Neurobehavioral Changes Research Articles

Embryonic Exposure to Thiamethoxam Reduces Survival and Alters Neurobehavior of Fathead Minnows.

Thiamethoxam is a commonly used neonicotinoid insecticide that acts as a nicotinic acetylcholine receptor (nAChR) agonist. Although vertebrates are less sensitive to neonicotinoid insecticides than invertebrates, some neonicotinoids have been shown to cause neurobehavioral changes in larval fishes. In the present study, we examine the neurobehavioral toxicity of acute and chronic exposure to environmentally relevant concentrations of thiamethoxam in fathead minnows at two different life stages. Whereas acute exposure of embryos to thiamethoxam does not appear to stimulate spontaneous contractions within 1 min, chronic exposure of embryos to 1.57 µg or more thiamethoxam/L caused increased mortality as well as a subtle increase in spontaneous contraction frequency (SCF), which was negatively correlated with early hatching success. Chronic exposure of embryos to 155 µg thiamethoxam/L impaired predator escape response, and chronic exposure to 0.02-14.61 µg thiamethoxam/L impaired foraging efficiency of some fish. Fathead minnows exposed to thiamethoxam beginning post hatch did not experience changes to measured health or neurobehavioral indicators. Taken together, our findings indicate that embryonic life stages are more sensitive to thiamethoxam exposure than later larval life stages. Because early exposure to thiamethoxam can cause deficits in predatory escape behaviors and may impair foraging success, further study of the potential direct and nondirect impacts of thiamethoxam on wild fish populations is warranted.Environ Toxicol Chem 2022;41:1276-1285. © 2022 SETAC.

Neurobehavioral Differences of Valproate and Risperidone on MK-801 Inducing Acute Hyperlocomotion in Mice.

Objective The glutamate system plays a major role in the development of neuropsychiatric disorders such as addiction, epilepsy, dementia, and psychosis. MK-801 (dizocilpine), an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, could increase locomotor activity and stereotyped neurobehaviors mimicking schizophrenic-like features in the mouse model. The study would explore the neuropharmacological differences of risperidone and valproic acid on the MK-801-induced neurobehavioral changes. Methods The subjects were male C57BL/6J mice obtained from the National Laboratory Animal Center. Drug effects were assessed using the open field with a video-tracking system and gaiting tests. After habitation, risperidone (0, 0.1 mg/kg) or valproic acid (0, 200 mg/kg) was injected and ran locomotion for 30 mins. Sequentially, mice were followed by intraperitoneal injection (i.p.) with MK-801 (0, 0.2 mg/kg) and ran locomotion for 60 mins. Gaiting behaviors such as step angles, stride lengths, and stance widths were measured following the study drugs. Results The results showed that risperidone and valproic acid alone could not alter the locomotor activities. Following the MK-801 injection, the travelled distance and speed in the entire open field dramatically increased. The dose 0.1 mg/kg of risperidone could totally inhibit the MK-801-induced hyperlocomotion compared with that of the saline-injected group (p < 0.001). The valproic acid (200 mg/kg) partially suppressed the hyperlocomotion which is induced by MK801. Conclusion The more dominant effect of risperidone to rescue MK-801 induced hyperlocomotion compared with that of valproic acid. The partial suppression of valproic acid may imply the psychopharmacological evidence as adjuvant effect to treat psychotic patients through tuning glutamatergic neurotransmission.

Noninvasive Electrophysiology: Emerging Prospects in Aquatic Neurotoxicity Testing.

The significance of neurotoxicological risks associated with anthropogenic pollution is gaining increasing recognition worldwide. In this regard, perturbations in behavioral traits upon exposure to environmentally relevant concentrations of neurotoxic and neuro-modulating contaminants have been linked to diminished ecological fitness of many aquatic species. Despite an increasing interest in behavioral testing in aquatic ecotoxicology there is, however, a notable gap in understanding of the neurophysiological foundations responsible for the altered behavioral phenotypes. One of the canonical approaches to explain the mechanisms of neuro-behavioral changes is functional analysis of neuronal transmission. In aquatic animals it requires, however, invasive, complex, and time-consuming electrophysiology techniques. In this perspective, we highlight emerging prospects of noninvasive, in situ electrophysiology based on multielectrode arrays (MEAs). This technology has only recently been pioneered for the detection and analysis of transient electrical signals in the central nervous system of small model organisms such as zebrafish. The analysis resembles electroencephalography (EEG) applications and provides an appealing strategy for mechanistic explorative studies as well as routine neurotoxicity risk assessment. We outline the prospective future applications and existing challenges of this emerging analytical strategy that is poised to bring new vistas for aquatic ecotoxicology such as greater mechanistic understanding of eco-neurotoxicity and thus more robust risk assessment protocols.

New evidence for neurobehavioral toxicity of deltamethrin at environmentally relevant levels in zebrafish

Deltamethrin, a widely used type II pyrethroid insecticide, was reported with neurotoxicity to aquatic organisms, such as fish. However, the effects and potential mechanisms on the central nervous system remain largely unknown, especially under environmental concentrations. Therefore, we exposed adult female zebrafish to environmentally relevant levels of deltamethrin (30, 100, and 333 ng/L) for 21 days to assess neurobehavioral changes related to the central nervous system and explore the modes of action. Behavioral assays revealed significant increases in the swimming speeds, residence time near other fish and the shoaling cohesion in exposed fish. Transcriptomic results enriched the disrupted neural functions involving the glutamatergic and dopaminergic synapses in the brain. The qRT-PCR confirmed the upregulation of the factors for promoting the glutamate release. The measurement of neurotransmitters showed significantly increased content of the excitatory neurotransmitter glutamate in the brain. Taken together, deltamethrin exposure increased the glutamate level and promoted the release of such an excitatory neurotransmitter between the glutamatergic synapses in the brain, which eventually led to hyperactivity of social behaviors in adult zebrafish.

SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies.

In this review, we discuss the functions and main effects on pregnancy outcomes of three agents that have the ability to induce epigenetic modifications: valproic acid (VPA), a well-known teratogen that is a histone deacetylase inhibitor; S-adenosylmethionine (SAMe), the most effective methyl donor; and choline, an important micronutrient involved in the one methyl group cycle and in the synthesis of SAMe. Our aim was to describe the possible effects of these compounds when administered during pregnancy on the developing embryo and fetus or, if administered postnatally, their effects on the developing child. These substances are able to modify gene expression and possibly alleviate neurobehavioral changes in disturbances that have epigenetic origins, such as autism spectrum disorder (ASD), depression, Rett syndrome, and fetal alcohol spectrum disorder (FASD). Valproic acid and SAMe are antagonistic epigenetic modulators whether administered in utero or postnatally. However, VPA is a major human teratogen and, whenever possible, should not be used by pregnant women. Most currently relevant data come from experimental animal studies that aimed to explore the possibility of using these substances as epigenetic modifiers and possible therapeutic agents. In experimental animals, each of these substances was able to alleviate the severity of several well-known diseases by inducing changes in the expression of affected genes or by other yet unknown mechanisms. We believe that additional studies are needed to further explore the possibility of using these substances, and similar compounds, for the treatment of ”epigenetic human diseases”.

Protective effects of L-arginine on cognitive deficits and biochemical parameters in an experimental model of type-2 diabetes mellitus induced Alzheimer's disease in rats.

Alzheimer's disease (AD) has been closely linked to type 2 diabetes mellitus (T2DM) and insulin resistance plays a key role in the onset and development of AD. It has also been reported that NO donors play an important role in diabetes and have neuroprotective activity. The present study evaluated the effects NOS substrate, L-arginine and NOS-blocker, NG-nitro-L-arginine methyl ester (L-NAME) on cognitive functions, brain amyloid β levels and other associated biochemical markers in diabetes (T2DM)-induced AD in rats. T2DM was induced by a combination of high fat diet (HFD) and streptozotocin (STZ) (35 mg/kg, i.p.). Pretreatment with L-arginine (100 mg/kg/day) improved diabetes related biochemical parameters viz. plasma glucose, triglycerides and cholesterol. In addition, L-arginine also improved insulin levels and glucose tolerance. On the other hand, NO synthase inhibitor, L-NAME (10 mg/kg), did not have much influence on these parameters. Further, L-arginine treatment showed ameliorative effects on cognitive deficits seen in the Morris water maze (MWM) test when compared to the vehicle (saline) treated group and similar results were observed in the passive avoidance test. These neurobehavioural changes were associated with predictable modulations in Aβ levels in hippocampus and cortex in HFD + STZ + saline group, which were attenuated in the L-arginine, but not in the L-NAME-treated group. Our results indicate that L-arginine could be a considered a potential therapeutic strategy to attenuate the diabetes induced cognitive deficits in AD.

Knockdown of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 protects against intracerebral hemorrhage through microRNA-146a-mediated inhibition of inflammation and oxidative stress

ABSTRACT Studies have demonstrated that long noncoding RNAs (lncRNAs) are important regulators of intracerebral hemorrhage (ICH) and participants in ICH pathogenesis. We designed this study to probe the potential functions and mechanisms of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in ICH. The ICH model was established and the rats were treated with MALAT1-shRNA or MALAT1-shRNA+miR-146a inhibitor 1 h after ICH induction. A dual-luciferase reporter assay was employed to examine the relationship between MALAT1 and miR-146a. In addition, rat neurobehavioral changes, brain water content, and neuronal apoptosis were measured in this study. Furthermore, the pro‑inflammatory markers tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β were determined by enzyme-linked immunosorbent assays (ELISAs), while the oxidative stress factors, including malondialdehyde (MDA) and superoxide dismutase (SOD), were also evaluated. Lastly, a Western blot assay was employed to examine the protein levels of phosphorylated (p)-p65 and p65. First, we found that MALAT1 was expressed at higher levels in ICH rats. miR-146a is a target gene of MALAT1 and is downregulated in ICH rats. Downregulation of MALAT1 inhibited the neurological scores, brain water content, and neuronal apoptosis, reduced the levels of pro-inflammatory cytokines, and prevented oxidative stress in ICH rats. In addition, the protein level of p-p65 and the ratio of p-p65/p65 were decreased in the MALAT1-shRNA group. All the effects of MALAT1-shRNA on ICH rats were reversed by miR-146a inhibitor co-treatment. In conclusion, downregulation of MALAT1 protected against ICH by suppressing inflammation and oxidative stress by upregulating miR-146a.

Nos2−/− mice infected with M. tuberculosis develop neurobehavioral changes and immunopathology mimicking human central nervous system tuberculosis

BackgroundUnderstanding the pathophysiology of central nervous system tuberculosis (CNS-TB) is hampered by the lack of a good pre-clinical model that mirrors the human CNS-TB infection. We developed a murine CNS-TB model that demonstrates neurobehavioral changes with similar immunopathology with human CNS-TB.MethodsWe injected two Mycobacterium tuberculosis (M.tb) strains, H37Rv and CDC1551, respectively, into two mouse strains, C3HeB/FeJ and Nos2−/− mice, either into the third ventricle or intravenous. We compared the neurological symptoms, histopathological changes and levels of adhesion molecules, chemokines, and inflammatory cytokines in the brain induced by the infections through different routes in different strains.ResultsIntra-cerebroventricular infection of Nos2−/− mice with M.tb led to development of neurological signs and more severe brain granulomas compared to C3HeB/FeJ mice. Compared with CDC1551 M.tb, H37Rv M.tb infection resulted in a higher neurobehavioral score and earlier mortality. Intra-cerebroventricular infection caused necrotic neutrophil-dominated pyogranulomas in the brain relative to intravenous infection which resulted in disseminated granulomas and mycobacteraemia. Histologically, intra-cerebroventricular infection of Nos2−/− mice with M.tb resembled human CNS-TB brain biopsy specimens. H37Rv intra-cerebroventricular infected mice demonstrated higher brain concentrations of inflammatory cytokines, chemokines and adhesion molecule ICAM-1 than H37Rv intravenous-infected mice.ConclusionsIntra-cerebroventricular infection of Nos2−/− mice with H37Rv creates a murine CNS-TB model that resembled human CNS-TB immunopathology, exhibiting the worst neurobehavioral score with a high and early mortality reflecting disease severity and its associated neurological morbidity. Our murine CNS-TB model serves as a pre-clinical platform to dissect host–pathogen interactions and evaluate therapeutic agents for CNS-TB.

Transgenerational Effects of Prenatal Endocrine Disruption on Reproductive and Sociosexual Behaviors in Sprague Dawley Male and Female Rats.

Endocrine-disrupting chemicals (EDCs) lead to endocrine and neurobehavioral changes, particularly due to developmental exposures during gestation and early life. Moreover, intergenerational and transgenerational phenotypic changes may be induced by germline exposure (F2) and epigenetic germline transmission (F3) generation, respectively. Here, we assessed reproductive and sociosexual behavioral outcomes of prenatal Aroclor 1221 (A1221), a lightly chlorinated mix of PCBs known to have weakly estrogenic mechanisms of action; estradiol benzoate (EB), a positive control; or vehicle (3% DMSO in sesame oil) in F1-, F2-, and F3-generation male and female rats. Treatment with EDCs was given on embryonic day (E) 16 and 18, and F1 offspring monitored for development and adult behavior. F2 offspring were generated by breeding with untreated rats, phenotyping of F2s was performed in adulthood, and the F3 generation were similarly produced and phenotyped. Although no effects of treatment were found on F1 or F3 development and physiology, in the F2 generation, body weight in males and uterine weight in females were increased by A1221. Mating behavior results in F1 and F2 generations showed that F1 A1221 females had a longer latency to lordosis. In males, the F2 generation showed decreased mount frequency in the EB group. In the F3 generation, numbers of ultrasonic vocalizations were decreased by EB in males, and by EB and A1221 when the sexes were combined. Finally, partner preference tests in the F3 generation revealed that naïve females preferred F3-EB over untreated males, and that naïve males preferred untreated over F3-EB or F3-A1221 males. As a whole, these results show that each generation has a unique, sex-specific behavioral phenotype due to direct or ancestral EDC exposure.

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury.

Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.

Diet Prevents Social Stress-Induced Maladaptive Neurobehavioural and Gut Microbiota Changes in a Histamine-Dependent Manner.

Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine (Hdc−/−) and their wild type (Hdc+/+) congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress. Behavioural tests across domains relevant to cognition and anxiety were performed. Hippocampal synaptic plasticity, cytokine expression, hippocampal fatty acids, oxylipins and microbiota composition were also assessed. Chronic stress induced social avoidance, poor recognition memory, affected hippocampal long-term potentiation, changed the microbiota profile, brain cytokines, fatty acid and oxylipins composition of both Hdc−/− and Hdc+/+ mice. Dietary enrichment counteracted stress-induced deficits only in Hdc+/+ mice as histamine deficiency prevented almost all the diet-related beneficial effects. Interpretation: Our results reveal a previously unexplored and novel role for brain histamine as a mediator of many favorable effects of the enriched diet. These data present long-reaching perspectives in the field of nutritional neuropsychopharmacology.

A SHORT EDITORIAL VIEW ON THE RELEVANCE OF EXOSOMES IN SOME NEUROPSYCHIATRIC MANIFESTATIONS - MODEL STUDIES

Exosomes are a class of extracellular vesicles derived from cells of endosomal origin and typically have a diameter between 40 to 100 nm, being the smallest type of extracellular vesicle. Although in recent years, the use of exosomes in experimental studies has increased, currently there are few studies that have as a research subject the neurobehavioral changes that exosomes have on model organisms. For this reason, our group is further looking to develop and apply the methodology regarding the neurobehavioral changes that exosomes have on zebrafish (Danio rerio). Thus, we present here a short editorial view on the relevance of exosomes in some neuropsychiatric manifestations-models studies, as wel as some of our future plans in this new area of reearch.

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BackgroundSubacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder of children and young adults that affects the central nervous system (CNS). It is a slow, but persistent, viral infection caused by defective measles virus. Dissociation in a case of SSPE is rare, so is very difficult to diagnose as the symptoms mimics neurobehavioural changes often seen in SSPE.Case PresentationThe child, 11yrs old girl, student, brought with complaints of pain in lower limbs from last 4 months and 3 episodes of unconsciousness & abnormal behaviour from last 3 months. Semiology- pain in lower limbs→ pricking sensation in LL→whole body→loss of consciousness→tightening of all 4 limbs. All episodes were precipitated by some stress at home. Also she had become irritable and there were multiple spells of anger outburst from last 3 months. There is a past h/o measles at 4 yrs. of age and fever f/b 1 episode of fits at 5 yrs. of age. EEG showed rademaker complexes & Antinuclear antibody IIF was positive both s/o SSPE.ResultsChild has been prescribed Tab Sodium Valproate 400mg and Tab. Aripiprazole 5mg along with JPMR exercises and coping skill training. Parents were taught contingency management principles after which she showed good improvement.DiscussionWill be done at the time of presentation.

Neurobehavioural and Neurochemical Changes in Arsenic Induced Cerebellar Toxicity in Male Sprague-Dawley Rats: An Experimental Study

Introduction: Sodium arsenite, an inorganic arsenic, is naturally present at high level (&gt;50 μg/L) in ground water. Drinking ground water is the biggest threat to public health. Though, there are numerous reports on arsenic neurotoxicity, the arsenic effect on cerebellar neurotoxicity remains vague especially its chronic effect on its neurobehavioural and neurochemical alterations. Aim: To evaluate the neurobehavioural and neurochemical alterations caused by sodium arsenite in cerebellum of rats. Materials and Methods: This experimental study was conducted in the Central Animal House at Sri Devaraj Urs Academy of Higher Education and Research (SDUAHER) from November 2019 to February 2020 for a period of 90 days. Total 16 male spraguedawley rats were randomised into two equal groups. Group I: Control, received normal saline. Group II: Sodium arsenite, Doses of 50 Parts per Millions (PPM) for 90 days through oral gavage. Rats were subjected to Open Field Test (OFT) for locomotor and exploratory behaviour and Beam Walking Test (BWT) for motor coordination and balance. Following behavioural tests, rats were anaesthetised. Blood was drawn from a retro-orbital puncture. Brains were dissected and cerebellum was separated. Concentration of Malondialdehyde (MDA), Nitric Oxide (NO) and activity of Glutathione Peroxidase (GPx) were assessed spectrophotometrically in serum and cerebellum of rats. Mean±SD was used for normally distributed data and groups were compared using independent t-test, whereas for non normally distributed data, Median (25th-75th Percentile) was used and Mann-Whitney U-test was used to compare between two groups. Results: Arsenic-treated rats showed a significant increase in arsenic concentration in serum and cerebellum (5.5±1.6 ng/mL, 2.76±0.56 µg/g, respectively) compared to control (1.14±0.43 ng/mL, 0.65±0.29 µg/g, respectively). There was a significant decrease in locomotor and exploratory behaviour and impairment in motor coordination and balance in arsenic treated rats with a p-value &lt;0.001 in comparison with control rats. The arsenic treated rats had significantly enhanced concentration of MDA and NO level and reduced activity of GPx in serum {16.84 (13.84-18.87), 33.79 (30.05-37.17) nmol/mL, and 6.89 (5.24- 8.5) mmoles of Reduced glutathione (GSH) oxidised/min/mL, respectively} compared to control {8.81 (8.36-9.48), 17.66 (15.33-21.29) nmol/mL, and 15.16 (12.77-16.59) mmoles of GSH oxidised/min/mL, respectively} and also found increased concentration of MDA and NO level and reduced activity of GPx in tissue {7.98 (7.14-8.92), 24.67 (21.4-28-22) nmol/mg of protein and 2.66 (1.19-3.86) mmoles of GSH oxidised/min/ mg protein, respectively} compared to control {3.02 (2.35-3.61), 13.93 (11.0-16.16) nmol/mg of protein and 7.63 (7.08-9.19) mmoles of GSH oxidised/min/mg protein, respectively}. Conclusion: The oral administration of sodium arsenite at the doses of 50 PPM for 90 days showed interesting alterations in neurobehavioural and neurochemical parameters related to cerebellum of rats.

Nigella sativa Oil Preserved Anxiety-Like, Motor and Memory Related Behaviours and Neuronal Integrity in Dichlorvos Induced Acetyl Cholinesterase Inhibitions in Rats

Organophosphates are irreversible cholinesterase (ChE) inhibitors with neurological consequences, and there is not yet an effective antidote. Here, we investigated the effects of Nigella sativa oil (NSO) on the ChE inhibition, neurobehavioural and histopathological changes following dichlorvos (DDVP) ingestions in rats. Thirty-two male Wistar rats were randomised into four groups, receiving 1 ml/kg of normal saline, 8.8 mg/kg of DDVP, 8.8 mg/kg of DDVP and 1 ml/kg of NSO, and 1 ml/kg of NSO only respectively, for 14 consecutive days. Locomotor, anxiety-like behaviours and spatial working memory were assessed on the 14th day, using open field (OF), Y-maze and modified elevated plus maze paradigms. The rats were euthanized on the 15th day and the brains excised; three brains were fixed for histopathology, and the other five prepared for biochemical analysis of acetyl cholinesterase (AChE). DDVP exposure caused significant reductions in frontal, amygdala and cerebella AChE activity, spontaneous alternations, line crossing and rearing frequencies and time in centre square, and caused increase in freezing period, transfer latency and necrotic-like cells. NSO intervention was able to reverse DDVP effects on AChE activities, explorative, locomotor, anxiety and spatial memory behaviours in co-exposed rats. It also preserved the histological integrity of the investigated brain regions. It can be concluded that NSO, may be potent against organophosphates induced neurotoxicity and their neurobehavioural consequences through the modulation of AChE activities.

Effects of Pharmacologic Treatment for Neonatal Abstinence Syndrome on DNA Methylation and Neurobehavior: A Prospective Cohort Study

To determine whether pharmacologic treatment for neonatal abstinence syndrome (NAS) is associated with changes in DNA methylation (DNAm) of the mu-opioid receptor gene (OPRM1) and improvements in neonatal neurobehavior. Buccal swabs were collected from 37 neonates before and after morphine treatment for NAS. Genomic DNA was extracted, and DNAm was examined at 4 cytosine-phosphate-guanine (CpG) sites within the OPRM1 gene. Assessment with the NICU Network Neurobehavioral Scales (NNNS) was also performed before and after NAS treatment. Changes in DNAm (DNAmpost-tx - DNAmpre-tx) and NNNS summary scores (NNNSpost-tx - NNNSpre-tx) were then calculated. Path analysis was used to examine associations among pharmacologic treatment (length of treatment [LOT] and total dose of morphine), changes in DNAm, and changes in NNNS summary scores. DNAm was significantly decreased from pretreatment to post-treatment at 1 of 4 CpG sites within the OPRM1 gene. Neonates also demonstrated decreased excitability, hypertonia, lethargy, signs of stress and abstinence, and increased quality of movement and regulation from pretreatment to post-treatment. Longer LOT and higher morphine dose were associated with greater decreases in DNAm; greater decreases in DNAm were associated with greater decreases in excitability and hypertonia on the NNNS. Pharmacologic treatment of NAS is associated with decreased DNAm of the OPRM1 gene and improved neonatal neurobehavior. Epigenetic changes may play a role in these changes in neonatal neurobehavior.

Neurobehavioral and Ultrastructural Changes Induced by Phytosynthesized Silver-Nanoparticle Toxicity in an In Vivo Rat Model.

(1) Background: The study aimed to assess neurobehavioral, ultrastructural, and biochemical changes induced by silver nanoparticles synthesized with Cornus mas L. extract (AgNPs-CM) in rat brains. (2) Methods: The study included 36 male adult rats divided into three groups. Over a period of 45 days, AgNPs-CM (0.8 and 1.5 mg/kg b.w.) were administered daily by gavage to two of the groups, while the control group received the vehicle used for AgNP. After treatment, OFT and EPM tests were conducted in order to assess neurobehavioral changes. Six of the animals from each group were sacrificed immediately after completion of treatment, while the remaining six were allowed to recuperate for an additional 15 days. Transmission electron microscopy (TEM), GFAP immunohistochemistry, and evaluation of TNFα, IL-6, MDA, and CAT activity were performed on the frontal cortex and hippocampus. (3) Results: Treated animals displayed a dose- and time-dependent increase in anxiety-like behavior and severe ultrastructural changes in neurons, astrocytes, and capillaries in both brain regions. Immunohistochemistry displayed astrogliosis with altered cell morphology. TNFα, IL-6, MDA, and CAT activity were significantly altered, depending on brain region and time post exposure. (4) Conclusions: AgNPs-CM induced neurobehavioral changes and severe cell lesions that continued to escalate after cessation of exposure.

Neurobehavioural Changes and not Structural Changes Occur in Rat Fed with Cassava Products (Fufu, Garri and Tapioca Diet)

The ability of cassava products (fufu, garri and tapioca) to produce behavioral and structural changes in the brain of adult rats was examined. Forty adult male rats (N=40) were used for this study and the experiment was divided into two phases (N=20 each).Rat were trained in a Reach-To-Grasp Task for 6 weeks and Quantitative assessments using a reaching movement scale and reach-to-grasp success rate were carried out to determine baseline values. After which administration of the various cassava products was done. The 1st phase had the rats trained to perform the reach to grasp experiment before been fed with various cassava diet. In this phase the animals performed significantly worse than the controls when determining the average success rate in a reach-to-grasp experiment (baseline=72.6%, fufu diet= 30%, garri diet =47%, tapioca diet =59%). The 2nd phase had the rats trained simultaneously as they were being fed withvarious cassava diet. In this phase the animals also performed significantly worse than the controls when determining the average success rate in a reach-to-grasp experiment (fufu diet= 37.5%, garri diet =46.5%, tapioca diet =56.5%). The various movement of the rat was assessed using Tracker software (Video Analysis and Modeling tool, version 5.1.2) and the movement pattens were determined. The animals fed with Fufu shows the worst movement pattern indicating aiming impairment which may be as a result of structural changes in the m1 region of the cerebral cortex. The data obtained were analysed using ANOVA and there was significant difference (p &lt; 0.05) in the movement pattern. Histological observation showed no neuropathological changes in the motor cortex. The rats fed with cassava diets shows no observable changes in the structures and sizes of the neurons as compared with the control. Cassava products (Fufu, Garri and Tapioca) have been demonstrated to cause neurobehavioural and mild structural changes in the M1 region of the cerebral cortex.

Weakened interaction of ATG14 and the SNARE complex blocks autophagosome-lysosome fusion contributes to fluoride-induced developmental neurotoxicity

Fluoride is capable of inducing developmental neurotoxicity, but the mechanisms involved remain unclear. We aimed to explore the role of autophagosome-lysosome fusion in developmental fluoride neurotoxicity, particularly focusing on the interaction between ATG14 and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. We developed in vivo models of Sprague–Dawley rats exposed to sodium fluoride (NaF) from the pregnancy of parental rats until the offspring were two months old and in vitro models of NaF and/or Ad-ATG14-treated SH-SY5Y cells. We assessed neurobehavioral changes in offspring and further investigated the effects of NaF exposure on autophagic flux, apoptosis, autophagosome-lysosome fusion, and the interaction between ATG14 and the SNARE complex. NaF exposure impaired offspring learning and memory capabilities and induced the accumulation of autophagosomes and autophagic flux blockage and apoptosis, as indicated by increased LC3-II, p62, and cleaved-caspase-3 expression in vivo and in vitro. In addition, NaF treatment downregulated the protein expression of ATG14 and the SNARE complex and induced autophagosome-lysosome fusion blockage as evidenced by decreased ATG14, STX17, SNAP29, and VAMP8 expression and diminished colocalization of autophagosomes and lysosomes in vivo and in vitro. Furthermore, ATG14 upregulation enhanced the interaction of ATG14 and the SNARE complex to facilitate autophagosome-lysosome fusion, thereby restoring autophagic flux and alleviating NaF-induced apoptosis. In conclusion, NaF exhibited developmental neurotoxicity by restraining the interaction of ATG14 with the SNARE complex and hindering autophagosome-lysosome fusion, thereby participating in the occurrence and development of fluoride neurotoxicity. Notably, ATG14 upregulation protects against developmental fluoride neurotoxicity, and ATG14 may serve as a promising biomarker for further epidemiological investigation.

How Learning to Read Changes the Listening Brain.

Reading acquisition reorganizes existing brain networks for speech and visual processing to form novel audio-visual language representations. This requires substantial cortical plasticity that is reflected in changes in brain activation and functional as well as structural connectivity between brain areas. The extent to which a child’s brain can accommodate these changes may underlie the high variability in reading outcome in both typical and dyslexic readers. In this review, we focus on reading-induced functional changes of the dorsal speech network in particular and discuss how its reciprocal interactions with the ventral reading network contributes to reading outcome. We discuss how the dynamic and intertwined development of both reading networks may be best captured by approaching reading from a skill learning perspective, using audio-visual learning paradigms and longitudinal designs to follow neuro-behavioral changes while children’s reading skills unfold.