scholarly journals Perinatal Exposure to Triclosan Results in Abnormal Brain Development and Behavior in Mice

2020 ◽  
Vol 21 (11) ◽  
pp. 4009 ◽  
Author(s):  
Dinh Nam Tran ◽  
Eui-Man Jung ◽  
Yeong-Min Yoo ◽  
Jae-Hwan Lee ◽  
Eui-Bae Jeung
Keyword(s):  
Brain Development ◽  
Spatial Learning ◽  
Cortical Neurons ◽  
Average Length ◽  
Axon Growth ◽  
Abnormal Behavior ◽  
Spatial Learning And Memory ◽  
Perinatal Exposure ◽  
Novelty Preference

Triclosan (TCS) is one of the most common endocrine-disrupting chemicals (EDCs) present in household and personal wash products. Recently, concerns have been raised about the association between abnormal behavior in children and exposure to EDC during gestation. We hypothesized that exposure to TCS during gestation could affect brain development. Cortical neurons of mice were exposed in vitro to TCS. In addition, we examined in vivo whether maternal TCS administration can affect neurobehavioral development in the offspring generation. We determined that TCS can impair dendrite and axon growth by reducing average length and numbers of axons and dendrites. Additionally, TCS inhibited the proliferation of and promoted apoptosis in neuronal progenitor cells. Detailed behavioral analyses showed impaired acquisition of spatial learning and reference memory in offspring derived from dams exposed to TCS. The TCS-treated groups also showed cognition dysfunction and impairments in sociability and social novelty preference. Furthermore, TCS-treated groups exhibited increased anxiety-like behavior, but there was no significant change in depression-like behaviors. In addition, TCS-treated groups exhibited deficits in nesting behavior. Taken together, our results indicate that perinatal exposure to TCS induces neurodevelopment disorder, resulting in abnormal social behaviors, cognitive impairment, and deficits in spatial learning and memory in offspring.

scholarly journals GABAB receptor antagonist promotes hippocampal neurogenesis and facilitates cognitive function recovery following acute cerebral ischemia in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dan Song ◽  
Yaohua Chen ◽  
Cheng Chen ◽  
Lili Chen ◽  
Oumei Cheng
Keyword(s):  
Cognitive Function ◽  
Cerebral Ischemia ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Hippocampal Neurogenesis ◽  
Morris Water Maze Test ◽  
Spatial Learning And Memory ◽  
In Vitro Experiments ◽  
Adult Mice

Abstract Purpose and background Previous studies have suggested that promoting endogenous neurogenesis has great significance for the recovery of cognitive dysfunction caused by cerebral ischemia (CI). Pharmacological inhibition of GABAB receptor can enhance neurogenesis in adult healthy and depressed mice. In the study, we intended to investigate the effects of GABAB receptor antagonists on cognitive function and hippocampal neurogenesis in mice following CI. Methods Adult mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min to induce CI and treated with CGP52432 (antagonist of GABAB receptor, CGP, 10 mg/kg intraperitoneal injection) starting 24 h after CI. The Morris water maze test was performed to test spatial learning and memory at day 28. Immunofluorescence was applied to detect neurogenesis in the DG region at day 14 and 28. In in vitro experiments, cell proliferation was detected by CCK8 and immunofluorescence, and the expression of cAMP/CREB signaling pathway-related proteins was detected by ELISA assay and Western blot. Results CGP significantly improved spatial learning and memory disorders caused by CI, and it enhanced the proliferation of neural stem cells (NSCs), the number of immature neurons, and the differentiation from newborn cells to neurons. In vitro experiments further confirmed that CGP dose-dependently enhanced the cell viability of NSCs, and immunofluorescence staining showed that CGP promoted the proliferation of NSCs. In addition, treatment with CGP increased the expression of cAMP, PKA, and pCREB in cultured NSCs. Conclusion Inhibition of GABAB receptor can effectively promote hippocampal neurogenesis and improve spatial learning and memory in adult mice following CI.

scholarly journals Milk Exosomes Cross the Blood-Brain Barrier in Murine Cerebral Cortex Endothelial Cells and Promote Dendritic Complexity in the Hippocampus and Brain Function in C57BL/6J Mice

2021 ◽  
Author(s):  
Fang Zhou ◽  
Pearl Ebea ◽  
Ezra Mutai ◽  
Sonal Sukreet ◽  
Shya Navazesh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Brain Development ◽  
Learning And Memory ◽  
Kainic Acid ◽  
Spatial Learning ◽  
Granule Cells ◽  
Spatial Learning And Memory ◽  
Adult Mice ◽  
Dendritic Complexity

Background: Human milk contains large amounts of exosomes (MEs) and their regulatory microRNA cargos, whereas infant formulas contain only trace amounts of MEs and microRNAs. Breastfeeding has been implicated in optimal brain development but experimental evidence linking ME intake with brain development is limited. Objectives: We assessed the transport of MEs across the blood-brain barrier (BBB) and ME accumulation in distinct regions of the brain in brain endothelial cells and suckling mice. We further assessed BME-dependent gene expression profiles and effects on the dendritic complexity of hippocampal granule cells and phenotypes of BME depletion in neonate, juvenile and adult mice. Methods: The transfer of MEs across the BBB was assessed by using bovine MEs labeled with FM4-64 or loaded with IRDye-labeled miR-34a in murine brain endothelial bEnd.3 cell monolayers and dual chamber systems, and in wild-type newborn pups fostered to exosome and cargo tracking (ECT) dams that express MEs endogenously labeled with a CD63-eGFP fusion protein for subsequent analysis by serial two-photon tomography and staining with anti-eGFP antibodies. Effects of MEs on gene expression and dendritic architecture of granule cells was analyzed in hippocampi from juvenile mice fed exosome and RNA-depleted (ERD) and exosome and RNA-sufficient (ERS) diets by using RNA-sequencing analysis and Golgi-Cox staining followed by integrated neuronal tracing and morphological analysis of neuronal dendrites, respectively. Spatial learning and severity of kainic acid-induced seizures were assessed in mice fed ERD and ERS diets. Results: bEnd.3 cells internalized MEs by using a saturable transport mechanism and secreted miR-34a across the basal membrane. MEs penetrated the entire brain in fostering experiments; major regions of accumulation included the hippocampus, cortex and cerebellum. Two hundred ninety-five genes were differentially expressed in hippocampi from male mice fed ERD and ERS diets; high-confidence gene networks included pathways implicated in axon guidance and calcium signaling. Only one gene was differentially expressed in females fed the experimental diets. Juvenile pups fed the ERD diet had reduced dendritic complexity of dentate granule cells in the hippocampus, scored nine-fold lower in the Barnes maze test of spatial learning and memory (P < 0.01), and the severity of seizures was 5-fold higher following kainic acid administration in adult mice fed the ERD diet compared to mice fed the ERS diet (P < 0.01). Conclusions: MEs cross the BBB and contribute toward optimal neuronal development, spatial learning and memory, and resistance to kainic acid-induced seizures in mice.

scholarly journals Nestin in immature embryonic neurons affects axon growth cone morphology and Semaphorin3a sensitivity

2019 ◽  
Vol 30 (10) ◽  
pp. 1214-1229 ◽  
Author(s):  
C. J. Bott ◽  
C. G. Johnson ◽  
C. C. Yap ◽  
N. D. Dwyer ◽  
K. A. Litwa ◽  
...  
Keyword(s):  
Growth Cone ◽  
Intermediate Filament ◽  
Cortical Neurons ◽  
Axon Growth ◽  
Neural Progenitors ◽  
Spatial Modulation ◽  
Nestin Expression ◽  
Guidance Cue ◽  
Newborn Neurons

Correct wiring in the neocortex requires that responses to an individual guidance cue vary among neurons in the same location, and within the same neuron over time. Nestin is an atypical intermediate filament expressed strongly in neural progenitors and is thus used widely as a progenitor marker. Here we show a subpopulation of embryonic cortical neurons that transiently express nestin in their axons. Nestin expression is thus not restricted to neural progenitors, but persists for 2–3 d at lower levels in newborn neurons. We found that nestin-expressing neurons have smaller growth cones, suggesting that nestin affects cytoskeletal dynamics. Nestin, unlike other intermediate filament subtypes, regulates cdk5 kinase by binding the cdk5 activator p35. Cdk5 activity is induced by the repulsive guidance cue Semaphorin3a (Sema3a), leading to axonal growth cone collapse in vitro. Therefore, we tested whether nestin-expressing neurons showed altered responses to Sema3a. We find that nestin-expressing newborn neurons are more sensitive to Sema3a in a roscovitine-sensitive manner, whereas nestin knockdown results in lowered sensitivity to Sema3a. We propose that nestin functions in immature neurons to modulate cdk5 downstream of the Sema3a response. Thus, the transient expression of nestin could allow temporal and/or spatial modulation of a neuron’s response to Sema3a, particularly during early axon guidance.

Perinatal exposure to alcohol disturbs spatial learning and glutamatergic neurotransmission in the hippocampus

2011 ◽  
Vol 26 (S2) ◽  
pp. 912-912
Author(s):  
M. Zink ◽  
T. Ferbert ◽  
S.T. Frank ◽  
P. Seufert ◽  
P.J. Gebicke-Härter ◽  
...  
Keyword(s):  
Spatial Learning ◽  
Maze Learning ◽  
Therapeutic Interventions ◽  
Perinatal Exposure ◽  
Glutamatergic Neurotransmission ◽  
Binding Assays ◽  
Plus Maze ◽  
In Situ Hybridizations

IntroductionPerinatal exposure to alcohol (PEA) induces general developmental and specific neuropsychiatric disturbances in association with disturbed synaptic plasticity and functions of the amino acid neurotransmitter glutamate.ObjectiveWe were interested in effects of ethanol during the terminal neurodevelopmental differentiation on glutamatergic neurotransmission.AimsTo establish an animal model based on vapor chamber exposure and to assess the expression of vGluT1, EAAT1 to 4, NMDA receptor (NR) subunits 1, 2A to D and NR binding with 3H-labeled MK 801.MethodsAfter delivery, female Wistar Han outbred rats (N = 4) and their pups were exposed until postnatal day 8 (P8). At the age of 5 months, the animals were behaviorally characterized. Both, at P8 and after the testing we performed in situ-hybridizations receptor binding assays.ResultsPEA-pubs showed a pronounced and highly significant retardation of body weight and length. Behavioral testing revealed no differences in locomotion and anxiety (open field and elevated plus maze) as well as T-maze-learning, but significantly impaired hippocampus-dependent spatial learning (MWM). We observed significant inductions of vGluT1, EAAT1, EAAT3, NR2A, 2B, 2C and 2D, as well as trends of increased NR1 mRNA. NR binding was found increased in hippocampus (P8) and parietal cortex (P8 and 5M).ConclusionsThe observed inductions of glial glutamate transporters validate previous in vitro data. Altered glutamatergic neurotransmission in general might be considered a molecular correlate of the learning deficit in our PEA model. This further supports the glutamatergic theory of PEA and suggests new targets for therapeutic interventions.

scholarly journals Spatial learning and memory deficits induced by prenatal glucocorticoid exposure depend on hippocampal CRHR1 and CXCL5 signaling in rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
You Zheng ◽  
Yan-Min Zhang ◽  
Zheng-Shan Tang ◽  
Jian-Kui Du ◽  
De-Wei Guo ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Spatial Learning ◽  
Memory Deficits ◽  
Morris Water Maze Test ◽  
Spatial Learning And Memory ◽  
Synapsin I ◽  
Postnatal Life ◽  
Pregnant Rats ◽  
Learning And Memory Deficits

Abstract Background Prenatal synthetic glucocorticoid (sGC) exposure increases the susceptibility to cognitive and affective disorders in postnatal life. We previously demonstrated that prenatal sGC exposure results in an increase in corticotropin-releasing hormone (CRH) receptor type 1 (CRHR1) expression in the hippocampus of rats, and CRHR1 is involved in synapse formation via regulation of C-X-C chemokine ligand 5 (CXCL5) in hippocampus. We sought to investigate that the roles of CRHR1 and CXCL5 in learning and memory impairment caused by prenatal sGC exposure. Methods Pregnant rats were administered with saline or dexamethasone (DEX) from gestational day (GD) 14 to GD21. DEX offspring at 2-day old were treated with saline and CRHR1 antagonists (antalarmin and CP154526) for 7 days. Some DEX offspring received intra-hippocampal injection of AAV9 carrying CXCL5 gene. Spatial learning and memory was assessed by Morris water maze test. Immunofluorescence analysis was applied to show synapsin I and PSD95 signals in hippocampus. Synapsin I and PSD95 protein level and CXCL5 concentration were determined by western blotting and ELISA, respectively. Organotypic hippocampal slice cultures were used to investigate the effect of DEX on CXCL5 production in vitro. Results Both male and female DEX offspring displayed impairment of spatial learning and memory in adulthood. Synapsin I and PSD95 signals and CXCL5 levels were decreased in DEX offspring. DEX offspring with antalarmin and CP154526 treatment showed improved spatial learning and memory. Antalarmin and CP154526 treatment increased synapsin I and PSD95 signals and CXCL5 concentration in hippocampus. Bilaterally hippocampal injection of AAV9 carrying CXCL5 gene improved the spatial learning and memory and increased CXCL5 concentration and synapsin I and PSD95 levels in hippocampus. DEX dose-dependently suppressed CXCL5 production in cultured hippocammpal slices, which was prevented by antalarmin treatment. Conclusion CRHR1 and CXCL5 signaling in the hippocampus are involved in spatial learning and memory deficits caused by prenatal DEX exposure. CRHR1 activation contributes to decreased CXCL5 production in hippocampus induced by prenatal DEX treatment. Our study provides a molecular basis of prenatal GC exposure programming spatial learning and memory.

scholarly journals Nestin in immature embryonic neurons regulates axon growth cone morphology and Semaphorin3a sensitivity

2017 ◽  
Author(s):  
C.J. Bott ◽  
C. G. Johnson ◽  
C.C. Yap ◽  
N.D. Dwyer ◽  
K.A. Litwa ◽  
...  
Keyword(s):  
Growth Cone ◽  
Intermediate Filament ◽  
Cortical Neurons ◽  
Axon Growth ◽  
Neural Progenitors ◽  
Nestin Expression ◽  
Guidance Cue ◽  
Cytoskeletal Dynamics ◽  
Newborn Neurons

AbstractCorrect wiring in the neocortex requires that responses to an individual guidance cue vary among neurons in the same location, and within the same neuron over time. Nestin is an atypical intermediate filament expressed highly in neural progenitors and is thus used widely as a progenitor marker. Here we show a subpopulation of embryonic cortical neurons which transiently express nestin in their axons. Nestin expression is thus not restricted to neural progenitors but persists at lower levels in some newborn neurons for 2-3 days. We found that nestin-expressing neurons have smaller growth cones, suggesting that nestin affects cytoskeletal dynamics. Nestin, unlike other intermediate filament subtypes, regulates cdk5 kinase. Cdk5 activity is induced by the repulsive guidance cue Sema3a leading to growth cone collapse in vitro. Therefore, we tested whether nestin-expressing neurons showed altered responses to Sema3a. We find that nestin-expressing newborn neurons are more sensitive to Sema3a in a roscovitine-sensitive manner, whereas nestin knockdown results in lowered sensitivity to Sema3a. We propose that nestin functions in immature neurons to modulate cdk5 and thereby the Sema3a response. Thus, the transient expression of nestin could allow for temporal modulation of a neuron's response to Sema3a particularly during early axon guidance decisions.

scholarly journals Human Cerebral Organoid Implantation Alleviated the Neurological Deficits of Traumatic Brain Injury in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Zhongyuan Bao ◽  
Kaiheng Fang ◽  
Zong Miao ◽  
Chong Li ◽  
Chaojuan Yang ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Cortical Neurons ◽  
Embryonic Stem ◽  
High Rate ◽  
Neurological Deficits ◽  
Spatial Learning And Memory ◽  
Electromyographic Activity

Traumatic brain injury (TBI) causes a high rate of mortality and disability, and its treatment is still limited. Loss of neurons in damaged area is hardly rescued by relative molecular therapies. Based on its disease characteristics, we transplanted human embryonic stem cell- (hESC-) derived cerebral organoids in the brain lesions of controlled cortical impact- (CCI-) modeled severe combined immunodeficient (SCID) mice. Grafted organoids survived and differentiated in CCI-induced lesion pools in mouse cortical tissue. Implanted cerebral organoids differentiated into various types of neuronal cells, extended long projections, and showed spontaneous action, as indicated by electromyographic activity in the grafts. Induced vascularization and reduced glial scar were also found after organoid implantation, suggesting grafting could improve local situation and promote neural repair. More importantly, the CCI mice’s spatial learning and memory improved after organoid grafting. These findings suggest that cerebral organoid implanted in lesion sites differentiates into cortical neurons, forms long projections, and reverses deficits in spatial learning and memory, a potential therapeutic avenue for TBI.

scholarly journals Perinatal Exposure to Low-Dose Bisphenol A Impairs Spatial Learning and Memory in Male Rats

2013 ◽  
Vol 123 (2) ◽  
pp. 132-139 ◽  
Author(s):  
Rika Kuwahara ◽  
Shinichiro Kawaguchi ◽  
Yumi Kohara ◽  
Haiming Cui ◽  
Kimihiro Yamashita
Keyword(s):  
Bisphenol A ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Low Dose ◽  
Male Rats ◽  
Spatial Learning And Memory ◽  
Perinatal Exposure

scholarly journals The ubiquitylome of developing cortical neurons

2020 ◽  
Author(s):  
Shalini Menon ◽  
Dennis Goldfarb ◽  
Emily M. Cousins ◽  
M. Ben Major ◽  
Stephanie L. Gupton
Keyword(s):  
Axon Guidance ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Cortical Neurons ◽  
Spatial Learning And Memory ◽  
Form And Function ◽  
Guidance Cue ◽  
Morphological Responses ◽  
And Function

AbstractTRIM9 and TRIM67 are neuronally-enriched E3 ubiquitin. Both genes are required for neuronal morphological responses to the axon guidance cue netrin-1. For example, our previously published work demonstrated that the actin polymerase VASP and the netrin receptor DCC exhibit TRIM9 dependent ubiquitylation that is lost upon netrin stimulation. Deletion of either gene in the mouse results in subtle neuroanatomical anomalies yet overt deficits in spatial learning and memory. Despite their role in neuronal form and function, the identity of few TRIM9 or TRIM67 substrates are known. Here we performed ubiquitin remnant profiling approach in cultured wildtype and knockout murine embryonic cortical neurons to identify ubiquitylated peptides and proteins, with the ultimate goal of identifying substrates of TRIM9 and TRIM67 that exhibited reduced ubiquitylation in the absence of the ligase. This work reveals the ubiquitylome of developing cortical neurons.

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