Neurodevelopmental Damage Research Articles

Raloxifene Protects Oxygen-Glucose-Deprived Astrocyte Cells Used to Mimic Hypoxic-Ischemic Brain Injury.

Perinatal asphyxia (PA) is a clinical condition characterized by oxygen supply suspension before, during, or immediately after birth, and it is an important risk factor for neurodevelopmental damage. Its estimated 1/1000 live births incidence in developed countries rises to 5-10-fold in developing countries. Schizophrenia, cerebral palsy, mental retardation, epilepsy, blindness, and others are among the highly disabling chronic pathologies associated with PA. However, so far, there is no effective therapy to neutralize or reduce PA-induced harm. Selective regulators of estrogen activity in tissues and selective estrogen receptor modulators like raloxifene have shown neuroprotective activity in different pathological scenarios. Their effect on PA is yet unknown. The purpose of this paper is to examine whether raloxifene showed neuroprotection in an oxygen-glucose deprivation/reoxygenation astrocyte cell model. To study this issue, T98G cells in culture were treated with a glucose-free DMEM medium and incubated at 37 °C in a hypoxia chamber with 1% O2 for 3, 6, 12, and 24 h. Cultures were supplemented with raloxifene 10, and 100 nM during both glucose and oxygen deprivation and reoxygenation periods. Raloxifene 100 nM and 10 nM improved cell survival-65.34% and 70.56%, respectively, compared with the control cell groups. Mitochondrial membrane potential was preserved by 58.9% 10 nM raloxifene and 81.57% 100 nM raloxifene cotreatment. Raloxifene co-treatment reduced superoxide production by 72.72% and peroxide production by 57%. Mitochondrial mass was preserved by 47.4%, 75.5%, and 89% in T98G cells exposed to 6-h oxygen-glucose deprivation followed by 3, 6, and 9 h of reoxygenation, respectively. Therefore, raloxifene improved cell survival and mitochondrial membrane potential and reduced lipid peroxidation and reactive oxygen species (ROS) production, suggesting a direct effect on mitochondria. In this study, raloxifene protected oxygen-glucose-deprived astrocyte cells, used to mimic hypoxic-ischemic brain injury. Two examiners performed the qualitative assessment in a double-blind fashion.

Folic acid ameliorates high glucose–induced neurotoxicity in human forebrain organoids: Insights from proteomics

AbstractPregestational diabetes (PGDM) has been associated with an elevated risk of congenital abnormalities, particularly those affecting the nervous system. The efficacy of folic acid (FA) supplementation in reducing the incidence of neurodevelopmental damage caused by PGDM has been well documented. However, the exact mechanism is unclear. Here, a human forebrain organoid model, which replicates the three‐dimensional structure of the early fetal neural tissue, was employed to study the neuroprotective effects of FA in PGDM. In this study, the forebrain organoids were cultured at high glucose (HG) concentrations from Days 20 to 40 with or without FA. Immunostaining revealed that the supplementation of FA significantly decreased HG‐induced neuron apoptosis. The proteomics examination suggested HG caused an increase in glial fibrillary acidic protein expression, a marker of astrocytes, leading to the upregulation of metallothionein expression and perturbation of mineral absorption, whereas FA reversed this effect. Proteomics analysis further showed that FA reduced HG‐induced cell migration. Moreover, Western blot analysis verified that FA mitigated HG‐induced apoptosis and cell migration via AMPK/FOXO pathway. Overall, current findings indicate that FA, as a functional food ingredient, has a protective effect on HG‐induced abnormal fetal neurodevelopment.

Research advances on CaMKs-mediated neurodevelopmental injury.

Calcium/calmodulin-dependent protein kinases (CaMKs) are important proteins in the calcium signaling cascade response pathway, which can broadly regulate biological functions in vivo. Multifunctional CaMKs play key roles in neural development, including neuronal circuit building, synaptic plasticity establishment, and neurotrophic factor secretion. Currently, four familial proteins, calcium/calmodulin-dependent protein kinase I (CaMKI), calcium/calmodulin-dependent protein kinase II (CaMKII), eukaryotic elongation factor 2 kinase (eEF2K, popularly known as CaMKIII) and calcium/calmodulin-dependent protein kinase IV (CaMKIV), are thought to have been the most extensively studied during neurodevelopment. Although their spatial structures are extremely similar, as well as the initial starting point of activation, both require the activation of calcium and calmodulin (CaM) complexes to be involved in the process, and the phosphorylation sites and modes of each member are different. Furthermore, due to the high structural similarity of CaMKs, their members may play synergistic roles in the regulation of neural development, but different CaMKs also have their own means of regulating neural development. In this review, we first describe the visualized protein structural forms of CaMKI, CaMKII, eEF2K and CaMKIV, and then describe the functions of each kinase in neurodevelopment. After that, we focus on four main mechanisms of neurodevelopmental damage caused by CaMKs: CaMKI/ERK/CREB pathway inhibition leading to dendritic spine structural damage; Ca2+/CaM/CaMKII through induction of mitochondrial kinetic disorders leading to neurodevelopmental damage; CaMKIII/eEF2 hyperphosphorylation affects the establishment of synaptic plasticity; and CaMKIV/JNK/NF-κB through induction of an inflammatory response leading to neurodevelopmental damage. In conclusion, we briefly discuss the pathophysiological significance of aberrant CaMK family expression in neurodevelopmental disorders, as well as the protective effects of conventional CaMKII and CaMKIII antagonists against neurodevelopmental injury.

Melatonin promotes cell cycle progression of neural stem cells subjected to manganese via Nurr1.

Excessive exposure to manganese (Mn) through drinking water and food during pregnancy significantly heightens the likelihood of neurodevelopmental damage in offspring. Multiple studies have indicated that melatonin (Mel) may help to relieve neurodevelopmental disorders caused by Mn, but potential mechanisms underlying this effect require further exploration. Here, we utilized primary neural stem cells (NSCs) as a model to elucidate the molecular mechanism underlying the protective function of Mel on Mn-induced cell proliferation dysfunction and cycle arrest. Our results showed that Mn disrupted the cell cycle in NSCs by suppressing positive regulatory proteins (CDK2, Cyclin A, Cyclin D1, and E2F1) and enhancing negative ones (p27KIP1 and p57KIP2), leading to cell proliferation dysfunction. Mel inhibited the Mn-dependent changes to these proteins and the cell cycle through nuclear receptor-related protein 1 (Nurr1), thus alleviating the proliferation dysfunction. Knockdown of Nurr1 using lentivirus-expressed shRNA in NSCs resulted in a diminished protective effect of Mel. We concluded that Mel mitigated Mn-induced proliferation dysfunction and cycle arrest in NSCs through Nurr1.

Modulation of vagal activity may help reduce neurodevelopmental damage in the offspring of mothers with pre-eclampsia.

Maternal Immune Activation (MIA) has been linked to the pathogenesis of pre-eclampsia and adverse neurodevelopmental outcomes in the offspring, such as cognitive deficits, behavioral abnormalities, and mental disorders. Pre-eclampsia is associated with an activation of the immune system characterized by persistently elevated levels of proinflammatory cytokines, as well as a decrease in immunoregulatory factors. The Cholinergic Anti-inflammatory Pathway (CAP) may play a relevant role in regulating the maternal inflammatory response during pre-eclampsia and protecting the developing fetus from inflammation-induced damage. Dysregulation in the CAP has been associated with the clinical evolution of pre-eclampsia. Some studies suggest that therapeutic stimulation of this pathway may improve maternal and fetal outcomes in preclinical models of pre-eclampsia. Modulation of vagal activity influences the CAP, improving maternal hemodynamics, limiting the inflammatory response, and promoting the growth of new neurons, which enhances synaptic plasticity and improves fetal neurodevelopment. Therefore, we postulate that modulation of vagal activity may improve maternal and fetal outcomes in pre-eclampsia by targeting underlying immune dysregulation and promoting better fetal neurodevelopment. In this perspective, we explore the clinical and experimental evidence of electrical, pharmacological, physical, and biological stimulation mechanisms capable of inducing therapeutical CAP, which may be applied in pre-eclampsia to improve the mother's and offspring's quality of life.

Intensive phototherapy as the initial management of severe hyperbilirubinemia in neonates

Hyperbilirubinemia is one of the most common clinical phenomena found in newborns, which is about 60% of term infants and 80% of preterm infants in the first week of life. Severe hyperbilirubinemia can cause encephalopathy and permanent neurodevelopmental damage with an incidence that varies between 4% - 60.3% and mortality rate of 13% to 56.8% worldwide. Phototherapy and exchange transfusion are therapeutic modalities for infants with severe hyperbilirubinemia. Intensive phototherapy has fewer side effects and can reduce the need for exchange transfusion. This treatment is rarely needed if intensive phototherapy is effective, current guidelines for the management of hyperbilirubinemia focus on the use of intensive phototherapy as initial treatment. This literature review aims to discuss intensive phototherapy as the initial management of severe hyperbilirubinemia in neonates.

Pathologic examination of the placenta and its benefits in treatment plan or follow-up of patients: a cross-sectional study

BackgroundThe placental examination provides important information about the effect of maternal abnormalities on the placenta or the cause of preterm delivery, fetal growth restriction, or fetal neurodevelopmental damage. In this study, the frequency of placental pathologies of patients in a tertiary hospital was investigated.MethodsIn this longitudinal and cross-sectional study, all removed placentas after any type of pregnancy termination referred to a pathological examination, within 1 year (2019–2020). All placentas were examined macroscopically and microscopically by two pathologists.ResultsUnfortunately, because of the COVID-19 pandemic, the number of pregnant women in our hospital declined. A total of 258 placentas were examined. The type of delivery in 193 cases (79.4%) was cesarean section and 50 cases (20.6%) had a vaginal delivery. In the pathological assessment of placentas, 238 (92.2%) cases were normal and 20 cases (7.8%) were abnormal. Infarct and chorioamnionitis were the pathologies with higher frequencies (4.3% and 2.7%, respectively). Intra-uterine fetal death (p = 0.701), preeclampsia (p = 0.51) had no significant difference was seen in normal and abnormal placentas. Maternal age (p = 0.83), gestational age based on the last menstrual period (p = 0.38), and gestational age based on the first ultrasound (p = 0.78) did not show a significant relationship with any of the pathological complications categories.ConclusionsPathological examination of the placenta from all live-birth deliveries is not worthwhile, and it’s recommended to modify the guidelines as to when the placenta is submitted for pathological evaluation.

Autism Spectrum Disorder Initiation by Inflammation-Facilitated Neurotoxin Transport.

Autism spectrum disorders have been linked to genetics, gut microbiota dysbiosis (gut dysbiosis), neurotoxin exposures, maternal allergies or autoimmune diseases. Two barriers to ingested neurotoxin transport into the central nervous system of a fetus or child are the gastrointestinal wall of the mother or child and the blood-brain barrier of the fetus or child. Inflammation from gut dysbiosis or inflammation from a disease or other agent can increase the gastrointestinal wall and the blood-brain barrier permeabilities to enable neurotoxins to reach the brain of a fetus or child. Postnatal gut dysbiosis is a particular inflammation risk for autism spectrum disorders caused by neurotoxin transport into a child's brain. An extensive gut dysbiosis or another source of inflammation such as a disease or other agent in combination with neurotoxins, including aluminum, mercury, lead, arsenic, cadmium, arsenic, organophosphates, and neurotoxic bacterial toxins and fungal toxins resulting from the gut dysbiosis, can elevate neurotoxin levels in a fetal or child brain to cause neurodevelopmental damage and initiate an autism spectrum disorder. The neurotoxins aluminum and mercury are especially synergistic in causing neurodevelopmental damage. There are three plausible causational pathways for autism spectrum disorders. They include inflammation and neurotoxin loading into the fetal brain during the prenatal neurodevelopment period, inflammation and neurotoxin loading into the brain during the postnatal neurodevelopment period or a two-stage loading of neurotoxins into the brain during both the prenatal and postnatal neurodevelopment periods.

Regulation of neurogenesis and cerebral angiogenesis by cell protein proteolysis products

Brain development is a unique process characterized by mechanisms defined as neuroplasticity (synaptogenesis, synapse elimination, neurogenesis, and cerebral angiogenesis). Numerous neurodevelopmental disorders brain damage, and aging are manifested by neurological deficits that are caused by aberrant neuroplasticity. The presence of stem and progenitor cells in neurogenic niches of the brain is responsible for the formation of new neurons capable of integrating into preexisting synaptic assemblies. The determining factors for the cells within the neurogenic niche are the activity of the vascular scaffold and the availability of active regulatory molecules that establish the optimal microenvironment. It has been found that regulated intramembrane proteolysis plays an important role in the control of neurogenesis in brain neurogenic niches. Molecules generated by the activity of specific proteases can stimulate or suppress the activity of neural stem and progenitor cells, their proliferation and differentiation, migration and integration of newly formed neurons into synaptic networks. Local neoangiogenesis supports the processes of neurogenesis in neurogenic niches, which is guaranteed by the multivalent action of peptides formed from transmembrane proteins. Identification of new molecules regulating the neuroplasticity (neurogenesis and angiogenesis). i. e. enzymes, substrates, and products of intramembrane proteolysis, will ensure the development of protocols for detecting the neuroplasticity markers and targets for efficient pharmacological modulation.

Role of PKA/CREB/BDNF signaling in PM2.5-induced neurodevelopmental damage to the hippocampal neurons of rats

Exposure to fine particulate matter (PM2.5) is implicated in neurodevelopmental disorders including cognitive decline, attention-deficit/hyperactivity disorder, and autism spectrum disorder. However, the specific molecular mechanisms by which PM2.5 impacts neurodevelopment are poorly understood. Accordingly, in the present study, the role of protein kinase A (PKA)/cAMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling in PM2.5-induced neurodevelopmental damage was investigated using primary cultured hippocampal neurons.When hippocampal neurons cultured for 3 days in vitro (DIV3) were exposed to PM2.5 for 24 h and 96 h, neuronal viability decreased by 18.8% and 32.7% respectively, percentage of TUNEL-positive neurons increased by 78.5% and 64.0% separately, caspase-9 expression increased, lower postsynaptic density and shorter active zones were observed by transmission electron microscopy, expression of synapse-related proteins including postsynaptic density-95 (PSD95), growth associated protein-43 (GAP43), and synaptophysin (SYP) were decreased, and the phosphorylation levels of PKA, CREB, and BDNF expression also decreased. However, the PM2.5-induced neuronal damage could be ameliorated or aggravated to varying degrees by up- or down-regulation of the PKA/CREB/BDNF signaling pathway, respectively.Our results indicate that PM2.5 exposure exerts neurodevelopmental toxicity as indicated by lower viability, apoptosis, and synaptic damage in primary cultured hippocampal neurons, and that the PKA/CREB/BDNF pathways could play a vital role in PM2.5-mediated neurodevelopmental toxicity.

CYP11A1 Upregulation Leads to Trophoblast Oxidative Stress and Fetal Neurodevelopmental Toxicity That can be Rescued by Vitamin D.

During normal pregnancy, the placental trophoblast secretes a variety of steroid hormones and participates in the regulation of maternal physiological functions and fetal development. The CYP11A1 gene encodes the cholesterol side-chain cleavage enzyme P450scc, which catalyzes the production of pregnenolone from cholesterol, which is the first step in the synthesis of all steroid hormones. Under the influence of genetic susceptibility and certain environmental factors, such as drugs and toxins, the expression of CYP11A1 can be upregulated, thereby affecting steroid metabolism and physiological functions in trophoblast cells, as well as fetal development. Here, we demonstrate that upregulation of CYP11A1 in the BeWo cell line triggers excessive mitochondrial oxidative stress, leads to mitochondrial damage and interleukin-6 release, and contributes to the inhibition of proliferation and DNA damage in neuronal stem cells (NSCs). Furthermore, oxidative stress and inflammation can be ameliorated by vitamin D3 in a dose-dependent manner, thereby facilitating the rescue of NSC impairment. Our findings reveal the underlying mechanism in which upregulation of CYP11A1 is detrimental to the physiological function of trophoblasts and demonstrate the beneficial effects of vitamin D supplementation in preventing placental and neurodevelopmental damage associated with CYP11A1 upregulation during pregnancy.

Rabbit neurospheres as a novel in vitro tool for studying neurodevelopmental effects induced by intrauterine growth restriction.

The aim of this study was to develop a rabbit neurosphere culture to characterize differences in basic processes of neurogenesis induced by intrauterine growth restriction (IUGR). A novel in vitro neurosphere culture has been established using fresh or frozen neural progenitor cells from newborn (PND0) rabbit brains. After surgical IUGR induction in pregnant rabbits and cesarean section 5 days later, neural progenitor cells from both control and IUGR groups were isolated and directly cultured or frozen at −80°C. These neural progenitor cells spontaneously formed neurospheres after 7 days in culture. The ability of control and IUGR neurospheres to migrate, proliferate, differentiate to neurons, astrocytes, or oligodendrocytes was compared and the possibility to modulate their responses was tested by exposure to several positive and negative controls. Neurospheres obtained from IUGR brains have a significant impairment in oligodendrocyte differentiation, whereas no significant differences are observed in other basic processes of neurogenesis. This impairment can be reverted by in vitro exposure of IUGR neurospheres to thyroid hormone, which is known to play an essential role in white matter maturation in vivo. Our new rabbit neurosphere model and the results of this study open the possibility to test several substances in vitro as neuroprotective candidates against IUGR induced neurodevelopmental damage while decreasing the number of animals and resources and allowing a more mechanistic approach at a cellular functional level.

Effects of in-hospital breast feeding on brain function development in preterm infants in China: study protocol for a prospective longitudinal cohort study

IntroductionDue to immature brain development, preterm infants are more likely to develop neurological developmental defects compared with full-term infants. Most preterm infants without neurodevelopmental damage can eventually reach the same...

Neuro Developmental Consequences of Neonatal Hypoglycemia.

Neonatal hypoglycemia (HG) can cause neurologic damage, epilepsy, mental retardation, behavioral and personality disorders and death. The longest the HG lasts and the greatest the glucose nadir the consequences are more pronounced. Comorbidities are rather important in development of neurological damage. Hypoxemia and ischemia can cause permanent brain damage. Small for gestational age (SGA), large for gestational age (LGA), intrauterine growth restriction, gestational age bellow the 37th week, low Apgar score, sepsis, children whose mothers have toxemia, diabetes or chorioamnionitis are all newborns with increased HG risk. Comparing 34 patients with NH and 34 children without NH with similar GA, BW, BL, the Apgar score, we found statistically significant differences in motor and mental development using the Griffith scale. Children with neonatal HG fared significantly worse than those without neonatal HG. Therefore, CBG measurements and early recognition of neonatal HG is of significant importance in preventing motor and mental damage in children. A larger and well-balanced cohort of patients followed for a longer period is also necessary to clarify and discern in detail the importance of neonatal HG and other perinatal factors in neurodevelopmental damage.

Prenatal alcohol exposure and maternal glutamine supplementation alter the mTOR signaling pathway in ovine fetal cerebellum and skeletal muscle.

Prenatal alcohol exposure causes fetal neurodevelopmental damage and growth restriction. Among regions of the brain, the cerebellum is the most vulnerable to developmental alcohol exposure. Despite vast research in the field, there is still a need to identify specific mechanisms by which alcohol causes this damage in order to design effective therapeutic interventions. The mammalian target of rapamycin (mTOR) is known to be associated with axonal regeneration, dendritic arborization, synaptic plasticity, cellular growth, autophagy, and many other cellular processes. Glutamine and glutamine-related amino acids play a key role in fetal development and are known to alter the mTOR pathway; recent research has shown that disturbances in their bioavailability and signaling pathways may mediate adverse effects of prenatal alcohol exposure. This study investigated the role of the mTOR signaling pathway in the fetal cerebellum and skeletal muscle after third trimester-equivalent prenatal alcohol exposure and maternal l-glutamine (GLN) supplementation using a sheep model. Fetal cerebella and skeletal muscles were sampled for Western blot analysis of mTOR and its downstream targets S6 kinase and eukaryotic initiation factor 4E-bindin protein (4E-BP1). The expression of cerebellar phosphorylated mTOR relative to the total mTOR was elevated in the alcohol+GLN group compared to the saline and GLN groups. Alcohol exposure increased the ratio of phosphorylated S6K to total S6K in fetal cerebellum, and no significant effect of GLN supplementation was observed. On contrary, maternal GLN supplementation reduced the activation of mTOR and S6K in fetal skeletal muscle, possibly to make GLN and other amino acids available for use by other organs. These findings suggest prenatal alcohol exposure and maternal GLN supplementation during the third trimester-equivalent alter the mTOR signaling cascade, which plays a possible key role in alcohol-induced developmental damage.

Effects of dexmedetomidine on the expression of inflammatory factors in children with congenital heart disease undergoing intraoperative cardiopulmonary bypass: a randomized controlled trial.

ImportanceDexmedetomidine inhibits the inflammatory response associated with cardiopulmonary bypass (CPB) and protects neural function. However, the mechanism of dexmedetomidine’s anti‐inflammatory pathway is unclear.ObjectiveTo investigate the effect of dexmedetomidine on the cognitive level and expression of inflammatory factors in children with congenital heart disease undergoing intraoperative CPB.MethodsNinety children with congenital heart disease were recruited and randomly divided into 3 groups of 30 children in each. In Group 1, a 1.0 µg·kg‐1·h‐1 intravenous bolus of dexmedetomidine was administered 10 minutes after induction of anesthesia, followed by a 0.2 µg·kg‐1·h‐1 infusion until the surgical incision. In Group 2, a 0.5 µg/kg intravenous bolus of dexmedetomidine was administered 10 minutes after induction of anesthesia, followed by a 0.1 µg·kg‐1·h‐1 infusion until the surgical incision. The control group was given physiological saline using the same method as in Groups 1 and 2. The serum levels of nuclear factor‐kappa B (NF‐κB), S‐100β protein, neuron‐specific enolase (NSE), tumor necrosis factor‐α (TNF‐α), and interleukin‐6 (IL‐6) were measured before the surgery (T1), at the end of CPB (T2), 2 hours after CPB (T3), 6 hours after CPB (T4), and 24 hours after CPB (T5). The Wechsler Intelligence Scale for children (WISC) was measured before the operation and at 3, 6, and 12 months after the operation to evaluate the neurodevelopmental state of the children.ResultsThe levels of the NF‐κB, S‐100β protein, NSE, TNF‐α, IL‐6 were significantly higher at T2, T3, or T4 than before the surgery (T1) in the control group or the dexmedetomidine groups. However, the increases of NF‐κB, TNF‐α, IL‐6, S‐100β and NSE levels were significantly smaller in the dexmedetomidine groups than those in the control group (P < 0.017). The WISC scores were similar among the three groups before or after the operation.InterpretationThe increases in NF‐κB, TNF‐α, and IL‐6 levels indicated aggravation of the inflammatory reaction and the increase S‐100β protein and NSE levels indicated that the nervous system was damaged. Administration of dexmedetomidine to children with congenital heart disease undergoing intraoperative CPB can inhibit the inflammatory response and may ameliorate the neurodevelopmental damage caused by CPB.

Exogenous GM1 Ganglioside Attenuates Ketamine-Induced Neurocognitive Impairment in the Developing Rat Brain

A prolonged exposure to ketamine triggers significant neurodegeneration and long-term neurocognitive deficits in the developing brain. Monosialotetrahexosylganglioside (GM1) can limit the neuronal damage from necrosis and apoptosis in neurodegenerative conditions. We aimed to assess whether GM1 can prevent ketamine-induced developmental neurotoxicity. Postnatal day 7 (P7) rat pups received 5 doses of intraperitoneal ketamine (20 mg/kg per dose) at 90-minute intervals for 6 hours. Cognitive functions, determined by using Morris water maze (MWM) including escape latency (at P32-36) and platform crossing (at P37), were compared among the ketamine-exposed pups treated with or without exogenous GM1 (30 mg/kg; n = 12/group). The effect of GM1 on apoptosis in hippocampus was determined by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining and activated caspase 3 measurement. The hippocampal expression of brain-derived neurotrophic factor (BDNF), along with the phosphorylation of protein kinase B (AKT) and extracellular signal-related kinases 1 and 2 (ERK1/2), was detected by western blotting (n = 6/group). Anti-BDNF antibody (2 μg per rat) administered before GM1 treatment was applied to determine the neuroprotective mechanisms of GM1. The rats receiving ketamine exposure experinced cognitive impairment in MWM test compared to the control rats, indicated by prolonged escape latency at P34 (P = .006), P35 (P = .002), and P36 (P = .005). However, in GM1-pretreated rats, ketamine exposure did not induce prolonged escape latency. The exogenous GM1 increased the platform-crossing times at P37 (3.00 ± 2.22 times vs 5.40 ± 1.53 times, mean ± standard deviation; P = .041) and reduced the hippocampal TUNEL-positive cells and cleaved-caspase 3 expression in ketamine-exposed young rats. Ketamine decreased BDNF expression and phosphorylation of AKT and ERK in the hippocampus, whereas exogenous GM1 blocked these ketamine-caused effects. However, for the ketamine-exposed rat pups receiving exogenous GM1, compared to immunoglobulin Y (IgY) isotype control, the BDNF-neutralizing antibody treatment counteracted the exogenous GM1-induced improvement of the escape latency at P36 (41.32 ± 12.37 seconds vs 25.14 ± 8.97 seconds, mean ± standard deviation; P = .036), platform-crossing times at P37 (2.16 ± 1.12 times vs 3.92 ± 1.97 times, mean ± standard deviation; P < .036), apoptotic activity, as well as AKT and ERK1/2 phosphorylation in the hippocampus of ketamine-challenged young rats. Our data suggest that the exogenous GM1 acts on BDNF signaling pathway to ameliorate the cognitive impairment and hippocampal apoptosis induced by ketamine in young rats. Our study may indicate a potential use of GM1 in preventing the cognitive deficits induced by ketamine in the young per se.

Studying Cortical Plasticity in Ophthalmic and Neurological Disorders: From Stimulus-Driven to Cortical Circuitry Modeling Approaches.

Unsolved questions in computational visual neuroscience research are whether and how neurons and their connecting cortical networks can adapt when normal vision is compromised by a neurodevelopmental disorder or damage to the visual system. This question on neuroplasticity is particularly relevant in the context of rehabilitation therapies that attempt to overcome limitations or damage, through either perceptual training or retinal and cortical implants. Studies on cortical neuroplasticity have generally made the assumption that neuronal population properties and the resulting visual field maps are stable in healthy observers. Consequently, differences in the estimates of these properties between patients and healthy observers have been taken as a straightforward indication for neuroplasticity. However, recent studies imply that the modeled neuronal properties and the cortical visual maps vary substantially within healthy participants, e.g., in response to specific stimuli or under the influence of cognitive factors such as attention. Although notable advances have been made to improve the reliability of stimulus-driven approaches, the reliance on the visual input remains a challenge for the interpretability of the obtained results. Therefore, we argue that there is an important role in the study of cortical neuroplasticity for approaches that assess intracortical signal processing and circuitry models that can link visual cortex anatomy, function, and dynamics.

Exposure of dams to fluoxetine during lactation disturbs maternal behavior but had no effect on the offspring behavior

Fluoxetine is one of the most commonly prescribed drugs for treatment of depression during pregnancy as well as postpartum. Nevertheless, fluoxetine can cross the placental barrier and/or be secreted through breastmilk and questions remain unanswered regarding safety of the unborn and/or nursing infant. Passive administration of antidepressants to infants can cause neurological developmental delay and/or dysfunction. To date, there are limited studies on neurobehavioral effects due to passive administration of fluoxetine in nursing animals. Thus, the aim of the present study was to evaluate the effects of fluoxetine exposure on the behavior of lactating dams and their offspring. Dams received either 1, 10 or 20 mg/kg fluoxetine via oral gavage (controls received water alone) from lactating day (LD) 1 to 21. Maternal behavioral studies were conducted from LD5 to LD7 and offspring studies were conducted from LD2 to LD60. Results showed dysfunction in maternal behavior, both in direct and indirect behavior, but there were no differences and/or deficiencies observed in offspring behavior. These data suggest that the impairment of dams maternal behavior combined with the amount of fluoxetine that the offspring received through breast milk during lactation did not alter their social behavior in infancy and/or adulthood, suggesting no neurodevelopmental damage associated with maternal use of fluoxetine. This study contributes to the field of human psychiatric diseases by further elucidating the effects of antidepressant medications on the health of mothers as well as children who were passively exposed to drug treatment.

C3aR signaling and gliosis in response to neurodevelopmental damage in the cerebellum

BackgroundConditional ablation of the Smarca5 gene in mice severely impairs the postnatal growth of the cerebellum and causes an ataxic phenotype. Comparative gene expression studies indicated that complement-related proteins were upregulated in the cerebellum of Smarca5 mutant mice. Complement proteins play critical roles within innate immune signaling pathways and, in the brain, are produced by glial cells under both normal and pathological conditions. The C3 complement protein-derived signaling peptide, C3a, has been implicated in contributing to both tissue damage and repair in conditions such as multiple sclerosis and stroke. Here, we investigated whether C3a receptor (C3aR) signaling promoted damage or repair in the developing cerebellum of Smarca5 mutant mice.MethodsBrain and cerebellum lysates from single Smarca5 conditional knockout (Smarca5 cKO) mice, C3aR1 KO mice, or double mutant mice were used for qRT-PCR and immunoblotting to assess the contribution of C3aR to the Smarca5 cKO brain pathology. Immunohistochemistry was used to characterize alterations to astroglia and phagocyte cells in the developing cerebellum of each of the genotypes.ResultsC3aR signaling was observed to limit gliosis and promote granule neuron survival during postnatal cerebellar development. In Smarca5 cKO mice, disorganized astroglia with increased GFAP expression develops concurrently with cerebellar granule neuron loss and phagocyte invasion over the first 10 days following birth. Potential ligand precursors of C3aR—VGF and C3—were found to have upregulated expression and/or altered processing during this time. Phagocytes (microglia and macrophages) in both the control and Smarca5 mutant mice were the only cells observed to express C3aR. Loss of C3aR in the Smarca5 cKO cerebellum resulted in increased numbers of apoptotic cells and early phagocyte invasion into the external granule cell layer, as well as an exacerbated disorganization of the Bergmann glia. The loss of C3aR expression also attenuated an increase in the expression of the efferocytosis-related protein, MerTK, whose transcript was upregulated ~ 2.5-fold in the Smarca5 mutant cerebellum at P10.ConclusionsThis data indicates that C3aR can play an important role in limiting astrogliosis and regulating phagocyte phenotypes following developmental cell loss in the brain.