Neurobehavioral Abnormalities Research Articles

Celecoxib, a cyclooxygenase-2 inhibitor, offers chemoprevention against reproductive and neurobehavioural abnormalities induced by atrazine in male Wistar rats

The cyclooxygenase-2/prostanoid pathway (COX-2) serves as a potential therapeutic target in various pathological conditions. Thus, the modulatory effect of celecoxib (CXB), a COX-2 inhibitor, in atrazine-induced toxicity was investigated. Five groups (n = 6 rats per group) of adult male Wistar rats received corn oil (2 ml/kg), atrazine (ATZ, 300 mg/kg) and CXB (5.7 mg/kg) respectively and their combinations via the oral route. Results obtained showed reduced (p < 0.05) sperm motility (25.8%) and counts (27.6%), testosterone (29.9%), luteinizing (33%) and follicle stimulating hormones (78.7%) plus elevated total cholesterol (112.3%), triglyceride (115.7%), malondialdehyde levels respectively in ATZ-treated rats. Similarly, ATZ administration causes reduced locomotion (33.6%), spontaneous motor activity (46.6%) and catalepsy effects (157.3%) respectively. However, CXB divided doses moderately reverse reproductive abnormalities, modulate neurobehavioural deficits and slightly preserved COX-2 elevation following ATZ intoxication. Furthermore, histopathology of testis shows improvement in treated rats. Overall, our data suggest chemopreventive actions via pharmacological inhibition of COX-2 activity during ATZ toxicity.

Systemic inflammation in asocial BTBR T+ tf/J mice predisposes them to increased psoriatic inflammation

Autistic Spectrum disorder (ASD) is a neurobehavioral disorder characterized by defects in communication skills leading to restricted sociability. ASD has immense dysregulation in immune responses which is thought to affect neuronal system and thus behavior. ASD patients and BTBR T+ tf/J (BTBR) autistic mice have increased systemic inflammation due to dysfunction in innate and adaptive immune responses. Recent studies suggest that ASD patients are associated with several co-morbid autoimmune disorders including psoriasis. However underlying mechanisms for this phenomenon have not been explored. In this study, we used imiquimod (IMQ)-induced psoriatic inflammation in social C57BL/6 (C57) mice and asocial BTBR mice to investigate whether systemic inflammation in BTBR is associated with increased susceptibility to psoriatic inflammation. Our data shows that BTBR mice have increased expression of TLR7/IL-6/IL-23 in systemic DCs but not in skin as compared to C57 mice at baseline. This leads to much greater psoriatic inflammation in BTBR mice upon IMQ application than C57 mice. Consequently, BTBR mice also have higher Th17 related immune responses in the skin and systemic compartment. Overall our study suggests that systemic innate (TLR7/IL-23/IL-6 in DCs) and adaptive (Th17 related signaling) immune responses are heightened in BTBR mice at baseline which predisposes them for greater psoriatic inflammation than C57 mice upon IMQ application. This could be one of the reasons for increased psoriatic inflammation in patients with ASD. Therapies that aim to decrease immune activation may not only benefit ASD-associated neurobehavioral abnormalities but also comorbid disorders such as psoriasis.

Neurobehavioral Abnormalities Associated with Executive Dysfunction after Traumatic Brain Injury.

Objective: This article will address how anomalies of executive function after traumatic brain injury (TBI) can translate into altered social behavior that has an impact on a person’s capacity to live safely and independently in the community.Method: Review of literature on executive and neurobehavioral function linked to cognitive ageing in neurologically healthy populations and late neurocognitive effects of serious TBI. Information was collated from internet searches involving MEDLINE, PubMed, PyscINFO and Google Scholar as well as the authors’ own catalogs.Conclusions: The conventional distinction between cognitive and emotional-behavioral sequelae of TBI is shown to be superficial in the light of increasing evidence that executive skills are critical for integrating and appraising environmental events in terms of cognitive, emotional and social significance. This is undertaken through multiple fronto-subcortical pathways within which it is possible to identify a predominantly dorsolateral network that subserves executive control of attention and cognition (so-called cold executive processes) and orbito-frontal/ventro-medial pathways that underpin the hot executive skills that drive much of behavior in daily life. TBI frequently involves disruption to both sets of executive functions but research is increasingly demonstrating the role of hot executive deficits underpinning a wide range of neurobehavioral disorders that compromise relationships, functional independence and mental capacity in daily life.

Lanthanum damages learning and memory and suppresses astrocyte-neuron lactate shuttle in rat hippocampus.

Rare-earth elements (REEs) are applied in various fields by virtue of their superior physical and chemical properties. Surveys have reported that REEs can impair learning and memory in children and induce neurobehavioral abnormalities in animals. However, the mechanism underlying this neurotoxicity is still unclear. Lanthanum (La) is often chosen to study the effects of REEs. Here, we investigated the role of astrocyte-neuron lactate shuttle (ANLS) in spatial learning and memory impairment induced by LaCl3 in hippocampus, an important spatial memory-related brain region. Pregnant Wistar rats were exposed to 0, 0.125, 0.25, 0.5, or 1% LaCl3 in drinking water during pregnancy and lactation. After weaning, young rats continued to receive 0, 0.125, 0.25, 0.5, and 1% LaCl3 in the drinking water for 1month. The results showed that LaCl3 exposure impaired the spatial learning and memory of rats in Morris water maze test, significantly reduced the mRNA and protein levels of glycogen synthetase, glycogen phosphorylase, lactate dehydrogenase A, monocarboxylate transporter 4, MCT-1, and MCT-2, and decreased total LDH activity and lactate contents in rat hippocampus. These results indicate that LaCl3 impairs spatial learning and memory in rats probably by suppressing ANLS in rat hippocampus. The study provides a novel clue of energy supply for neurons to clarify the neurotoxicity of REEs.

Neuroendocrine stress reactivity of male C57BL/6N mice following chronic oral corticosterone exposure during adulthood or adolescence

Adolescence is associated with the maturation of the hypothalamic-pituitary-adrenal (HPA) axis, the major neuroendocrine axis mediating the hormonal stress response. Adolescence is also a period in development marked by a variety of stress-related vulnerabilities, including psychological and physiological dysfunctions. Many of these vulnerabilities are accompanied by a disrupted HPA axis. In adult mice, a model of disrupted HPA function has been developed using oral chronic corticosterone administration via the drinking water, which results in various physiological and neurobehavioral abnormalities, including changes in stress reactivity and anxiety-like behaviors. In an effort to further complement and extend this model, we tested the impact of HPA disruption in adolescent mice. We also examined whether this disruption led to different outcomes depending on whether the treatment happened during adolescence or adulthood. In the current set of experiments, we exposed adult (70days of age) or adolescent (30days of age) male C57BL/6N mice to 4 weeks of either 0 or 25μg/ml oral corticosterone via their drinking water. We measured body weight during treatment and plasma corticosterone levels and activation of the paraventricular nucleus (PVN), as indexed by FOS immunohistochemistry, before and after a 30min session of restraint stress. Our data indicate that adolescent animals exposed to chronic corticosterone showed weight loss during treatment, an effect not observed in adults. Further, we found stress failed to elevate plasma corticosterone levels in treated mice, regardless of whether exposure occurred in adulthood or adolescence. Despite this reduced hormonal responsiveness, we found significant neural activation in the PVN of both adult- and adolescent-treated mice, indicating a dissociation between stress-induced peripheral and central stress responses following chronic corticosterone exposure. Moreover, stress-induced neural activation in the PVN was unaffected by chronic corticosterone treatment in adult animals, but led to a hyper-responsive PVN in the corticosterone-treated adolescent animals, suggesting an age-specific effect of corticosterone treatment on later PVN stress reactivity. Together, these experiments highlight the influence of developmental stage on somatic and neuroendocrine outcomes following chronic HPA disruption by noninvasive, oral corticosterone treatment. Given the substantial vulnerabilities to HPA dysfunctions during adolescence this model may prove useful in better understanding these vulnerabilities.

Subsequent maternal separation exacerbates neurobehavioral abnormalities in rats neonatally exposed to sevoflurane anesthesia.

Several recent studies suggest that in the human population, a routine, short anesthetic in otherwise healthy infants is void of neurodevelopmental insult. On the other hand, many human retrospective epidemiological studies report evidence of cognitive abnormalities in children after testing those who had different anesthesia-requiring procedures in early childhood. We tested in a rat model whether post-anesthesia stressful environmental factors can contribute to developmental abnormalities that were initiated by a relatively short exposure to sevoflurane, the most widely used anesthetic in pediatric anesthesia, whose polyvalent actions include enhancement of gamma-aminobutyric acid type A receptor (GABAAR) activity. Postnatal day 6 (P6) male Sprague-Dawley rats were anesthetized with sevoflurane for 60min. To simulate subsequent stress, the animals were subjected to a single maternal separation for 180min at P10. To study the role of GABAAR-mediated depolarization, subgroups of P6 rats received a single injection of the Na+-K+-2Cl- (NKCC1) inhibitor, bumetanide, prior to initiation of anesthesia with sevoflurane. Rats that were exposed to sevoflurane had decreased hypothalamic K+-2Cl- (KCC2) mRNA level (F(2,13)=3.839, P=0.049), increased NKCC1/KCC2 mRNA ratio (F(2,13)=5.043, P=0.024) and increased corticotropin-releasing hormone (CRH) mRNA level (F(2,12)=9.450, P=0.003) at P10, the age at which maternal separation was imposed. Adult rats, neonatally exposed to a combination of sevoflurane and maternal separation, exhibited increases in the escape latencies greater than animals exposed to sevoflurane only (P=0.012), and only rats in the sevoflurane plus maternal separation group spent significantly less time in the target quadrant during the Morris water maze test (F(4,55)=4.856, P=0.002). Bumetanide ameliorated abnormalities induced by sevoflurane and a combination of sevoflurane plus maternal separation. Neonatal exposure to sevoflurane may sensitize to stressors later in life, and post-exposure stress may exacerbate neurodevelopmental abnormalities even after a relatively short exposure to sevoflurane in rodents. The NKCC1 downregulation prior to exposure to the anesthetic may be therapeutic.

5.16 AMO-01 in the SHANK3 Knockout Transgenic Mouse Model of Phelan Mcdermid Syndrome

Phelan McDermid Syndrome (PMS) is a rare neurodevelopmental disorder associated with a chromosomal deletion at 22q13.3 involving the SHANK3 gene. SHANK3 is a scaffold protein in dendrites essential for synapse formation. A key molecular aberration in PMS is overactivity of the Ras-ERK (extracellular signal-regulated kinase) enzymatic pathway that plays a critical role in synaptic plasticity and neuronal survival. Autism spectrum disorder (ASD) is a frequent, co-occurring condition in patients with PMS. Several high-quality SHANK3 knockout mouse models have been developed for preclinical assessment of potential therapeutic agents for both PMS and ASD. These models recapitulate the neurobehavioral abnormalities and neurological problems (e.g., seizures) common in patients with PMS and ASD.

Treadmill exercise alleviated prenatal buprenorphine exposure-induced depression in rats

Mounting evidence suggests that physical exercise shows health benefits in a range of diseases, including psychiatric disorders. Perinatal opioid exposure produces neurobehavioral abnormality, which includes depression symptoms, in patients and their offspring following chronic use of buprenorphine, a mixed agonist/antagonist with a high affinity to opioid receptors, for pain control. Previously, we demonstrated that prenatal buprenorphine exposure in pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days caused the development of depression-like phenotypes in pups at postnatal day 21. Using the same prenatal buprenorphine exposure model, we further demonstrated that a 4-week course of moderate treadmill exercise conducted on pups starting from postnatal day 22 improved depression-like neurobehaviors. Prenatal buprenorphine exposure-induced neurobehavioral changes were accompanied by reductions of neuronal survival, neural stem cell-associated genes, plasma level of brain-derived neurotrophic factor (BDNF) and serotonin, phosphorylated tropomyosin-related kinase receptor type B (TrkB), phosphorylated extracellular signal-regulated kinase (ERK), PKA activity, phosphorylated cAMP response element-binding protein (CREB), and CREB DNA binding activity, as well as elevation of repressor element-1 silencing transcription factor (REST), oxidative stress, and inflammatory responses. Those changes in parameters of plasma and brain were improved by treadmill exercise. In conclusion, the findings of the current study suggest that a non-pharmacological option, i.e., moderate treadmill exercise, alleviated the development of depression-like neurobehaviors by resolving the oxidative and inflammatory burden as well as by enhancing neurochemical and neuroendocrine signaling.

Cross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV

IntroductionIn vivo imaging biomarkers of various HIV neuropathologies, including dopaminergic dysfunction, are still lacking. Towards developing dopaminergic biomarkers of brain involvement in HIV, we assessed the pre and postsynaptic components of the dopaminergic system in the HIV-1 transgenic rat (Tg), a well-characterized model of treated HIV+ patients, using small-animal PET imaging. MethodsFifteen to 18 month-old Tg and wild type (WT) rats were imaged with both [18F]-FP-CMT, a dopamine transporter (DAT) ligand (n=16), and [18F]-Fallypride, a D2/D3 dopamine receptor (D2/D3DR) ligand (n=16). Five to 8 month-old Tg and WT rats (n=18) were also imaged with [18F]-FP-CMT. A subset of animals was imaged longitudinally at 7 and 17 months of age. Multiplex immunohistochemistry staining for DAT, tyrosine hydroxylase, D2DR, D3DR, GFAP, Iba1 and NeuN was performed on a subgroup of the scanned animals. Results[18F]-FP-CMT and [18F]-Fallypride binding potential (BPND) values were significantly lower in 15–18 month-old Tg compared to age-matched WT rats (p<0.0001 and 0.001, respectively). [18F]-FP-CMT BPND values in 5–8 month-old rats, however, were not significantly different. Longitudinal age-related decrease in [18F]-FP-CMT BPND was exacerbated in the Tg rat. Immunohistochemistry showed decreased staining of dopaminergic markers in Tg rats. Rats with higher serum gp120 had lower mean BPND values for both ligands. ConclusionsWe found presynaptic and postsynaptic dopaminergic dysfunction/loss in older Tg compared to WT rats. We believe this to be related to neurotoxicity of viral proteins present in the Tg rats’ serum and brain. Advances in knowledgeOur findings confirm prior reports of neurobehavioral abnormalities suggestive of dopaminergic dysfunction in this model. They also suggest similarities between the Tg rat and HIV+ patients as far as dopaminergic dysfunction. Implications for patient careThe Tg rat, along with the above-described quantitative PET imaging biomarkers, can have a role in the evaluation of HIV neuroprotective therapies prior to human translation.

Neuroscience: From embryo mutation to adult degeneration.

Mutations in embryonic blood-cell precursors called erythro-myeloid progenitors cause abnormal activation of their descendants — immune cells called microglia — leading to neurodegeneration in mice. See Letter p.389 Microglia—immune cells in the brain—derive from yolk-sac erythro-myeloid progenitors (EMPs), which are distinct from haematopoietic stem cells (HSCs). Frederic Geissmann and colleagues show that mosaic expression of a mutant BRAF, which activates the RAS–MEK–ERK pathway and causes tumours when expressed in HSCs, results in expansion of tissue-resident macrophages and late-onset neurodegeneration when expressed in EMPs. They show in a mouse model that neurobehavioural abnormalities, astrogliosis, deposition of amyloid precursor protein, synaptic loss and neuronal death are driven by ERK-activated microglia and can be prevented by BRAF inhibition. These results show that, in mice, activation of the MAP kinase pathway in microglia can cause neurodegeneration. These findings may explain the neurodegeneration observed in patients with histiocytosis—disorders of myeloid cell expansion associated with somatic mutations in the RAS–MEK–ERK pathway, such as the BRAF mutation studied here.

D-cycloserine improves synaptic transmission in an animal mode of Rett syndrome

Rett syndrome (RTT), a leading cause of intellectual disability in girls, is predominantly caused by mutations in the X-linked gene MECP2. Disruption of Mecp2 in mice recapitulates major features of RTT, including neurobehavioral abnormalities, which can be reversed by re-expression of normal Mecp2. Thus, there is reason to believe that RTT could be amenable to therapeutic intervention throughout the lifespan of patients after the onset of symptoms. A common feature underlying neuropsychiatric disorders, including RTT, is altered synaptic function in the brain. Here, we show that Mecp2tm1.1Jae/y mice display lower presynaptic function as assessed by paired pulse ratio, as well as decreased long term potentiation (LTP) at hippocampal Schaffer–collateral-CA1 synapses. Treatment of Mecp2tm1.1Jae/y mice with D-cycloserine (DCS), an FDA-approved analog of the amino acid D-alanine with antibiotic and glycinergic activity, corrected the presynaptic but not LTP deficit without affecting deficient hippocampal BDNF levels. DCS treatment did, however, partially restore lower BDNF levels in the brain stem and striatum. Thus, treatment with DCS may mitigate the severity of some of the neurobehavioral symptoms experienced by patients with Rett syndrome.

Attenuation of neurobehavioral and neurochemical abnormalities in animal model of cognitive deficits of Alzheimer's disease by fermented soybean nanonutraceutical.

The present study was performed to evaluate the efficacy of nanonutraceuticals (NN) for attenuation of neurobehavioral and neurochemical abnormalities in Alzheimer's disease. Solid-state fermentation of soybean with Bacillus subtilis was performed to produce different metabolites (nattokinase, daidzin, genistin and glycitin and menaquinone-7). Intoxication of rats with colchicine caused impairment in learning and memory which was demonstrated in neurobehavioral paradigms (Morris water maze and passive avoidance) linked with decreased activity of acetylcholinesterase (AChE). NN treatment led to a significant increase in TLT in the retention trials as compared to acquisition trial TLT suggesting an improved learning and memory in rats. Further, treatment of NN caused an increase in the activity of AChE (42%), accompanied with a reduced activity of glutathione (42%), superoxide dismutase (43%) and catalase (41%). It also decreased the level of lipid peroxidation (28%) and protein carbonyl contents (30%) in hippocampus as compared to those treated with colchicine alone, suggesting a possible neuroprotective efficacy of NN. Interestingly, in silico studies also demonstrated an effective amyloid-β and BACE-1 inhibition activity. These findings clearly indicated that NN reversed colchicine-induced behavioral and neurochemical alterations through potent antioxidant activity and could possibly impart beneficial effects in cognitive defects associated with Alzheimer's disease.

Minimal Long-Term Neurobehavioral Impairments after Endovascular Perforation Subarachnoid Hemorrhage in Mice

Cognitive deficits are among the most severe and pervasive consequences of aneurysmal subarachnoid hemorrhage (SAH). A critical step in developing therapies targeting such outcomes is the characterization of experimentally-tractable pre-clinical models that exhibit multi-domain neurobehavioral deficits similar to those afflicting humans. We therefore searched for neurobehavioral abnormalities following endovascular perforation induction of SAH in mice, a heavily-utilized model. We instituted a functional screen to manage variability in injury severity, then assessed acute functional deficits, as well as activity, anxiety-related behavior, learning and memory, socialization, and depressive-like behavior at sub-acute and chronic time points (up to 1 month post-injury). Animals in which SAH was induced exhibited reduced acute functional capacity and reduced general activity to 1 month post-injury. Tests of anxiety-related behavior including central area time in the elevated plus maze and thigmotaxis in the open field test revealed increased anxiety-like behavior at subacute and chronic time-points, respectively. Effect sizes for subacute and chronic neurobehavioral endpoints in other domains, however, were small. In combination with persistent variability, this led to non-significant effects of injury on all remaining neurobehavioral outcomes. These results suggest that, with the exception of anxiety-related behavior, alternate mouse models are required to effectively analyze cognitive outcomes after SAH.

Vitamin D deficiency impairs neurobehavioral development in male mice

Vitamin D deficiency is prevalent especially in pregnant women and children. Several studies found that vitamin D status was negatively correlated with risk of senile neurobehavioral abnormality. The aim of this study was to investigate the effects of vitamin D deficiency on neurobehavioral development in mice. In vitamin D deficiency group, dams and their male pups were fed with vitamin D deficient (VDD) diet, in which vitamin D was depleted. Anxiety-related behavior, depressive-like behavior, spatial learning and memory were measured. As expected, serum 25(OH)D level was reduced in VDD diet-fed mice. An anhedonia state, a key depressive-like behavior, was observed in VDD diet-fed mice. In open-field test, peripheral time was decreased and internal time was increased in VDD diet-fed mice. In elevated plus maze, the latency of the first entry into open arms was increased and the number of crossing in open arms was elevated in VDD diet-fed mice. Morris Water Maze showed that VDD-fed mice showed longer escape latency in the first six days. On the seventh day, escape latency was increased in VDD diet-fed mice. These results provide evidence that vitamin D deficiency impairs neurobehavioral development.

Risk factors for development of postoperative cerebellar mutism syndrome in children after medulloblastoma surgery.

OBJECTIVE Postoperative cerebellar mutism syndrome (pCMS) occurs in 7%-50% of children after cerebellar tumor surgery. Typical features include a latent onset of 1-2 days after surgery, transient mutism, emotional lability, and a wide variety of motor and neurobehavioral abnormalities. Sequelae of this syndrome usually persist long term. The principal causal factor is bilateral surgical damage (regardless of tumor location) to any component of the proximal efferent cerebellar pathway, which leads to temporary dysfunction of cerebral cortical regions as a result of diaschisis. Tumor type, cerebellar midline location, and brainstem involvement are risk factors for pCMS that have been identified repeatedly, but they do not explain its latent onset. Ambiguous or negative results for other factors, such as hydrocephalus, postoperative meningitis, length of vermian incision, and tumor size, have been reached. The aim of this study was to identify perioperative clinical, radiological, and laboratory factors that also increase risk for the development of pCMS. The focus was on factors that might explain the delayed onset of pCMS and thus might provide a time window for taking precautionary measures to prevent pCMS or reduce its severity. The study was focused specifically on children who had undergone surgery for medulloblastoma. METHODS In this single-center retrospective cohort study, the authors included 71 children with medulloblastoma, 28 of whom developed pCMS after primary resection. Clinical and laboratory data were collected prospectively and analyzed systematically. Variables were included for univariate and multivariate analysis. RESULTS Univariate regression analysis revealed 7 variables that had a significant influence on pCMS onset, namely, tumor size, maximum tumor diameter > 5 cm, tumor infiltration or compression of the brainstem, significantly larger decreases in hemoglobin (p = 0.010) and hematocrit (p = 0.003) in the pCMS group after surgery than in the no-pCMS group, significantly more reported incidents of severe bleeding in the tumor bed during surgery in the pCMS group, preoperative hydrocephalus, and a mean body temperature rise of 0.5°C in the first 4 days after surgery in the pCMS group. Multiple regression analysis revealed that tumor size, tumor infiltration into or compression of the brainstem, and higher mean body temperature in the first 4 postoperative days were independent and highly significant predictors for pCMS. CONCLUSIONS The authors confirmed earlier findings that tumor-associated preoperative conditions, such as a maximum tumor diameter ≥ 5 cm and infiltration into or compression of the brainstem, are associated with a higher risk for the development of pCMS. Most importantly, the authors found that a 0.5°C higher mean body temperature in the first 4 postoperative days increased the odds ratio for the development of pCMS almost 5-fold. These data suggest that an important focus for the prevention of pCMS in children who have undergone medulloblastoma surgery might be rigorous maintenance of normothermia as standard care after surgery.

Rai1 Haploinsufficiency Is Associated with Social Abnormalities in Mice

Background: Autism is characterized by difficulties in social interaction, communication, and repetitive behaviors; with different degrees of severity in each of the core areas. Haploinsufficiency and point mutations of RAI1 are associated with Smith-Magenis syndrome (SMS), a genetic condition that scores within the autism spectrum range for social responsiveness and communication, and is characterized by neurobehavioral abnormalities, intellectual disability, developmental delay, sleep disturbance, and self-injurious behaviors. Methods: To investigate the relationship between Rai1 and social impairment, we evaluated the Rai1+/− mice with a battery of tests to address social behavior in mice. Results: We found that the mutant mice showed diminished interest in social odors, abnormal submissive tendencies, and increased repetitive behaviors when compared to wild type littermates. Conclusions: These findings suggest that Rai1 contributes to social behavior in mice, and prompt it as a candidate gene for the social behaviors observed in Smith-Magenis Syndrome patients.

Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats

Propofol is a general anesthetic commonly used in pediatric clinical practices. Experimental findings demonstrate that anesthetics induce widespread apoptosis and cognitive decline in a developing brain. Although anesthesia-mediated neurotoxicity is the most prominent during intense period of synaptogenesis, the effects of an early anesthesia exposure on the synapses are not well understood. The aim of this study was to examine the effects of neonatal propofol anesthesia on the expression of key proteins that participate in synaptogenesis and synaptic plasticity and to evaluate long-term neurobehavioral abnormalities in the mature adult brain. Propofol-injected 7-day-old rats were maintained under 2-, 4-, and 6-h-long anesthesia and sacrificed 0, 4, 16, and 24h after the termination of each exposure. We showed that propofol anesthesia strongly influenced spatiotemporal expression and/or proteolytic processing of crucial presynaptic (GAP-43, synaptophysin, α-synuclein), trans-synaptic (N-cadherin), and postsynaptic (drebrin, MAP-2) proteins in the cortex and thalamus. An overall decrease of synaptophysin, α-synuclein, N-cadherin, and drebrin indicated impaired function and structure of the synaptic contacts immediately after anesthesia cessation. GAP-43 and MAP-2 adult and juvenile isoforms are upregulated following anesthesia, suggesting compensatory mechanism in the maintaining of the structural integrity and stabilization of developing axons and dendritic arbors. Neonatal propofol exposure significantly altered spontaneous motor activity (increased stereotypic/repetitive movements) and changed emotional behavior (reduced anxiety-like response) in the adulthood, 6months later. These findings suggest that propofol anesthesia is synaptotoxic in the developing brain, disturbing synaptic dynamics and producing neuroplastic changes permanently incorporated into existing networks with long-lasting functional consequences.

A novel nuclear xenobiotic receptors (AhR/PXR/CAR)-mediated mechanism of DEHP-induced cerebellar toxicity in quails (Coturnix japonica) via disrupting CYP enzyme system homeostasis

Di-(2-ethylhexyl)-phthalate (DEHP) is causing serious health hazard in wildlife animal and human through environment and food chain, including the effect of brain development and impacted neurobehavioral outcomes. However, DEHP exposure caused cerebellar toxicity in bird remains unclear. To evaluate DEHP-exerted potential neurotoxicity in cerebellum, male quails were exposed with 0, 250, 500 and 750 mg/kg BW/day DEHP by gavage treatment for 45 days. Neurobehavioral abnormality and cerebellar histopathological alternation were observed in DEHP-induced quails. DEHP exposure increased the contents of total Cytochrome P450s (CYPs) and Cytochrome b5 (Cyt b5) and the activities of NADPH-cytochrome c reductase (NCR) and aniline-4-hydeoxylase (AH) in quail cerebellum. The expression of nuclear xenobiotic receptors (NXRs) and the transcriptions of CYP enzyme isoforms were also influenced in cerebellum by DEHP exposure. These results suggested that DEHP exposure caused the toxic effects of quail cerebellum. DEHP exposure disrupted the cerebellar CYP enzyme system homeostasis via affecting the transcription of CYP enzyme isoforms. The cerebellar P450arom and CYP3A4 might be biomarkers in evaluating the neurotoxicity of DEHP in bird. Finally, this study provided new evidence that DEHP-induced toxic effect of quail cerebellum was associated with activating the NXRs responses and disrupting the CYP enzyme system homeostasis.

Tanshinone IIA Attenuates Sevoflurane Neurotoxicity in Neonatal Mice.

Sevoflurane is the most widely used inhalational anesthetic in pediatric medicine. Despite this, sevoflurane has been reported to exert potentially neurotoxic effects on the developing brain. Clinical interventions and treatments for these effects are limited. Tanshinone IIA (Tan IIA), extracted from Salvia miltiorrhiza (Danshen), has been documented to alleviate cognitive decline in traditional applications. Therefore, we hypothesized that preadministration of Tan IIA may attenuate sevoflurane-induced neurotoxicity, suggesting that Tan IIA is a new and promising drug capable of counteracting the effects of cognitive dysfunction produced by general anesthetics. To test this hypothesis, neonatal C57 mice (P6) were exposed to 3% sevoflurane for 2 hours with or without Tan IIA pretreatment at a dose of 10 mg/kg or 20 mg/kg for 3 consecutive days. Cognitive behavior tests such as open field tests and fear conditioning were performed to evaluate locomotor and cognitive function at P31 and P32. At P8, other separate tests, including TdT mediated dUTP Nick End Labeling (TUNEL) assay, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assay, and electron microscopy, were performed. The mean differences among groups were compared using 1-way analysis of variance followed by Bonferroni post hoc multiple comparison tests. Repeated exposure to sevoflurane leads to significant cognitive impairment in mice, which may be explained by increased apoptosis, overexpression of neuroinflammatory markers, and changes in synaptic ultrastructure. Interestingly, preadministration of Tan IIA ameliorated these neurocognitive deficits, as shown by increased freezing percentages on the fear conditioning test (sevoflurane+Tan IIA [20 mg/kg] versus sevoflurane, mean difference, 19, 99% confidence interval for difference, 6.4-31, P < .0001, n = 6). The treatment also reduced the percentage of TUNEL-positive nuclei (sevoflurane versus sevoflurane+Tan IIA [20 mg/kg], 2.6, 0.73-4.5, P = .0004, n = 6) and the normalized expression of cleaved caspase-3 (sevoflurane versus sevoflurane+Tan IIA [20 mg/kg], 0.27, 0.02-0.51, P = .0046, n = 5). Moreover, it attenuated the production of the neuroinflammatory mediators interleukin (IL)-1β and IL-6 (normalized sevoflurane versus sevoflurane+Tan IIA [20 mg/kg]: IL-1β: 0.75, 0.47-1.0; P < .0001; IL-6: 0.66, 0.35-0.97; P < .0001; n = 10 per group). Finally, based on measurements of postsynaptic density, the treatment preserved synaptic ultrastructure (sevoflurane+Tan IIA [20 mg/kg] versus sevoflurane, 42, 20-66; P < .0001; n = 12 per group). These results indicate that Tan IIA can alleviate sevoflurane-induced neurobehavioral abnormalities and may decrease neuroapoptosis and neuroinflammation.

Prenatal nicotine exposure decreases the release of dopamine in the medial frontal cortex and induces atomoxetine-responsive neurobehavioral deficits in mice.

Increased risk of attention-deficit/hyperactivity disorder (AD/HD) is partly associated with the early developmental exposure to nicotine in tobacco smoke. Emerging reports link tobacco smoke exposure or prenatal nicotine exposure (PNE) with AD/HD-like behaviors in rodent models. We have previously reported that PNE induces cognitive behavioral deficits in offspring and decreases the contents of dopamine (DA) and its turnover in the prefrontal cortex (PFC) of offspring It is well known that the dysfunction of DAergic system in the brain is one of the core factors in the pathophysiology of AD/HD. Therefore, we examined whether the effects of PNE on the DAergic system underlie the AD/HD-related behavioral changes in mouse offspring. PNE reduced the release of DA in the medial PFC (mPFC) in mouse offspring. PNE reduced the number of tyrosine hydroxylase (TH)-positive varicosities in the mPFC and in the core as well as the shell of nucleus accumbens, but not in the striatum. PNE also induced behavioral deficits in cliff avoidance, object-based attention, and sensorimotor gating in offspring. These behavioral deficits were attenuated by acute treatment with atomoxetine (3mg/kg, s.c.) or partially attenuated by acute treatment with MPH (1mg/kg, s.c.). Taken together, our findings support the notion that PNE induces neurobehavioral abnormalities in mouse offspring by disrupting the DAergic system and improve our understanding about the incidence of AD/HD in children whose mothers were exposed to nicotine during their pregnancy.