Reduction In Brain Weight Research Articles

Vrk1 partial Knockdown in Mice Results in Reduced Brain Weight and Mild Motor Dysfunction, and Indicates Neuronal VRK1 Target Pathways

Mutations in Vaccinia-related kinase 1 (VRK1) have emerged as a cause of severe neuronal phenotypes in human, including brain developmental defects and degeneration of spinal motor neurons, leading to Spinal Muscular Atrophy (SMA) or early onset Amyotrophic Lateral Sclerosis (ALS). Vrk1 gene-trap partial Knockout (KO) mice (Vrk1GT3/GT3), which express decreased levels of Vrk1, are sterile due to impaired gamete production. Here, we examined whether this mouse model also presents neuronal phenotypes. We found a 20–50% reduction in Vrk1 expression in neuronal tissues of the Vrk1GT3/GT3 mice, leading to mild neuronal phenotypes including significant but small reduction in brain mass and motor (rotarod) impairment. Analysis of gene expression in the Vrk1GT3/GT3 cortex predicts novel roles for VRK1 in neuronal pathways including neurotrophin signaling, axon guidance and pathways implicated in the pathogenesis of ALS. Together, our studies of the partial KO Vrk1 mice reveal that even moderately reduced levels of Vrk1 expression result in minor neurological impairment and indicate new neuronal pathways likely involving VRK1.

Abnormalities in behaviour, histology and prefrontal cortical gene expression profiles relevant to schizophrenia in embryonic day 17 MAM-Exposed C57BL/6 mice

Gestational and perinatal disruption of neural development increases the risk of developing schizophrenia (SCZ) later in life. Embryonic day 17 (E17) methylazoxymethanol (MAM) treatment leads to histological, physiological and behavioural abnormalities in post-puberty rats that model the neuropathological and cognitive deficits reported in SCZ patients. However, the validity of E17 MAM-exposed mice to model SCZ has not been explored. Here we treated E17 C57BL/6 mouse dams with various dosages of MAM. We found that this mouse strain was more vulnerable to MAM treatment than rats and there were gender differences in behavioural abnormalities, histological changes and prefrontal cortical gene expression profiles in MAM (7.5 mg/kg)-exposed mice. Both male and female MAM-exposed mice had deficits in prepulse inhibition. Female MAM-exposed mice exhibited mildly increased spontaneous locomotion activity and social recognition deficits, while male mice were normal. Consistently, only female MAM-exposed mice exhibited reduced brain weight, decreased size of prefrontal cortex (PFC) and enlarged lateral ventricles. Transcriptome analysis of the PFC revealed that there were more differentially expressed genes in female MAM-exposed mice than those in male mice. Moreover, expression of Pvalb, Arc and genes in their association networks were downregulated in the PFC of female MAM-exposed mice. These results indicate that E17 MAM-exposure in C57BL/6 mice leads to behavioural changes that model certain deficits reported in SCZ patients. MAM-exposed female mice may be used to study gene expression changes, inhibitory neural circuit dysfunction and glutamatergic synaptic plasticity deficits with a possible relation to those in the brains of SCZ patients.

Immuno-modulator inter-alpha inhibitor proteins ameliorate complex auditory processing deficits in rats with neonatal hypoxic-ischemic brain injury

Hypoxic-ischemic (HI) brain injury is recognized as a significant problem in the perinatal period, contributing to life-long language-learning and other cognitive impairments. Central auditory processing deficits are common in infants with hypoxic-ischemic encephalopathy and have been shown to predict language learning deficits in other at risk infant populations. Inter-alpha inhibitor proteins (IAIPs) are a family of structurally related plasma proteins that modulate the systemic inflammatory response to infection and have been shown to attenuate cell death and improve learning outcomes after neonatal brain injury in rats. Here, we show that systemic administration of IAIPs during the early HI injury cascade ameliorates complex auditory discrimination deficits as compared to untreated HI injured subjects, despite reductions in brain weight. These findings have significant clinical implications for improving central auditory processing deficits linked to language learning in neonates with HI related brain injury.

Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice.

Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1nihNpc1−/− mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1−/− animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.

A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems.

A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The protein encoded by Bckdk is an integral part of an enzyme complex located in the mitochondrial matrix of many tissues which regulates the levels of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine. BCAAs are essential amino acids (not synthesized by the body), and circulating levels must be tightly regulated; levels that are too high or too low are both deleterious. BCKDK phosphorylates Ser293 of the E1α subunit of the BCKDH protein, which catalyzes the rate-limiting step in the catabolism of the BCAAs, inhibiting BCKDH and thereby, limiting breakdown of the BCAAs. In contrast, when Ser293 is not phosphorylated, BCKDH activity is unchecked and the levels of the BCAAs will decrease dramatically. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging. Consistent with this, we show that in rats homozygous for the mutation, phosphorylation of BCKDH in the brain is markedly decreased relative to wild type or heterozygous littermates. Further, circulating levels of the BCAAs are reduced by 70–80% in animals homozygous for the mutation. The frogleg phenotype shares important characteristics with a previously described Bckdk knockout mouse and with human subjects with Bckdk mutations. In addition, we report novel data regarding peripheral neuropathy of the hind limbs.

Scopolamine으로 유도된 기억 손상 마우스에서 청국장 식이의 항산화 효과

In this study, the antioxidant effect of Chungkukjang supplementation against memory impairment and oxidative stress in scopolamine (2 mg/kg i.p)-injected mice was investigated. The experimental animals were divided into five groups and fed experimental diets for 12 weeks; normal diet group (C), scopolamine + normal diet group (S), scopolamine + 63.0% soybean Chungkukjang supplementation group (SS), scopolamine + 45.0% Yakkong Chungkukjang supplementation group (SY), and scopolamine + 50.0% black foods such as black rice, black sesame seeds, and sea tangle added Yakkong Chungkukjang group (SYB). For the results of food intake, body weight gain, and brain weights, levels of scopolamine-injected groups were lower than the levels of the control group. The reduced brain weight of the scopolamine-injected group (S) was regulated to control level by supplementation of three types Chungkukjang. In the oxidative stress indicator, nitric oxide and malondialdehyde levels in serum of scopolamine-injected mice were higher than those of other groups. However, supplementation of soybeans, Yakkong and black foods added Yakkong Chungkukjang was proven to regulate them. Antioxidant enzyme activities such as superoxide dismutase (SOD) and glutathione-S-transferase (GST) in serum showed no significant differences among the groups. The reduced levels of vitamin A and vitamin E in serum and brain tissue of scopolamine-injected mice were controlled by supplementation of three types of Chungkukjang. Total antioxidant capacity (TAC) of scopolamine-injected group was lower than those of other groups. However, TAC was significantly elevated by Chunggukjang supplementation. Therefore, antioxidative effects of soybeans, Yakkong, and black foods added Yakkong Chungkukjang supplementations against oxidative stress in scopolamineinjected in mice could expected.

Deletion of Prdm8 impairs development of upper-layer neocortical neurons.

Upper-layer (UL) neocortical neurons are the most prominent distinguishing features of the mammalian neocortex compared with those of the avian dorsal cortex and are vastly expanded in primates. However, little is known about the identities of the genes that control the specification of UL neurons. Here, we found that Prdm8, a member of the PR (PRDI-BF1 and RIZ homology) domain protein family, was specifically expressed in the postnatal UL neocortex, particular those in late-born RORß-positive layer IV neurons. We generated homozygous Prdm8 knockout (Prdm8 KO) mice and found that the deletion of Prdm8 causes growth retardation and a reduced brain weight, although the brain weight-to-body weight ratio is unchanged at postnatal day 8 (P8). Immunohistochemistry showed that the relative UL thickness, but not the thickness of the deep layer (DL), was significantly reduced in Prdm8 KO mice compared with wild-type (WT) mice. In addition, we found that a number of late-born Brn2-positive UL neurons were significantly decreased in Prdm8 KO mice. To identify genes regulated by Prdm8 during neocortical development, we compared expression profiling analysis in Prdm8 KO and WT mice, and identified some candidate genes. These results suggest that the proper expression of Prdm8 is required for the normal development and construction of UL neurons in the mammalian neocortex.

Factors associated with morphometric brain changes in cognitively normal aging.

ObjectiveCognitive impairment is associated with reductions in brain weight and volume. The factors related to morphometric brain changes in cognitively normal aging remain unknown. We aimed to identify which clinical factors are associated with morphometric brain changes in cognitively normal aging.MethodsA cross-sectional study of 414 subjects, ≥50 years old submitted to clinical assessment and brain autopsy, after informed consent, was carried out at the São Paulo Autopsy Service, Brazil. Data on cognitive and functional evaluations were collected through structured interview applied to the next-of-kin. Brain weight (g) and volume (mL) measurements were obtained and adjusted for head circumference (cm). Associations between brain weight/volume and related factors were obtained through univariate and multivariate analysis.ResultsParticipants were predominantly male (60.4%), Caucasian (69%), with mean age of 67.1 ± 10.9 years. Mean brain weight was 1219.2 ± 140.9 g, and mean brain volume was 1217.1 ± 152.3 mL. Head circumference was independently associated with low brain weight (p<0.001) and volume (p<0.001). Total and adjusted brain weight and volume decreased in some conditions. Female gender (p<0.001), hypertension (p<0.009), coronary artery disease (p<0.013) and walking assistance (p<0.011) were associated with lower adjusted brain weight while schooling was associated with higher adjusted brain weight (p<0.003). Female gender (p<0.001), age (p<0.001) and hypertension (p<0.011) were associated with low adjusted brain volume.ConclusionMorphometric brain changes occur despite the absence of cognitive impairment and were predominantly associated with age, female gender, mobility impairment and cardiovascular conditions. Schooling may be a protective factor.

Characterization of a Novel Mouse Model of Alzheimer's Disease--Amyloid Pathology and Unique β-Amyloid Oligomer Profile.

Amyloid plaques composed of β-amyloid (Aβ) protein are a pathological hallmark of Alzheimer’s disease. We here report the generation and characterization of a novel transgenic mouse model of Aβ toxicity. The rTg9191 mice harbor a transgene encoding the 695 amino-acid isoform of human amyloid precursor protein (APP) with the Swedish and London mutations (APPNLI) linked to familial Alzheimer’s disease, under the control of a tetracycline-response element, as well as a transgene encoding the tetracycline transactivator, under the control of the promoter for calcium-calmodulin kinase IIα. In these mice, APPNLI is expressed at a level four-fold that of endogenous mouse APP and its expression is restricted to forebrain regions. Transgene expression was suppressed by 87% after two months of doxycycline administration. Histologically, we showed that (1) Aβ plaques emerged in cerebral cortex and hippocampus as early as 8 and 10.5-12.5 months of age, respectively; (2) plaque deposition progressed in an age-dependent manner, occupying up to 19% of cortex at ~25 months of age; and (3) neuropathology—such as abnormal neuronal architecture, tau hyperphosphorylation and misfolding, and neuroinflammation—was observed in the vicinity of neuritic plaques. Biochemically, we determined total Aβ production at varied ages of mice, and we showed that mice produced primarily fibrillar Aβ assemblies recognized by conformation-selective OC antibodies, but few non-fibrillar oligomers (e.g., Aβ*56) detectable by A11 antibodies. Finally, we showed that expression of the tetracycline transactivator resulted in reduced brain weight and smaller dentate-gyrus size. Collectively, these data indicate that rTg9191 mice may serve as a model for studying the neurological effects of the fibrillar Aβ assemblies in situ.

Seipin is necessary for normal brain development and spermatogenesis in addition to adipogenesis

Seipin, encoded by BSCL2 gene, is a protein whose physiological functions remain unclear. Mutations of BSCL2 cause the most-severe form of congenital generalized lipodystrophy (CGL). BSCL2 mRNA is highly expressed in the brain and testis in addition to the adipose tissue in human, suggesting physiological roles of seipin in non-adipose tissues. Since we found BSCL2 mRNA expression pattern among organs in rat is similar to human while it is not highly expressed in mouse brain, we generated a Bscl2/seipin knockout (SKO) rat using the method with ENU (N-ethyl-N-nitrosourea) mutagenesis. SKO rats showed total lack of white adipose tissues including mechanical fat such as bone marrow and retro-orbital fats, while physiologically functional brown adipose tissue was preserved. Besides the lipodystrophic phenotypes, SKO rats showed impairment of spatial working memory with brain weight reduction and infertility with azoospermia. We confirmed reduction of brain volume and number of sperm in human patients with BSCL2 mutation. This is the first report demonstrating that seipin is necessary for normal brain development and spermatogenesis in addition to white adipose tissue development.

Toxicity assessment due to sub-chronic exposure to individual and mixtures of four toxic heavy metals

Humans are exposed to a cocktail of heavy metal toxicants in the environment. Though heavy metals are deleterious, there is a paucity of information on toxicity of low dose mixtures. In this study, lead (Pb) (0.01mg/L), mercury (Hg) (0.001mg/L), cadmium (Cd) (0.005mg/L) and arsenic (As) (0.01mg/L) were administered individually and as mixtures to 10 groups of 40 three-week old mice (20 males and 20 females), for 120 days. The study established that low dose exposures induced toxicity to the brain, liver, and kidney of mice. Metal mixtures showed higher toxicities compared to individual metals, as exposure to low dose Pb+Hg+Cd reduced brain weight and induced structural lesions, such as neuronal degeneration in 30-days. Pb+Hg+Cd and Pb+Hg+As+Cd exposure induced hepatocellular injury to mice evidenced by decreased antioxidant activities with marginal increases in MDA. These were accentuated by increases in ALT, AST and ALP. Interactions in metal mixtures were basically synergistic in nature and exposure to Pb+Hg+As+Cd induced renal tubular necrosis in kidneys of mice. This study underlines the importance of elucidating the toxicity of low dose metal mixtures so as to protect public health.

Prediabetes and type 2 diabetes implication in central proliferation and neurogenesis

Type 2 diabetes (T2D) is an important risk factor for developing dementias, including Alzheimer's disease (AD). Hyperinsulinemia and glucose intolerance, as features of T2D, might increase the neurodegeneration process, synaptic loss and brain atrophy, leading to cognitive impairment observed in AD. Also, adult neurogenesis seems to be impaired in AD models. Therefore, we have studied morphological alterations, cell proliferation and neurogenesis in the central nervous system (CNS) from a classical model of T2D, the db/db mouse, and in a prediabetes insulin-resistant model, obtained after long-term high fat diet (HFD) administration to C57Bl/6 mice. Db/db mice showed an age-dependent cortical and hippocampal atrophy, whereas in HFD mice cortex and hippocampus were preserved. Neurogenesis and cell proliferation were increased in young db/db mice, when compared with control mice, whereas no differences were detected in the prediabetic model. We also detected significant correlations between metabolic parameters and central atrophy, altered proliferation and neurogenesis in the central nervous system. Altogether these data support that glycaemia control in elderly patients, could help to control central alterations and improve dementia prognosis.

Hypoxic Preconditioning Suppresses Glial Activation and Neuroinflammation in Neonatal Brain Insults.

Perinatal insults and subsequent neuroinflammation are the major mechanisms of neonatal brain injury, but there have been only scarce reports on the associations between hypoxic preconditioning and glial activation. Here we use neonatal hypoxia-ischemia brain injury model in 7-day-old rats and in vitro hypoxia model with primary mixed glial culture and the BV-2 microglial cell line to assess the effects of hypoxia and hypoxic preconditioning on glial activation. Hypoxia-ischemia brain insult induced significant brain weight reduction, profound cell loss, and reactive gliosis in the damaged hemisphere. Hypoxic preconditioning significantly attenuated glial activation and resulted in robust neuroprotection. As early as 2 h after the hypoxia-ischemia insult, proinflammatory gene upregulation was suppressed in the hypoxic preconditioning group. In vitro experiments showed that exposure to 0.5% oxygen for 4 h induced a glial inflammatory response. Exposure to brief hypoxia (0.5 h) 24 h before the hypoxic insult significantly ameliorated this response. In conclusion, hypoxic preconditioning confers strong neuroprotection, possibly through suppression of glial activation and subsequent inflammatory responses after hypoxia-ischemia insults in neonatal rats. This might therefore be a promising therapeutic approach for rescuing neonatal brain injury.

Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder.

Williams-Beuren syndrome is a developmental multisystemic disorder caused by a recurrent 1.55-1.83 Mb heterozygous deletion on human chromosome band 7q11.23. Through chromosomal engineering with the cre-loxP system, we have generated mice with an almost complete deletion (CD) of the conserved syntenic region on chromosome 5G2. Heterozygous CD mice were viable, fertile and had a normal lifespan, while homozygotes were early embryonic lethal. Transcript levels of most deleted genes were reduced 50% in several tissues, consistent with gene dosage. Heterozygous mutant mice showed postnatal growth delay with reduced body weight and craniofacial abnormalities such as small mandible. The cardiovascular phenotype was only manifested with borderline hypertension, mildly increased arterial wall thickness and cardiac hypertrophy. The neurobehavioral phenotype revealed impairments in motor coordination, increased startle response to acoustic stimuli and hypersociability. Mutant mice showed a general reduction in brain weight. Cellular and histological abnormalities were present in the amygdala, cortex and hippocampus, including increased proportion of immature neurons. In summary, these mice recapitulate most crucial phenotypes of the human disorder, provide novel insights into the pathophysiological mechanisms of the disease such as the neural substrates of the behavioral manifestations, and will be valuable to evaluate novel therapeutic approaches.

Gestational lead exposure induces developmental abnormalities and up-regulates apoptosis of fetal cerebellar cells in rats

Lead (Pb), a known environmental toxicant, adversely affects almost all organ systems. In this study, we investigated the effects of maternal lead exposure on fetal rat cerebellum. Female Sprague–Dawley rats were given lead nitrate in drinking water (0, 0.5, and 1%) for two weeks before conception, and during pregnancy. Fetuses were collected by caesarian section on gestational day 21 and observed for developmental abnormalities. The fetal cerebellar sections from control and 1% lead group were stained with cresyl violet. Immunohistochemical expressions of p53, Bax, Bcl-2, and caspase 3 were quantified by AnalySIS image analyzer (Life Science, Germany). Lead exposure induced developmental abnormalities of eyes, ear, limbs, neck and ventral abdominal wall; however, these abnormalities were commonly seen in the 1% lead-treated group. In addition, lead also caused fetal mortality and reduced body growth in both dose groups and reduced brain weight in the 1% lead-treated group. The fetal cerebella from the 1% lead-treated group showed unorganized cerebellar cortical layers, and degenerative changes in granule and Purkinje cells such as the formation of clumps of Nissl granules. An increase in Bax and caspase 3, and a decrease in Bcl-2 (p < 0.05), but not in p53, showed apoptosis of the neurons. In conclusion, gestational lead exposure in rats induces fetal toxicity and developmental abnormalities. The lead exposure also impairs development of cerebellar layers, induces structural changes, and apoptosis in the fetal cerebellar cortex. These results suggest that lead exposure during gestation is extremely toxic to developing cerebellum in rats.

Histological evaluation of the prefrontal cortex of infantile Wistar rats exposed to nicotine during the embryonic period

Exposure to nicotine in utero is neuroteratogenic, predisposing the developing brain to cell injury and many forms of neurological and neurobehavioural problems that persist after birth. The current study examined some of the histological effects of prenatal nicotine exposure on the prefrontal cortex of infantile rats. Primiparous Wistar rats were mated, and pregnancy was confirmed. A daily dose of 0.03 mg/kg of nicotine was administered intra-peritoneally to each treated rat for five consecutive days during their first two weeks of gestation. The rate of development and maturation of brain cells was reduced, as well as a reduction in the population of cells, though no apparent reduction of brain weight or morphological changes was noticed.Keywords: prenatal nicotine, prefrontal cortex, infantile rats

早产儿的临床特点及营养支持对其生产发育的影响

早产儿是指凡胎龄满28周以上，不足37周，出生体重在2500 g以下，身长47 cm以下的活产新生儿。早产儿具有体温调节中枢发育不全、胃动力不成熟、免疫力低下、并发症多等特点，是一个极度未成熟的群体。人类和动物研究均表明，在妊娠晚期和生后早期敏感阶段的营养不良将会对远期的生长发育产生不良影响，表现为大脑重量降低、脑细胞数减少、运动协调能力降低，另外也有足够证据表明，在关键时期的营养不良可造成大脑结构和功能的永久性损害。鉴于早产儿特殊的生理特点，营养支持对早产儿的生长发育起到十分重要的作用。 Premature refers to a live birth infant ,whose gestation period is between 28 weeks and 37 weeks; birth weight is less than 2500 g; born height is below 47 cm. Premature infant is an extremely immature group, always accompanying with hypoplasia in temperature-regulating center, immature in stomach function, low immunity and some complications. In reluctant experiments on human and animals, it’s acknowledged that malnutrition occurring at the initial phase and maturation phase will be harmful for further growth and development, characterized by reduction of brain weight or an amount of brain cells, and weak coordination function. By the way, it’s proved by enough evidence that the damage on the brain structure and function caused by malnutrition in critical period is permanent and irreversible. In consideration of the particularity of physiological needs of premature, nutrition intervention will play a very important role in the growth and development of premature infants.

Impact of Maternal Thyroperoxidase Status on Fetal Body and Brain Size

The obstetric consequences of abnormal thyroid function during pregnancy have been established. Less understood is the influence of maternal thyroid autoantibodies on infant outcomes. The objective of this study was to examine the influence of maternal thyroperoxidase (TPO) status on fetal/infant brain and body growth. Six-hundred thirty-one (631) euthyroid pregnant women were recruited from prenatal clinics in Tampa Bay, Florida, and the surrounding area between November 2007 and December 2010. TPO status was determined during pregnancy and fetal/infant brain and body growth variables were assessed at delivery. Regression analysis revealed maternal that TPO positivity was significantly associated with smaller head circumference, reduced brain weight, and lower brain-to-body ratio among infants born to TPO+ white, non-Hispanic mothers only, distinguishing race/ethnicity as an effect modifier in the relationship. No significant differences were noted in body growth measurements among infants born to TPO positive mothers of any racial/ethnic group. Currently, TPO antibody status is not assessed as part of the standard prenatal care laboratory work-up, but findings from this study suggest that fetal brain growth may be impaired by TPO positivity among certain populations; therefore autoantibody screening among high-risk subgroups may be useful for clinicians to determine whether prenatal thyroid treatment is warranted.

Impact of neonatal NOS-1 inhibitor exposure on neurobehavioural measures and prefrontal-temporolimbic integration in the rat nucleus accumbens

Nitric oxide (NO) is a gaseous neurotransmitter that plays a significant role in the establishment and refinement of functional neural circuits. Genetic and post-mortem studies have suggested that neuronal NO synthase (NOS-1) activity may be compromised in frontal and temporal lobes, and related structures, in schizophrenia. The goal of this study was to determine if there is a link between neonatal disruptions in NO signalling and disturbances in the development and function of prefrontal-temporolimbic circuits. Neonatal rats were injected on postnatal days PD3-5 with the selective NOS-1 inhibitor Nω-propyl-L-arginine (NPA) and tested in adulthood (≥PD60) or as juveniles (PD30). Adult rats treated with NPA as neonates exhibited increased amphetamine-induced locomotion compared to animals receiving vehicle as neonates, whereas this was not observed in juvenile rats treated with NPA as neonates. Adult rats exposed to NPA as neonates also exhibited deficits in social interaction and short-term recognition memory, as well as reduced brain weight, compared to vehicle-treated controls. Finally, neonatal NPA exposure increased the responsiveness of nucleus accumbens neurons to prefrontal cortical input and disrupted the modulation of cortico-accumbens circuits by hippocampal afferents that is normally observed in adult animals. These results show for the first time that neonatal inhibition of NOS-1 during a critical neurodevelopmental period leads to aberrant behaviours that manifest in adulthood, as well as electrophysiological abnormalities in prefrontal-temporolimbic circuits. Greater understanding of the role of NOS-1 in the development of these circuits will shed light on how developmental insults translate to pathophysiology associated with schizophrenia.

Effect of Phenobarbital on Bcl-2 and Bax expressions in brain tissue of young rats

Objective To study the effect of Phenobarbital (PB) on experimental rats, observe the histological changes of immature brain and the expressions of apoptosis-related proteins Bcl-2 and Bax in neurons detected by immunohistochemistry, and to explore the influence and mechanism of PB on brain damage at therapeutic levels to immature brain maturation of rat in order to provide the theoretical and experimental base for clinic. Methods A total of 40 healthy 18-day-old Sprague-Dawley(SD) rats(male or female) were randomly assigned into 2 groups: normal saline(NS) treated as control group(20 cases), PB group(20 cases). Each group was further randomly divided into long-term(4 weeks) treated group and short-term(2 weeks) treated group(10 rats in each group). The rats in PB group received intragastricadministration with PB (30 mg/kg). The rats in control group were handled by injection of NS into stomach and abdomen according to 4 mL/kg.All performances were undertaken for twice every day.At the end of the therapeutic period, body and brain weight were measured when the rats were sacrificed.Histological studies on the tissues of frontal lobes and hippocampus were performed by Hematoxylin-Eosin(HE) staining and Nissl staining.Expressions of apoptosis-related proteins Bcl-2 and Bax in neurons were detected by immunohistochemistry. Results There were no significant differences in body and brain weights or histological studies index among control group as well as PB group before and after treatment for short term(P>0.05). Remarkable reduction of brain weight was only observed in immature rats exposed to PB compared to control group for long period, and significant neurodegeneration, neuronal necrosis were observed in immature rats exposed to PB compared to control group(all P<0.01). The expression of Bax protein in the frontal lobe increased significantly in immature rats receiving PB for long period comparing with control(P<0.01). In contrast, expression of Bcl-2 protein did not change at therapeutic level.The ratio of Bax/Bcl-2 was obviously increased. Conclusions Chronic treatment with PB will result in significant neuronal apoptosis and necrosis and persistent cognitive impairment and brain damage to immature rates.Brain damage of PB at therapeutic level to immature brain may be irreversible.The significant expression of Bax protein in the frontal lobe and the high rate of Bax/Bcl-2 are probably the main reasons which cause brain weight decreasing and brain damage by PB in immature brain tissue. Key words: Rat; Antiepileptic drug; Brain tissue