Reduction In Brain Weight Research Articles

Impaired glutamate recycling and GluN2B‐mediated neuronal calcium overload in mice lacking TGF‐β1 in the CNS

Transforming growth factor β1 (TGF-β1) is a pleiotropic cytokine expressed throughout the CNS. Previous studies demonstrated that TGF-β1 contributes to maintain neuronal survival, but mechanistically this effect is not well understood. We generated a CNS-specific TGF-β1-deficient mouse model to investigate the functional consequences of TGF-β1-deficiency in the adult mouse brain. We found that depletion of TGF-β1 in the CNS resulted in a loss of the astrocyte glutamate transporter (GluT) proteins GLT-1 (EAAT2) and GLAST (EAAT1) and decreased glutamate uptake in the mouse hippocampus. Treatment with TGF-β1 induced the expression of GLAST and GLT-1 in cultured astrocytes and enhanced astroglial glutamate uptake. Similar to GLT-1-deficient mice, CNS-TGF-β1-deficient mice had reduced brain weight and neuronal loss in the CA1 hippocampal region. CNS-TGF-β1-deficient mice showed GluN2B-dependent aberrant synaptic plasticity in the CA1 area of the hippocampus similar to the glutamate transport inhibitor DL-TBOA and these mice were highly sensitive to excitotoxic injury. In addition, hippocampal neurons from TGF-β1-deficient mice had elevated GluN2B-mediated calcium signals in response to extrasynaptic glutamate receptor stimulation, whereas cells treated with TGF-β1 exhibited reduced GluN2B-mediated calcium signals. In summary, our study demonstrates a previously unrecognized function of TGF-β1 in the CNS to control extracellular glutamate homeostasis and GluN2B-mediated calcium responses in the mouse hippocampus.

Spatial memory and learning deficit following prenatal exposure to fenugreek seeds aqueous extract in adolescent mice

Event Abstract Back to Event Spatial memory and learning deficit following prenatal exposure to fenugreek seeds aqueous extract in adolescent mice Khalki Loubna1*, BENNIS Mohamed1*, Sokar Zahra1* and BA-M'Hamed Saadia1* 1 University Caddi Ayyad, Faculty of Sciences Semlalia Marrakech, Morroco, Departement of Biology, Morocco Disturbance of endogenous hormones actions by chemicals, have been implicated in birth defects associated with hormone-dependent development. Phytoestrogens are a class of endocrine disruptors found in plants. In the current study we examined the effects of prenatal exposure to Fenugreek seeds, a phytoestrogen plant; on learning and memory ability of the offspring mice. Female swiss mice were randomized into 3 groups and subjected to daily oral gavage of Fenugreek seeds aqueous extract at the doses of 500 mg/kg (group A), 1000 mg/kg (group B), or distilled water (group C, as control). Pups body weight was measured at 1, 7, 14, 21 and 28 day of age. From each group, 20 male weaning mice of the first generation were randomly selected to examine their spatial memory (3 weeks) using continuous alternation in T-maze task and to assess associative learning ability by the shuttle-box avoidance learning test (14 weeks). The brain of the offspring was removed and cut for histological evaluation. The progeny of exposed mice displayed reduced body weight at birth (1000 mg/kg group: 27%; 500 mg/kg group: 32%) and reduced brain weight (10% in both treated groups). Assessment on a continuous alternation T-maze test showed a significant reduction in successful spontaneous alternations in exposed mice but only in the 1000 mg/kg group. In the shuttle-box, the avoidance performance of the treated groups was significantly inferior to that of controls in the 2nd, 3rd and 4the days of the test. These results allow us to conclude that maternal fenugreek seeds exposure induces growth retardation and disturbance of the learning and memorizing abilities in the offspring mice. Keywords: Mice, Prenatal exposure, Spacial memory, behavioral teratology, Fenugreek seeds aqueous extract Conference: 4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Turkey, 30 Sep - 3 Oct, 2012. Presentation Type: Poster Presentation Topic: Abstracts Citation: Loubna K, Mohamed B, Zahra S and Saadia B (2013). Spatial memory and learning deficit following prenatal exposure to fenugreek seeds aqueous extract in adolescent mice. Conference Abstract: 4th Conference of the Mediterrarnean Neuroscience Society. doi: 10.3389/conf.fnhum.2013.210.00045 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 25 Jan 2013; Published Online: 11 Apr 2013. * Correspondence: Miss. Khalki Loubna, University Caddi Ayyad, Faculty of Sciences Semlalia Marrakech, Morroco, Departement of Biology, Marrakech, 40 000, Morocco, lkhalki@gmail.com Prof. BENNIS Mohamed, University Caddi Ayyad, Faculty of Sciences Semlalia Marrakech, Morroco, Departement of Biology, Marrakech, 40 000, Morocco, mbennis@ucam.ac.ma Prof. Sokar Zahra, University Caddi Ayyad, Faculty of Sciences Semlalia Marrakech, Morroco, Departement of Biology, Marrakech, 40 000, Morocco, sokar@ucam.ac.ma Prof. BA-M'Hamed Saadia, University Caddi Ayyad, Faculty of Sciences Semlalia Marrakech, Morroco, Departement of Biology, Marrakech, 40 000, Morocco, bamhamed@ucam.ac.ma Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Khalki Loubna BENNIS Mohamed Sokar Zahra BA-M'Hamed Saadia Google Khalki Loubna BENNIS Mohamed Sokar Zahra BA-M'Hamed Saadia Google Scholar Khalki Loubna BENNIS Mohamed Sokar Zahra BA-M'Hamed Saadia PubMed Khalki Loubna BENNIS Mohamed Sokar Zahra BA-M'Hamed Saadia Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Effects of Rat Prenatal Exposure to Valproic Acid on Behaviour and Neuro-Anatomy

Autism is a highly debilitating disorder that has recently displayed a dramatic rise in incidence. In order to realistically study preventative and remedial strategies, it is important that we develop and understand useful animal models of the disorder. The purpose of this study was to investigate the efficacy of the prenatal valproic acid (VPA) rat model of autism by examining the neuro-anatomical and behavioural outcomes of offspring exposed to this paradigm. The VPA-treated rats exhibited behavioural changes in the delayed non-match-to-sample task, novel object recognition, activity box, and Whishaw tray reaching task. Anatomically, there was a reduction in brain weight and cortical thickness, along with decreased dendritic branching in the orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), and decreased spine density in the mPFC, OFC, and cerebellum. Behavioural and anatomical findings from this study produced reliable results indicating that prenatal VPA exposure may be a viable model for the study of autism in rats.

Editorial (Hot Topic: Epidemiology & Risk Factors for Alzheimer’s Disease)

Clinical-pathologic studies have had an enormous impact on our understanding of aging and the conditions that lead to loss of cognitive and motor function in advanced age. In the mid to late 19th century, clinical-pathologic studies of persons with dementia demonstrated atrophy and a reduction of brain weight, which were thought to result from ‘hardening of the arteries’ [1]. Senile plaques were first identified by Blocq and Marinesco in 1892 but these investigators did not make the link to dementia [2]. However, in separate papers in 1906, Alzheimer and Fischer each reported that senile plaques and neurofibrillary tangles were associated with dementia [3, 4]. In 1910, Kraepelin introduced the term Alzheimer's disease (AD) in his textbook of psychiatry referring to a relatively rare cause of pre-senile dementia that was thought to be something quite distinct from senile dementia which resulted from hardening of the arteries [5]. The distinction between pre-senile and senile dementia lasted six decades until an elegant series of papers by Tomlinson, Blessed and Roth demonstrated that senile plaques and neurofibrillary angles were also a major cause of senile dementia [6-9]. Clinical and pathologic criteria for AD introduced in the mid 1980s set up a clinical-pathologic dichotomy in which the clinical diagnosis of AD required no evidence of known factors (including cerebrovascular disease) that may lead to dementia (i.e., a diagnosis of exclusion), and the pathologic diagnosis which required a moderate number of neocortical neuritic plaques [10,11]. Almost immediately, two studies published in 1988 challenged this dichotomy by identifying people without dementia during life who had significant AD pathology at autopsy [12, 13]. Thus, it became clear that a complete picture of AD would require the clinical study of people with a wide range of cognitive functioning, especially persons without dementia, who subsequently come to autopsy. Early efforts to assemble such a sample met with limited success. For example, between 1987 and 1995, the Consortium to Establish a Registry for AD (CERAD) which included 24 federally funded AD centers from across the United States conducted only 8 autopsies out of 25 deaths among those recruited without dementia [14]. It was clear that federally funded AD centers established at tertiary care medical centers had much expertise to contribute to the study of aging and AD, but their capacity to secure large numbers of autopsies from persons without dementia was limited. The need for such data led to the realization that community-based autopsy series could play a critical role in understanding AD, and more broadly, dementia-causing pathology, in addition to other age-related conditions associated with morbidity and mortality including parkinsonism and loss of motor function.

The developmental neurobehavioral effects of fenugreek seeds on prenatally exposed mice

Ethnopharmacological relevanceFenugreek (Trigonella foenum graecum (L.)), is a medicinal plant whose seeds and leaves are widely used in Moroccan traditional medicine. Consumption of fenugreek seeds during pregnancy has been associated with a range of congenital malformations, including hydrocephalus, anencephaly and spina bifida.In previous work we have shown that exposure of pregnant mice to Aqueous Extract of Fenugreek Seeds (AEFS) leads to reduced litter size, intrauterine growth retardation, and malformations. However, there have been no studies to date of its longer-term neurobehavioral effects. We investigated these effects in prenatally exposed mice. Materials and methodsPregnant females were exposed to 0, 500 or 1000mg/kg/day AEFS, by gavage, for the whole period of gestation. Pups body weight was measured at 1, 7, 14, 21 and 28 day of age. Behavior of progeny was evaluated three weeks after birth using the open field, the rotarod test and the continuous alternation task by the T-maze. At 28 postnatal day age, brain of progeny was removed and cut for histological evaluation. ResultsThe progeny of exposed mice displayed reduced body weight at birth (1000mg/kg group: 27%; 500mg/kg group: 32%) and reduced brain weight (10% in both treated groups). Both males and females mice prenatally exposed to AEFS displayed a significant decrease in the locomotor activity, in the boli deposits during the open field test and in motor coordination. These results seem to show that exposure to AEFS induces a depressive effect in the offspring. Assessment on a continuous alternation T-maze test showed a significant reduction in successful spontaneous alternations in males and females but only in the 1000mg/kg group. ConclusionThese results suggest that prenatal exposure of mice to high dose of fenugreek seeds causes growth retardation and altered neurobehavioral performance in the post-weaning period in both male and female.

Maternal omega-3 fatty acid supplementation protects against lipopolysaccharide-induced white matter injury in the neonatal rat brain

Objectives: Periventricular leukomalacia (PVL) is the predominant form of brain injury in premature infants, and no specific treatment currently exists for this condition. We have evaluated whether maternal omega-3 fatty acid (ω3 FA) treatment reduces endotoxin-induced PVL in the developing rat brain. Methods: Wistar rats with dated pregnancies were fed a standard diet or a diet enriched in ω3 FA (70% docosahexaenoic acid + 30% eicosapentaenoic acid mixture) during gestation. Intraperitoneal injection of lipopolysaccharide (LPS) was administered consecutively on the 18th and 19th embryonic days to establish the endotoxin-induced PVL rat model. The animals were divided into four groups: (i) control, (ii) PVL, (iii) PVL+low-dose ω3 FA and (iv) PVL+high-dose ω3 FA. At day P7, apoptosis and hypomyelination in periventricular white matter were evaluated by immunohistochemical assessments. Results: High-dose maternal ω3 FA treatment reduced brain weight loss. Maternal ω3 FA treatment given either in low or high doses greatly decreased caspase-3 immunoreactivity and increased myelin basic protein immunoreactivity, indicating a decrease in apoptosis and hypomyelination. Conclusion: Considering that no specific treatment is available for PVL, maternal ω3 FA supplementation may provide a nutritional strategy to limit periventricular white matter damage caused by infections during pregnancy.

Carnitine palmitoyltransferase‐1c gain‐of‐function in the brain results in postnatal microencephaly

Carnitine palmitoyltransferase-1c (CPT1c) is a newly identified and poorly understood brain-specific CPT1 homologue. Here, we have generated a new animal model that allows the conditional expression of CPT1c in a tissue specific and/or temporal manner via Cre-lox mediated recombination. Brain-specific, exogenous expression of CPT1c was achieved by crossing transgenic CPT1c mice to Nestin-Cre mice. The resulting double transgenic mice (CPT1c-TgN) displayed severe growth retardation in the postnatal period with a stunted development at 2 weeks of age. CPT1c-TgN mice had a greater than 2.3-fold reduction in brain weight. Even with this degree of microencephaly, CPT1c-TgN mice were viable and fertile and exhibited normal post-weaning growth. When fed a high fat diet CPT1c-TgN mice were protected from weight gain and the difference in body weight between CPT1c-TgN and control mice was further exaggerated. Conversely, low fat, high carbohydrate feeding partially reversed the body weight defects in CPT1c-TgN mice. Analysis of total brain lipids of low fat fed mice revealed a depletion of total very long chain fatty acids in adult CPT1c-TgN mice which was not evident in high fat fed CPT1c-TgN mice. These data show that CPT1c can elicit profound effects on brain physiology and total fatty acid profiles, which can be modulated by the nutritional composition of the diet.

583 Lactoferrin Supplementation Protects Brain Development in Rat Pups Exposed to Prenatal Dexamethasone

Background: In rats, in utero exposure to dexamethasone mimics gestational stress and showed reduction in brain weight and myelination. At postnatal day 7 (P7), in vivo 1H-MRS showed alterations of cerebral metabolism in cortex and hippocampus, suggesting impairment of brain structure, energy metabolism and neurotransmitter. Lactoferrin (Lf) an iron-binding glycoprotein secreted in milk with an antioxidant activity is transferred into the the brain after oral administration. Aims: We hypothesized that Lf could influence brain development and prevent cerebral damages following prenatal exposure to glucocorticoids. Methods: Rats were treated with DEX (100 µg/kg/ day) during the third week of gestation with access to standard diet (Ctrl-DEX), or Lactoferrin-enriched diet (1 g/kg/day) during gestation and lactation (Lf-DEX). Sham rats not exposed to DEX fed with standard diet (Ctrl-Veh). In vivo 1H-MRSpectroscopy of hippocampus and cortex were acquired at P7 and compared using a Kruskal-Wallis test. Results: Ctrl-DEX group showed decreased of NAA-NAAG in the hippocampus compared to Ctrl- Veh group (2.55±0.26mM vs 3.37±0.10mM, p< 0.05). A decrease of Glu-Gln was observed in both the hippocampus (3.74±0.85mM vs 5.32±0.66mM, p< 0.05) and the cortex (2.95±0.66mM vs 5.62±0.78mM, p< 0.05). No differences have been found between Lf-DEX group and both Ctrl-Veh and Ctrl-DEX groups. Conclusions: Variation of NAA-NAAG and Glu-Gln, considered as markers of neuronal integrity and function, confirmed the altered brain development after Dex exposure and revealed the potential protective effect of the lactoferrin in a rat model of prenatal exposure to adverse conditions.

Solvent inhalation (toluene and n-hexane) during the brain growth spurt impairs the maturation of frontal, parietal and occipital cerebrocortical neurons in rats

Solvent abuse during pregnancy may cause “fetal solvent syndrome”, which is characterized by mild brain atrophy and associated with behavioral, cognitive, and emotional abnormalities. The present study investigated whether solvent inhalation during the preweaning period (P2–P21) alters the morphological maturation of frontal, parietal, and occipital cortical neurons. Twelve hours after delivery (postnatal day 0, P0), litters were cross-fostered, culled to 8 pups/dam and housed together with a dam in standard laboratory cages. Litters were randomly assigned to the “air-only” group (n=64, 8 litters) and to the “solvent-sniffer” group (n=72, 9 litters). During P2–P21, each animal was exposed daily to either organic solvent vapors (75% toluene and 18% n-hexane, a solvent mixture commonly found in glues and adhesives) or clean air. To determine the impact of early solvent inhalation on cortical neuronal differentiation, brains were stained using the Golgi-Cox-Sholl procedure to quantitatively assess neocortical pyramidal cell dendrogenesis. Preweaning, solvent-exposed animals displayed dramatic impairments in dendritic growth as well as significant reductions in brain weight and size.

Veranderungen von Hirn- und Augengröißen bei wilden und domestizierten Truthühnern (Meleagris gallopavo L., 1758)1

Reductions of brain and eye weight in the wild and domestic turkey (Meleagris gallopavo) Studied is the intraspecific relationship between brain and eye weight to total body weight in native turkes and domestic strains. Brain. The turkeys show a common allometric exponent of a = 0.25. Differences in sex are found only within wild turkeys; gobbler and hen differ by 17.9 %. A reduction in brain weight of 35.2 % between wild male and domestic turkeys and of 23.8 % between wild hen and domestic turkeys are observed. Eyes. Differences in sex within each class independent from body size are not found. But there exist considerable reductions in eye weight from wild to domestic state. In wild turkeys eye weight is by 26.9 % heavier than in domestic strains. Changes in brain size are compared with observations found in other fowls. The two heritable complexes wildness and domesticity are discussed with evolutional, functional and environmental connexions.

Effects of brief postnatal fasting upon brain development in rabbits.

Newborn animals were subjected to a two-day postnatal fast immediately after birth. These animals and control littermates matched for birth weight were killed at 60 days of age. The brain was weighed, divided into regional brain areas, and analyzed for DNA, RNA, protein, and cholesterol content. Those fasted animals whose body weight was more than 25% below the control littermate at 12 days of age exhibited a significant reduction of brain weight and constituents at 60 days of age (group II). Cholesterol accumulation was slowed to a greater extent than other constituents (84% of control values) but DNA, RNA, and protein levels were also diminished in a statistically significant manner. Those fasted animals whose body weight nearly caught up to the controls after the fast did not manifest differences of brain size and composition at 60 days of age (group I). When adjusted for life span, the timetable of resumption of weight gain in fasted rabbits is comparable to the time required for regaining birth weight of very low birth weight human infants. These data indicate that the degree of body weight catch-up after a brief postnatal fast will affect subsequent brain development in the rabbit, a species which, like the human, is a perinatal brain developer.

Brain autopsy in organic solvent syndrome.

General autopsy findings, brain weight and brain pathology were studied in 98 men and five women who had been exposed occupationally to organic solvents over several years and assessed by the Danish National Board of Industrial Injuries for chronic toxic encephalopathy. The findings were compared with a forensic control material and a hospital control material. As in the general population, the most common causes of death among the exposed workers were heart failure and other vascular diseases. Due to the composition of the material (forensic cases), the number of suicides and violent deaths was high. Atherosclerosis was the most common CNS finding, but in comparison with the two control materials, no increase in the frequency of atherosclerosis or of Alzheimer's disease was found. Brain weights of the exposed workers corresponded closely to brain weights in the control materials, after correction for body height, body weight and age. Chronic alcoholism was correlated with slightly reduced brain weight.

Neuroprotective Effects of Vascular Endothelial Growth Factor Following Hypoxic Ischemic Brain Injury in Neonatal Rats

Vascular Endothelial Growth Factor (VEGF) protects the brain against ischemic injury in adult animals. We evaluated whether VEGF has neuroprotective effects against hypoxic-ischemic (HI) brain injury in newborn rats. Seven-day-old rat pups had the right carotid artery permanently ligated followed by 140 min of hypoxia (8% oxygen). VEGF (5, 10, 20, or 40 ng) or vehicle was administered intracerebroventricularly 5 min after reoxygenation following HI. Brain damage was evaluated by weight loss of the right hemisphere at 22 d after HI and by gross and microscopic morphology. Body weight, rectal temperature, and mortality were not significantly different in the VEGF and vehicle treated groups. VEGF treatment increased brain VEGF levels at 15 min after injection. VEGF (10 and 20 ng) significantly reduced brain weight loss (p < 0.05) and gross brain injury (p < 0.05); however, treatment with 5 or 40 ng did not. VEGF (10 ng) also decreased brain damage assessed by histologic scoring. VEGF increased phosphorylation of protein kinase B (Akt) and extracellular-signal regulated kinase 1/2 (ERK1/2) in the cortex (p < 0.05). These results suggest that VEGF has neuroprotective effects in the neonatal rat HI model that may be related to activation of the Akt/ERK signaling pathway.

High concentrations of phenylalanine stimulate peroxisome proliferator-activated receptor γ: Implications for the pathophysiology of phenylketonuria

If left untreated, the common inherited metabolic disorder phenylketonuria (PKU) presents with mental retardation and reduced brain weight. The underlying molecular reasons for these deficits are unknown so far. Using human neuroblastoma cells as a model for normal human neuroblasts, elevated phenylalanine concentrations suppressed proliferation of these cells in culture. Furthermore, microarray and functional assays of these cells revealed that both phenylalanine and the known PPARγ agonist rosiglitazone regulated the same set of genes causing subsequently similar changes in the functional assays. The lowered brain weight of PKU patients may thus be the result of reduced neuroblast proliferation caused by phenylalanine-induced stimulation of PPARγ receptors. The observation that high concentrations of small substrates can activate receptors may serve as a new paradigm for other metabolic diseases and provides a new approach for the treatment of these disorders by application of specific receptor antagonists.

The evolutionarily conserved G protein-coupled receptor SREB2/GPR85 influences brain size, behavior, and vulnerability to schizophrenia

The G protein-coupled receptor (GPCR) family is highly diversified and involved in many forms of information processing. SREB2 (GPR85) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, e.g., the hippocampal dentate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to schizophrenia. Mild overexpression of SREB2 caused significant brain weight reduction and ventricular enlargement in transgenic (Tg) mice as well as behavioral abnormalities mirroring psychiatric disorders, e.g., decreased social interaction, abnormal sensorimotor gating, and impaired memory. SREB2 KO mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavioral abnormalities. In both Tg and KO mice, no gross malformation of brain structures was observed. Because of phenotypic overlap between SREB2 Tg mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 SNPs, located in intron 2 and in the 3' UTR, were overtransmitted to schizophrenia patients in a family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy.

Generation recruitment and death of brain cells throughout the life cycle ofSorexshrews (Lipotyphla)

Young shrews of the genus Sorex that are born in early summer reduce their body size before wintering, including a reduction of brain weight of 10-30%. In the spring they mature sexually, double their body weight and regain about half of the loss in brain weight. To investigate the mechanisms of brain weight oscillations we studied the rate of cell death and generation in the brain during the whole life cycle of the common shrew (Sorex araneus) and pygmy shrew (S. minutus). After weaning, shrews generate new brain cells in only two mammalian neurogenic zones and approximately 80% of these develop into neurones. The increase of the shrew brain weight in the spring did not depend on recruitment of new cells. Moreover, adult Sorex shrews did not generate new cells in the dentate gyri. Injections of 5-HT1A receptor agonists in the adult shrews induced neurogenesis in their dentate gyri, showing the presence of dormant progenitor cells. Generation of new neurones in the subventricular zone of the lateral ventricles and their recruitment to olfactory bulbs continued throughout life. TUNEL labelling showed that the rate of cell death in all brain structures, including the proliferation zones and olfactory bulb, was very low throughout life. We conclude that neither cell death nor recruitment significantly contributes to seasonal oscillations and the net loss of brain weight in the Sorex shrews. With the exception of dentate gyrus and olfactory bulb, cellular populations of brain structures are stable throughout the life cycle of these shrews.

Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

Rett syndrome (RTT) is caused by mutations in the X-linked gene MECP2. While patients with RTT show widespread changes in brain function, relatively few studies document changes in brain structure and none examine in detail whether mutations causing more severe clinical phenotypes are linked to more marked changes in brain structure. To study the influence of MeCP2-deficiency on the morphology of brain areas and axonal bundles, we carried out an extensive morphometric study of two Mecp2-mutant mouse models (Mecp2B and Mecp2J) of RTT. Compared to wildtype littermates, striking changes included reduced brain weight ( approximately 13% and approximately 9%) and the volumes of cortex ( approximately 11% and approximately 7%), hippocampus (both by approximately 8%), and cerebellum ( approximately 12% and 8%) in both mutant mice. At 3 weeks of age, most (24 of 47) morphological parameters were significantly altered in Mecp2B mice; fewer (18) were abnormal in Mecp2J mice. In Mecp2B mice, significantly lower values for cortical area were distributed along the rostrocaudal axis, and there was a reduced length of the olfactory bulb ( approximately 10%) and periaqueductal gray matter ( approximately 16%). In Mecp2J mice, while there was significant reduction in rostrocaudal length of cortex, this parameter was also abnormal in hippocampus ( approximately 10%), periaqueductal gray matter ( approximately 13%), fimbria ( approximately 18%), and anterior commissure ( approximately 10%). Our findings define patterns of Mecp2 mutation-induced changes in brain structure that are widespread and show that while some changes are present in both mutants, others are not. These observations provide the underpinning for studies to further define microarchitectural and physiological consequences of MECP2 deficiency.

Neuroprotective effects of sodium orthovanadate after hypoxic-ischemic brain injury in neonatal rats

Sodium orthovanadate (SOV), a competitive inhibitor of protein tyrosine phosphatases, is neuroprotective in adult animals following an ischemic event. The present study evaluated whether SOV might be protective in a rat pup hypoxic-ischemic (HI) model. Seven-day-old rat pups had the right carotid artery permanently ligated followed by 140 min of hypoxia (8% oxygen). SOV 1.15, 2.3, 4.6, 9.2 or 18.4 mg/kg and vehicle were administered by i.p. injection at 5 min after reoxygenation. Brain damage was evaluated by weight loss of the right hemisphere at 22 days after hypoxia and by gross and microscopic morphology. SOV lowered blood glucose at doses of 1.15, 2.3 and 4.6 mg/kg and induced toxic effects at 9.2 mg/kg. The doses of 2.3 and 4.6 mg/kg of SOV significantly reduced brain weight loss ( p < 0.05), but treatment with 1.15 or 9.2 mg/kg did not. SOV 4.6 mg/kg also improved the histopathologic score and diminished the HI induced reduction of Akt and ERK-1/2 phosphorylation in the cortex ( p < 0.05) and increased the density of BrdU-positive cells in the subventricular zone ( p < 0.01). In conclusion, SOV has neuroprotective effects in the neonatal rat HI model partially mediated by activating Akt and ERK-1/2 pathways.

Fetal Down Syndrome Brains Exhibit Aberrant Levels of Neurotransmitters Critical for Normal Brain Development

In the immature developing fetal brain, amino acids (such as gamma-aminobutyric acid, and taurine) and monoamines (serotonin, noradrenaline, and dopamine) act as developmental signals or regulators. In subjects with Down syndrome, dysfunctional brain development is evident from birth as reduction in brain weight, as well as volume reductions in specific brain regions, and an altered number of neurons, dendrites, and dendritic branching is observed. However, mechanisms that underlie the observed dysfunctional brain development in Down syndrome are not clear. Because diverse amino acids and monoamines are critical for normal brain development, we wanted to determine whether dysfunctional brain development observed in subjects with Down syndrome is associated with altered brain amino acid and/or monoamine levels. We quantified tissue concentrations of diverse amino acids, including gamma-aminobutyric acid and taurine, and the monoamines serotonin, noradrenaline, and dopamine in the frontal cortex of fetal Down syndrome tissue at a gestational age of approximately 20 weeks versus age-matched control aborted fetuses. Fetal Down syndrome brains showed reductions in the levels of serotonin, gamma-aminobutyric acid, taurine, and dopamine in the frontal cortex. No alteration in the levels of arginine, aspartate, glutamine, glutamate, glycine, histidine, serine, or noradrenaline was observed. Serotonin, gamma-aminobutyric acid, taurine, and dopamine are critical for the acquisition of brain morphologic features, neuronal and glia proliferation, and synapse formation. The detected reductions in the levels of these neurotransmitters may indicate potential mechanisms for the observed dysfunctional neuronal development in the Down syndrome fetal brain.

Age at developmental cortical injury differentially Alters corpus callosum volume in the rat

BackgroundFreezing lesions to developing rat cortex induced between postnatal day (P) one and three (P1 – 3) lead to malformations similar to human microgyria, and further correspond to reductions in brain weight and cortical volume. In contrast, comparable lesions on P5 do not produce microgyric malformations, nor the changes in brain weight seen with microgyria. However, injury occurring at all three ages does lead to rapid auditory processing deficits as measured in the juvenile period. Interestingly, these deficits persist into adulthood only in the P1 lesion case [1]. Given prior evidence that early focal cortical lesions induce abnormalities in cortical morphology and connectivity [1-4], we hypothesized that the differential behavioral effects of focal cortical lesions on P1, P3 or P5 may be associated with underlying neuroanatomical changes that are sensitive to timing of injury. Clinical studies indicate that humans with perinatal brain injury often show regional reductions in corpus callosum size and abnormal symmetry, which frequently correspond to learning impairments [5-7]. Therefore, in the current study the brains of P1, 3 or 5 lesion rats, previously evaluated for brain weight, and cortical volume changes and auditory processing impairments (P21-90), were further analyzed for changes in corpus callosum volume.ResultsResults showed a significant main effect of Treatment on corpus callosum volume [F (1,57) = 10.2, P < .01], with lesion subjects showing significantly smaller callosal volumes as compared to shams. An Age at Treatment × Treatment interaction [F(2,57) = 3.2, P < .05], indicated that corpus callosum size decreased as the age of injury decreased from P5 to P1. Simple effects analysis showed significant differences between P1 and P3 [F(1,28) = 8.7, P < .01], and P1 and P5 [F(1,28) = 15.1, P < .001], subjects. Rats with P1 injury resulting in microgyria had the greatest reduction in corpus callosum volume (22% reduction), followed by the P3 group (11% reduction), which showed a significant reduction in corpus callosum volume compared to shams [F(1,31) = 5.9, P < .05]. Finally, the P5 lesion group did not significantly differ from the sham subjects in callosal volume.ConclusionDecrements in corpus callosum volume in the P1 and 3 lesion groups are consistent with the reductions in brain weight and cortical volume previously reported for microgyric rats [1,8]. Current results suggest that disruption to the cortical plate during early postnatal development may lead to more widely dispersed neurovolumetric anomalies and subsequent behavioral impairments [1], compared with injury that occurs later in development. Further, these results suggest that in a human clinical setting decreased corpus callosum volume may represent an additional marker for long-term behavioral outcome.