causes the ventricular wall to be stretched thin. Moreover, we show that maximum wall loading coincides with the pvWMH locations observed in our patient scans. These results warrant further analysis of white matter pathology in the periventricular zone that includes a mechanics-driven deterioration model for the ventricular wall.

Chronic bisphenol A exposure induces temporal neurobehavioral transformation and augmented chromatin condensation in the periventricular gray zone of zebrafish brain

Bisphenol A (BPA) is an industrial synthetic chemical that is extensively used for manufacturing polycarbonate plastics and epoxy resins. However, there is limited literature on BPA-induced temporal neurobehavioral transformation and oxidative stress-mediated neurodegeneration in the subtle region of the zebrafish brain. Consequently, an investigational setup was prepared to study the temporal response to duration-dependent BPA exposure on neurobehavioral, oxidative stress, and neurodegeneration in zebrafish. Zebrafish were divided into five groups: naïve, control, 7 days (BPA7D), 14 days (BPA14D), and 21 days (BPA21D). Our findings indicated that chronic waterborne exposure to BPA substantially altered the light/dark preference and bottom-dwelling behavior of zebrafish in the BPA14D, and BPA21D groups compared with naïve and control groups. Biochemical studies revealed that there was a significant downregulation in the cellular level of small-molecule antioxidants evidenced by reduced glutathione (GSH) and activity of antioxidant enzymes of glutathione biosynthesis in a duration-dependent manner after exposure to BPA. However, exposure to BPA for 7 days did not induce substantial alteration in biochemical parameters, such as GSH level, protein carbonylation, and superoxide dismutase activity, although the neurobehavioral responses expressively differed from those of the naïve and control groups. Moreover, our histopathological observation also indicated a temporal augmentation in chromatin condensation in the periventricular gray zone (PGZ) of the zebrafish brain after chronic exposure to BPA. The overall outcomes of the present study indicated that the transformed neurobehavioral phenotypes in zebrafish are a consequence of BPA-induced oxidative stress and PGZ neurodegeneration and clearly show a temporal transformation under BPA exposure.

Suppression of bisphenol A-induced oxidative stress by taurine promotes neuroprotection and restores altered neurobehavioral response in zebrafish (Danio rerio).

Bisphenol A (BPA) has been documented as a mediator for a number of health effects, including inflammation, oxidative stress, carcinogenicity, and mood dysfunction. The literature on the role of BPA in inducing altered neurobehavioral response and brain morphology and plausible neuroprotective role of taurine against BPA induced oxidative stress mediated neurotoxicity is limited. Therefore, the present experimental paradigm was set for 21 days to expound the neuroprotective efficacy of taurine against BPA-induced neurotoxicity in zebrafish (Danio rerio) following waterborne exposure. Neurobehavioral studies were conducted by light-dark preference test (LDPT) and novel tank diving test (NTDT). To validate that the neuroprotective efficacy of taurine against BPA-induced neurotoxicity is associated with the modulation of the antioxidant defense system, we have conducted biochemical studies in zebrafish brain. Changes in brain morphology leading to neurobehavioral variations following co-supplementation of BPA and taurine were evaluated by Hoechst staining and cresyl violet staining (CVS) in periventricular gray zone (PGZ) of zebrafish brain. Our findings show that taurine co-supplementation significantly improved the BPA-induced altered scototaxis and explorative behavior of zebrafish. Further, BPA-induced augmented oxidative stress was considerably ameliorated by taurine co-supplementation. Subsequently, our observation also points toward the neuroprotective role of taurine against BPA-induced neuronal pyknosis and chromatin condensation in PGZ of zebrafish brain. In a nutshell, the findings of the current study show the neuroprotective efficacy of taurine against BPA-induced oxidative stress-mediated neurotoxicity. Elucidation of the underlying signaling mechanism of taurine-mediated neuroprotection would provide novel strategies for the prevention/treatment of BPA-persuaded serious neurological consequences.

Exposure to Iodoacetic Acid, a Water Disinfection Byproduct, Leads to Abnormal Expression of Key Reproductive Axis Genes in the Hypothalamus and Pituitary

Iodoacetic acid (IAA) – a water disinfection byproduct (DBP) formed from the reaction between an oxidizing disinfectant, i.e. chlorine, and iodide – is an understudied, yet potentially dangerous environmental toxicant. DBPs have been epidemiologically associated with reproductive dysfunction. In vitro studies have indicated that IAA is one of the most cyto- and genotoxic DBPs. Further, murine ovarian research has shown that IAA exposure significantly inhibits antral follicle growth and reduces estradiol levels. Despite this evidence, little is known about the other components of the reproductive axis: the hypothalamus and pituitary. To address this, we tested the hypothesis that IAA exposure would lead to disrupted expression of key hypothalamic and pituitary genes related to reproductive function. We exposed adult female CD1 mice to 0.5, 10, 100, or 500 mg/L IAA in their drinking water from postnatal day 40 (P40) to their first day in diestrus after P75. From this experiment, we collected whole pituitaries and hypothalamic punches containing the arcuate nucleus (ARC), anteroventral periventricular zone (AVPV), and medial preoptic nucleus (mPOA), and processed them for mRNA analysis. We also exposed pituitary explant cultures to IAA to observe direct effects on gene expression. In vivo, we found that mRNA levels of kisspeptin (Kiss1) are significantly increased in the ARC, the region that controls pulsatile GnRH release, at 0.5 and 10 mg/L IAA concentrations. Kiss1 is unchanged in the AVPV, the neuron population responsible for generating the LH surge. We also measured ARC expression of neurokinin B (Tac2) and dynorphin (Pdyn), neuropeptides secreted by kisspeptin co-expressing neurons to autosynaptically stimulate Kiss1 release. We saw no difference in either. GnRH (Gnrh1) expression was also unchanged. Both in vivo at 10 mg/L IAA and in culture, we found IAA exposure significantly reduced Fshb mRNA. Preliminary immunohistochemistry (IHC) data suggests it also leads to an apparent reduction in FSH-positive cells in vitro (N=2). Lhb and the α-subunit (Cga) were unaltered in vivo, though were significantly reduced with in vitro exposure. In neither context was mRNA expression of the GnRH receptor (Gnrhr) changed. Noting apparent direct effects of IAA on the pituitary, we assessed expression of the cell-cycle inhibitor p21 (Cdkn1a), which has been shown to increase with toxicant exposure. We found Cdkn1a increased in vivo at 500 mg/L IAA, trending at 100 mg/L (p=.070), and in vitro. IHC data in vitro suggests a marked increase in P21-positivity following IAA exposure. These data, together with prior ovarian findings, implicate IAA as a potential reproductive axis disruptor at each major level – through ARC Kiss1 expression, Fshb expression in vivo and in vitro, FSH expression in vitro, and Lhb and Cga in vitro. Further, Cdkn1a/P21 induction indicates IAA toxicity at the level of the pituitary.

CNS demyelination with TNFα inhibitor exposure: A retrospective cohort study

ObjectiveTo study long-term outcomes in patients with CNS demyelinating events exposed to TNFa-inhibitors (TNFai), including subsequent clinical relapse, MRI lesions, and use of disease modifying therapy (DMT) for MS. MethodsAdult patients evaluated for a CNS demyelinating disease during TNFai use were identified at Mass General Brigham [01/1998–08/2020] and analyzed in clinically-relevant subgroups. Inclusion criteria required a first neurological event while taking a TNFai, MRI lesions consistent with demyelination, and the absence of a more probable alternative diagnosis. Results21 cases (mean age 44 years, 20 female, 14 ≥ 2 MS risk factors) had an index neurological event (INE) at a median of 12 months (range 1–176) from onset of TNFai use (adalimumab in 10, etanercept 6, infliximab 5). MRI lesions were most often present in periventricular (16/20, 80%) and spinal zones (10/20, 50%); 37% (7/19) met ≥ 2 Barkhof criteria at onset. CSF testing was abnormal in 64% (7/11). 67% (10/15) with available follow-up MRIs developed new lesions by a median of 29.5 months of MRI surveillance (median MRI surveillance 60 months); 55% (11/20) met ≥ 2 Barkhof criteria. 47% (8/17) suffered a clinical relapse by a median of 40.5 months of clinic follow-up (median clinic follow-up since INE: 26 months). In patients discontinuing TNFai (18/21, 86%) at INE onset, 56% (10/18) had further evidence of CNS demyelination. Six patients (6/21, 29%) started an MS disease modifying therapy (DMT) at INE of whom 50% (3/6) had subsequent disease activity. Continuing or restarting TNFai was followed by relapse in 75% (3/4). 65% (13/20) met 2017 McDonald criteria for MS at INE with another 10% (15/20, 75%) by study conclusion. ConclusionsWith extended follow-up, a majority of patients had a relapsing CNS demyelinating disorder—as evidenced by new MRI lesions or clinical relapses—despite TNFai discontinuation.

The effect of amisulpride, olanzapine, quetiapine, and aripiprazole single administration on c-Fos expression in vasopressinergic and oxytocinergic neurons of the rat hypothalamic paraventricular nucleus

Antipsychotics, including amisulpride (AMI), quetiapine (QUE), aripiprazole (ARI), and olanzapine (OLA), are used to treat mental illnesses associated with psychotic symptoms. The effect of these drugs on c-Fos expression in vasopressinergic (AVP) and oxytocinergic (OXY) neurons was studied in the hypothalamic paraventricular nucleus (PVN) of rats. The presence of c-Fos in AVP and OXY perikarya was investigated in seven PVN cells segregations: the anterior (Ant), dorsal cup (Dc), wing-shaped (Wi), periventricular zone (Pe), circle-shaped core (Co) and shell of core (Sh), and the posterior (pPVN) after an acute treatment with AMI-20 mg/kg, QUE-15 mg/kg, ARI-10 mg/kg, and OLA-5 mg/kg/bw in rats. Ninety min after treatments, the animals were sacrificed by transcardial perfusion with fixative and the PVN area sliced into 35 μm thick coronal sections for immunohistochemistry. The c-Fos was processed by avidin-biotin-peroxidase complex intensified with nickel-enhanced 3,3′-diaminobenzidine tetrahydrochloride. Visualization of AVP- and OXY-synthesizing neurons was achieved by a fluorescent marker Alexa Flour 568. The c-Fos-AVP and c-Fos-OXY colocalizations were evaluated from c-Fos stained sections merged with AVP or OXY ones. AMI, QUE, ARI, and OLA, single administration distinctly increased the c-Fos expression in each of the PVN cells segregations. QUE induced the highest magnitude of activation of AVP and OXY neurons, while OLA and AMI had only moderate effects. Incontestable variabilities detected in c-Fos expression in PVN AVP and OXY neurons extend the knowledge of selected antipsychotics extra-striatal actions and may also be helpful in a presumption of their possible functional impact.

Periventricular zone involvement as a predictor of survival in glioblastoma patients: A single centre cohort-comparison investigation concerning a distinct clinical entity

BackgroundGlioblastoma (GBM) contacting the Subventricular Zone (SVZ) may display a more aggressive pattern of invasiveness with higher potential to recruit migratory progenitor cells. We aims to determine the relationships between the location of the lesion and the clinical, molecular characteristics and outcome in patients affected by GBM. MethodsThe surgical, radiological and clinical outcomes of patients have been retrospectively reviewed for the present study. All patients have been classified according their anatomical relationship with SVZ in SVZ + and SVZ-. A review of our surgical series was conducted to compare the results of SVZ tumors in regards to clinical and molecular characteristics, localization, and Extent of Resection (EOR). Uni- and Multivariate ANOVA and survival analyses were performed to investigate the cohort. ResultsA total of 177 patients were included in the final cohort. A statistical analysis by means of multivariate analyses to demonstrate that SVZ + tumors were significantly associated to a greater volume at presentation, a lesser EOR, lesser functional postoperative outcome and a short overall survival. ConclusionsThere are specific characteristics to consider the SVZ + GBMs a specific clinical entity how greater tumors at presentation, clinical associated with Headache and Sensory Disturbances, which are associated to a higher risk of partial resection and with a less satisfactory functional outcome in the early postoperative period. Our multivariate analysis demonstrated a clear and statistically significant survival advantage of cortical GBM over V-SVZ GBM.

Mechanical Brain Injury Increases Cells' Production of Cystathionine β-Synthase and Glutamine Synthetase, but Reduces Pax2 Expression in the Telencephalon of Juvenile Chum Salmon, Oncorhynchus keta.

The considerable post-traumatic brain recovery in fishes makes them a useful model for studying the mechanisms that provide reparative neurogenesis, which is poorly represented in mammals. After a mechanical injury to the telencephalon in adult fish, lost neurons are actively replaced due to the proliferative activity of neuroepithelial cells and radial glia in the neurogenic periventricular zone. However, it is not enough clear which signaling mechanisms are involved in the activation of adult neural stem cells (aNSC) after the injury (reactive proliferation) and in the production of new neurons (regenerative neurogenesis) from progenitor cells (NPC). In juvenile Pacific salmon, the predominant type of NSCs in the telencephalon are neuroepithelial cells corresponding to embryonic NSCs. Expression of glutamine synthetase (GS), a NSC molecular marker, was detected in the neuroepithelial cells of the pallium and subpallium of juvenile chum salmon, Oncorhynchus keta. At 3 days after a traumatic brain injury (TBI) in juvenile chum salmon, the GS expression was detected in the radial glia corresponding to aNSC in the pallium and subpallium. The maximum density of distribution of GS+ radial glia was found in the dorsal pallial region. Hydrogen sulfide (H2S) is a proneurogenic factor that reduces oxidative stress and excitotoxicity effects, along with the increased GS production in the brain cells of juvenile chum salmon. In the fish brain, H2S producing by cystathionine β-synthase in neurogenic zones may be involved in maintaining the microenvironment that provides optimal conditions for the functioning of neurogenic niches during constitutive neurogenesis. After injury, H2S can determine cell survivability, providing a neuroprotective effect in the area of injury and reducing the process of glutamate excitotoxicity, acting as a signaling molecule involved in changing the neurogenic environment, which leads to the reactivation of neurogenic niches and cell regeneration programs. The results of studies on the control of the expression of regulatory Sonic Hedgehog genes (Shh) and the transcription factors Paired Box2 (Pax2) regulated by them are still insufficient. A comparative analysis of Pax2 expression in the telencephalon of intact chum salmon showed the presence of constitutive patterns of Pax2 expression in neurogenic areas and non-neurogenic parenchymal zones of the pallium and subpallium. After mechanical injury, the patterns of Pax2 expression changed, and the amount of Pax2+ decreased (p < 0.05) in lateral (Dl), medial (Dm) zones of the pallium, and the lateral zone (Vl) of the subpallium compared to the control. We believe that the decrease in the expression of Pax2 may be caused by the inhibitory effect of the Pax6 transcription factor, whose expression in the juvenile salmon brain increases upon injury.

CADASIL in a patient with bilateral internal carotid artery agenesis

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a well-recognised cause of stroke in the young. Bilateral internal carotid artery (ICA) agenesis is a rare congenital malformation, with few previous reported cases in the literature. CADASIL is not reported to be associated with ICA agenesis. We report the case of a 41 year old man who presented with recurrent orthostatic symptoms associated with increasingly frequent falls. Initial investigation with CT angiography revealed absent bilateral ICAs with an ectatic vertebrobasilar arterial tree supplying the intracranial circulation. Skull base CT revealed simultaneous absence of ICAs and bilateral carotid canals, confirming agenesis of bilateral ICAs. MRI of the brain revealed extensive areas of confluent high T2 signal intensity in the subcortical and periventricular zones of both hemispheres. The patient subsequently developed episodic and progressive headache, dysarthria, ataxia, cognitive impairment and personality changes. Radiological progression of cerebral subcortical and periventricular abnormalities was demonstrated with established lacunar infarcts and generalised atrophic changes. Genetic testing confirmed the diagnosis of CADASIL with the presence of a heterozygous c.994C > T (p.Arg332Cys) mutation in exon 6 of the NOTCH 3 gene.We report the first case of coexistent bilateral ICA agenesis and CADASIL. This case highlights the need to consider CADASIL in patients with cerebral subcortical and periventricular imaging abnormalities, even with coexistent large vessel pathology.

Sexually dimorphic effects of prolactin treatment on the onset of puberty and olfactory function in mice

The onset of puberty is associated with the psychophysiological maturation of the adolescent to an adult capable of reproduction when olfactory signals play an important role. This period begins with the secretion of the gonadotropin-releasing hormone (GnRH) from GnRH neurons within the hypothalamus. This is regulated by kisspeptin neurons that express high levels of transmembrane prolactin receptors (PRLR) that bind to and are activated by prolactin (PRL). The elevated levels of serum PRL found during lactation, or caused by chronic PRL infusion, decreases the secretion of gonadotropins and kisspeptin and compromised the estrous cyclicity and the ovulation. In the present work, we aimed to evaluate the effects of either increased or decreased PRL circulating levels within the peripubertal murine brain by administration of PRL or treatment with cabergoline (Cab) respectively. We showed that either treatment delayed the onset of puberty in females, but not in males. This was associated with the augmentation of the PRL receptor (Prlr) mRNA expression in the arcuate nucleus and decreased Kiss1 expression in the anteroventral periventricular zone. Then, during adulthood, we assessed the activation of the mitral and granular cells of the main (MOB) and accessory olfactory bulb (AOB) by cFos immunoreactivity (ir) after the exposure to soiled bedding of the opposite sex. In the MOB, the PRL treatment promoted an increased cFos-ir of the mitral cells of males and females. In the granular cells of male of either treatment an augmented activation was observed. In the AOB, an impaired cFos-ir was observed in PRL and Cab treated females after exposure to male soiled bedding. However, in males, only Cab impaired its activation. No effects were observed in the AOB-mitral cells. In conclusion, our results demonstrate that PRL contributes to pubertal development and maturation of the MOB-AOB during the murine juvenile period in a sex-dependent way.

Benzo[a]pyrene exposure and overcrowding stress impacts anxiety-like behavior and impairs learning and memory in adult zebrafish, Danio rerio.

Benzo[a]pyrene (B[a]P), a prototype of polycyclic aromatic hydrocarbons and ubiquitous environmental pollutant, alters neurobehavioral responses in aquatic organisms like zebrafish. Increasing organic load on water bodies causes population explosion leading to overcrowding (OC) stress. The effect of OC stress on neurobehavioral alterations remains unclear. The objective of our study is to elucidate the impact of OC stress on behavioral alterations and neurodegenerative phenotypes on exposure to B[a]P in zebrafish. We demonstrate the effects of OC stress (12 fish/L) on acute waterborne exposure to B[a]P (0.2 mg L-1 ) in adult wild zebrafish. Anxiety-like behavior, learning, and memory impairment were assayed by novel tank diving test, light/dark preference test, and T-maze test. Oxidative stress bio-markers were assayed along with histopathological changes in zebrafish brain. OC stress significantly impaired the learning ability and mood behavior by increasing the number of transition and time spent in the alter zones. Increased lipid peroxidation and protein carbonyl formation with significant decreased catalase activity and reduced glutathione level showed oxidative stress on exposure to OC stress and B[a]P. Pyknotic neuronal counts dramatically increased in periventricular grey zone of optic tectum brain region of zebrafish. Our findings showed that OC stress modulates the B[a]P-induced behavioral alterations causing learning and memory deficiency with histopathological changes in adult zebrafish brain. OC stress may act as an early risk factor for the eventual development of cognitive impairments and B[a]P exposure plays a key role in mediating both the facilitating and impairing actions of OC stress in memory processes.

Quercetin abrogates bisphenol A induced altered neurobehavioral response and oxidative stress in zebrafish by modulating brain antioxidant defence system

Bisphenol A (BPA), a well-recognized anthropogenic xenoestrogen, has been identified as a causative agent responsible for inducing carcinogenicity, cognitive impairment, neurotoxicity, oxidative stress, etc. However, BPA-induced neurotoxicity and its possible amelioration through natural compound intervention remain elusive. The current study was performed to elucidate the neurotoxic potential of BPA in zebrafish (Danio rerio) by waterborne exposure and its possible amelioration by quercetin co-supplementation. Protective effect of quercetin against BPA-induced altered neurobehavioral response, oxidative stress and neuromorphological changes were evaluated in zebrafish brain. The present findings reveal that BPA-induced altered neurobehavioral response was ameliorated by quercetin. Biochemical studies advocate the potential therapeutic efficacy of quercetin against BPA-induced oxidative stress in zebrafish brain. Quercetin also shows neuroprotection against BPA-induced augmented neuronal pyknosis in periventricular grey zone (PGZ) of zebrafish brain. These basic findings indicate that quercetin may act as an effective intervention against BPA-induced neurotoxicity in zebrafish through down-regulation of oxidative stress.

Congenital Anomaly of Central Nervous System Associated with Antenatal Coinfection with Cytomegalovirus and Toxoplasma: Clinical Case

Background . The development of central nervous system (CNS) malformations may occur due to antenatal infection. Specific pathomorphological changes in CNS structures require further study. Clinical Case Description . The autopsy morphological study of the brain of a child who had antenatal toxoplasma and cytomegalovirus infections and who died at the age of 2 years was performed. Thickening of the pia mater with cloudy surface due to edema and focal sclerosis, generalized thrombosis of superior sagittal sinus, sinus rectus and sinus transverses, absence of corpus callosum, major commissural fibers, opened third ventricle and vermis of cerebellum agenesia, as well as mixed forms of obstructive hydrocephalus were revealed. Diffuse gliosis with glial cysts in the periventricular zones were revealed at histological examination of the alba. Pseudocysts filled with toxoplasms were identified in the cysts’ wall. Signs of productive vasculitis were noted. Comparison of pathomorphological changes in the brain and internal organs with anamnestic data of the patient (toxoplasma and cytomegalovirus infection during recent pregnancy, brain abnormality of the fetus on the second ultrasound screening at 21–22 weeks of gestation) and the results of histological examination of placenta was carried out to prove the correlation of antenatal infection with the development of brain anomalies. Pathognomonic signs of cytomegalovirus infection and toxoplasmosis were revealed in the placenta: cytomegalic cells, vascular thrombosis, white infarcts, fibrinoid necrosis of basal lamina, placental hypoplasia. Toxoplasmic cysts were detected in chorionic villae stroma, parietal thophoblast, amnion, decidual tissue. Conclusion . Antenatal viral-parasitic infection may be the cause of brain anomalies of the fetus. However, the child had no specific signs of cytomegalovirus infection (such as cytomegalic cells — owl eye cells), even when the placenta had pathomorphological changes typical for this infection. It can be assumed that the development of brain anomaly in this child could be associated with toxoplasma infection.

Fetal brain damage in congenital hydrocephalus.

Congenital hydrocephalus (HCP) is a developmental brain disorder characterized by the abnormal accumulation of cerebrospinal fluid within the ventricles. It is caused by genetic and acquired factors that start during early embryogenesis with disruption of the neurogerminal areas. As might be expected, early-onset hydrocephalus alters the process of brain development leading to irreparable neurological deficit. A primary alteration of the ependyma/neural stem cells (affecting vesicle trafficking and abnormal cell junctions) leads to its loss or denudation and translocation of neural progenitor cells (NPCs) and neural stem cells (NSCs) into the cerebrospinal fluid (CSF). Under these abnormal conditions, morphological and functional processes, underlying the concept of astroglial reaction, are initiated in an attempt to recover homeostasis in the periventricular zone. This astroglial reaction includes astrocyte hypertrophy, hyperplasia, and development of a new layer with reorganized functional features that resemble the ependyma. Despite decades of research, there is a lack of information concerning the biological basis of the brain abnormalities that are associated with HCP. The present review of current literature discusses the neuropathological changes during gestation following the onset of congenital hydrocephalus and the unanswered questions into the pathophysiology of the disease. A better understanding of those missing points might help create novel therapeutic strategies that can reverse or even prevent the ultimate neurological impairment that affects this population and improve long-term clinical outcome.