Top PDF Maternal immune activation and abnormal behavior in the adult offspring : towards a mechanism

Maternal immune activation and abnormal behavior in the adult offspring : towards a mechanism

Maternal immune activation and abnormal behavior in the adult offspring : towards a mechanism

undergraduate, Jennifer Li, to establish a model of MIA that displays brain inflammation like that seen in autism. This work is ongoing. Appendix B covers work by myself, with a contribution by rotating graduate student Illana Goldflam, on the effects of MIA on the placenta. Appendix C describes work towards the establishment of a model of gene- environment interaction using a DISC-1 mutant mouse. This work is being continued by a postdoctoral fellow in our lab, Catherine Bregere, and will eventually be included in a publication with a Canadian group working with different strains of DISC-1 mice. Appendix D describes cytokine assays that I performed as part of a collaboration with U.C. Davis, in which we aim to establish the MIA model in a non-human primate. The offspring of these monkeys will be behaviorally analyzed by the group of Dr. David Amaral at U.C. Davis. Appendix E describes preliminary results looking for targets downstream of IL-6 in the fetal brain, in an attempt to extend the mechanism of maternal immune activation beyond the cytokine. Appendix F describes a method that I developed for maintaining physiologically relevant levels of cytokines in the serum of mice without continued stress from injections or minipumps by electroporating plasmid DNA in the leg muscles. This technique may be useful in the future. Finally, Appendix G describes a collaboration with the Gage laboratory at the Salk Institute, analyzing retrotransposon activation during MIA in L1 transgenic mice. I generated the MIA offspring and postdoctoral fellow Dr. Alysson Muotri preformed the majority of the described
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Region Specific Effects of Maternal Immune Activation on Offspring Neuroimmune Function

Region Specific Effects of Maternal Immune Activation on Offspring Neuroimmune Function

A well-organized neuroimmune response is essential for appropriate tissue maintenance and immune surveil- lance of the CNS, to defend the CNS against pathogens, and to help it recover from stress and injury [19]-[22]. Neuroinflammation has generally been regarded as a double-edged sword that can cause injury to or protect the CNS. There is evidence that neuroinflammation is a risk factor for neurodegenerative disorders, such as Alz- heimer’s [23] and Parkinson’s diseases [20] [24]. On the other hand, insufficient neuroinflammation and micro- glial dysfunction could lead to insufficient clearance of β -amyloid plaques and have been proposed as a possible pathway in the pathogenesis of Alzheimer’s disease [25] [26]. Additionally, a neuroimmune-based mechanism has been posited for the etiology of schizophrenia and autism [27]-[30]. Graciarena et al. reported that subcuta- neous injections of LPS into pregnant rats every other day from gestational days 14 to 20 leads to persistent mi- croglial activation specifically in the hippocampus of adult offspring animals [31]. The present study did ex- amine the mRNA induction of cytokines and chemokines in L/S and S/S pups and found that the mRNA expres- sion of IL-1 β trended higher in all four brain regions of L/S than S/S pups while the basal level of IL-6, KC, and Mob-1 expression was barely detectable in L/S and S/S pups under the experimental conditions. While it is of interest to further examine the status of neuroinflammation of the offspring at the basal level, the results in this study suggest that the offspring’s neuroimmune response to an immune insult may be impacted to different de- grees depending on the brain regions. Considering that neuroinflammation involves finely regulated expression of pro-inflammatory and anti-inflammatory mediators [20]-[22], profiling of neuroinflammatory mediators at different time points following LPS stimulation would help to further delineate the effects of maternal immune activation on the neuroimmune function of the offspring pups and provide a better understanding of the interplay between disturbances in maternal environment and development of neuropathologies in the offspring later in life.
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Effects of Immune Activation during Early or Late Gestation on N Methyl ᴅ Aspartate Receptor Measures in Adult Rat Offspring

Effects of Immune Activation during Early or Late Gestation on N Methyl ᴅ Aspartate Receptor Measures in Adult Rat Offspring

Epidemiological investigations implicate gestational inflammation as a significant risk factor in the manifestation of psychiatric dis- orders, including schizophrenia, in offspring (1). Studies suggest either the first (2) or second (1) trimester as the critical window of vulnerability for maternal infection to increase schizophrenia risk in people. Maternal immune activation (MIA), as modeled in rodents and non-human primates, suggests pro-inflammatory cytokines that result from MIA, rather than the pathogen itself, are critical in the development of schizophrenia-like behaviors and neuropathology in adult offspring (3–6). Deficits in sensorimotor gating and working memory are prevalent in schizophrenia (7, 8) and found in MIA rodents. The use of MIA in animal models has therefore been pivotal to establish a causal link between gestational inflammation and the development of neuropsychiatric-related phenotypes; however, only limited changes in brain cytokines are still found in the adult (9), suggesting that molecular alterations in neurotransmitter pathways including monoamines (10, 11) and GABA (12) may be more long lasting. Since pharmacologi- cal manipulations of glutamate neurotransmission are known to cause deficits in sensorimotor gating and in working memory, which are reminiscent of changes found in schizophrenia, we predict that widespread changes in glutamate receptors may be found in adult offspring of mothers who experienced immune activation while pregnant. While there is a report of a reduction in one subunit of the N-methyl-d-aspartate receptor (NMDAR) in one brain region (the hippocampus) (13), there are still gaps in our knowledge regarding the putative changes in other NMDAR subunits and the extent of NMDAR changes outside the hippocampus. It is important to determine the nature and extent of NMDAR changes more fully to not only correlate them with behavior but to also aid in the design of treatments aimed to either prevent or ameliorate changes in NMDAR-mediated neurotransmission that may underlie symptoms and cognitive deficits resulting from developmental overactivation of the immune system. This knowledge will expand our understanding of how gestational inflammation impacts glutamatergic signaling in psychiatric disorders with a neurodevelopmental etiology.
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Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation

Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation

Our study demonstrates that prenatal immune challenge with poly(I:C) on GD9 disrupts social approach behavior in prepubertal offspring. This finding corroborates the results of previous studies reporting impaired social ap- proach behavior in adult offspring who were subjected to poly(I:C)-induced MIA [9, 19–21, 48]. Our findings showing a prepubertal onset of social interaction deficits are an important extension to this previous data in adults. First, it increases the face validity of poly(I:C)- based MIA models for ASD, which is characterized by deficiencies in social interaction starting early in child- hood. Second, these findings highlight that MIA-induced impairments in social interaction are an early patho- logical manifestation preceding many other behavioral and cognitive dysfunctions in this model which do not appear until early adulthood [49]. Such adult-onset be- haviors include deficits in sensorimotor gating [14, 50], selective attention [15, 16], and working memory [51]. Finally, in the context of this study, an even more im- portant finding was that maternal treatment with the active vitamin D hormone 1,25OHD was capable of pre- venting this altered social behavior in juvenile MIA offspring.
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Maternal cholestasis during pregnancy programs metabolic disease in offspring

Maternal cholestasis during pregnancy programs metabolic disease in offspring

Female C57BL6 mice between 10 and 12 weeks of age (Harlan, UK) that had already delivered their first litter were used. Mice were fed an NC diet (RM3 control diet) or an RM3 diet supplemented with 0.5% CA (Lillico) for 1 week before mating and throughout gestation. Pregnant mothers were either sacrificed on day 18 of pregnancy (day 1 of pregnancy was considered the day of plug identification) after a 4-hour fast, following which fetal and maternal tissues and serum were collected, or they were allowed to deliver. Mothers were switched to an NC diet upon delivery, and the litter size was reduced to 4 pups (when possible, 2 males and 2 females). No differences in the female/male ratio were observed in the offspring of NC-fed or CA-fed mice (data not shown). The offspring were weaned after 3 weeks’ lactation. When they reached 12 weeks of age, 1 female and 1 male offspring from each litter were fed a WD (Lillico) for 6 weeks, whereas their littermates were kept on an NC diet. At 18 weeks of age, the offspring were sacrificed for further analysis after a 4-hour fast. Body weight and food intake (in grams) were monitored weekly from weaning to termination. Fasting consistently took place from 8:30 am to 12:30 pm. Two independent cohorts of animals were set up (8 litters from NC-fed and 8 litters from CA-fed mothers, with different mothers for each cohort). Data from 1 animal cohort are presented for simplicity, but both gave consistent results.
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Hereditary abnormal activation in Pleurodeles waltl oocytes

Hereditary abnormal activation in Pleurodeles waltl oocytes

In! I lie Hinl 37 609 61~ (1993) 609 Shorl COlllri/J/Iliol/ Hereditary abnormal activation in Pleurodeles waltloocytes ALAIN COLLENOT' and CHRISTIAN AIMAR> 'Laboratoire de Biofogie du Deve/oppement an[.]

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Quantitative Trait Loci for Maternal Performance for Offspring Survival in Mice

Quantitative Trait Loci for Maternal Performance for Offspring Survival in Mice

tion. It causes QTL analyses to underestimate the num- by-dominance epistasis between chromosome 8 and ber of loci involved in complex traits (Routman and chromosome 15. Note that D8Mit25 ⫹ 2 cM has additive Cheverud 1997). In additive-by-additive epistasis, addi- effects with the LL homozygote displaying superior ma- tivity is detected only within classes of genotypes at the ternal performance for both D15Mit2 ⫹ 20 cM homozy- interacting locus. In Figure 5, for example, if D5Mit61 ⫹ gotes but that this effect is reversed in D15Mit2 ⫹ 20 38 cM is SS, D1Mit3 ⫹ 8 cM is additive with SS having cM heterozygotes. Likewise, D15Mit2 ⫹ 20 cM shows the highest maternal performance. On the other hand, overdominance among D8Mit25 ⫹ 2 cM SS animals and if D5Mit61 ⫹ 38 cM is LL, the pattern is reversed. D1Mit3 ⫹ underdominance among D8Mit25 ⫹ 2 cM LL animals. 8 cM is still additive, but LL has the best maternal perfor- Most observed cases of dominance-by-dominance epista- mance. When we average genotypic effects at one locus sis are negative (Table 3). An example of this kind of interaction (Figure 7) shows that double heterozygotes have a lower genotypic value than that of single heterozy- gotes for each locus. Despite this, double heterozygotes still have better maternal performance than that of pa- rental or recombinant homozygotes. This heterosis may explain why no unsuccessful females were observed in the F 1 generation. While investigating body weight in
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Effects of maternal obesity on early and long-term outcomes for offspring

Effects of maternal obesity on early and long-term outcomes for offspring

Maternal obesity is a potentially modifiable risk factor for adverse outcomes that can occur during pregnancy and the neonatal period. There is emerging evidence to sug- gest that maternal obesity also has longer-lasting effects for the offspring, including increased risk of developing cardiovascular risk factors and disease. The physiological changes during pregnancy including increased inflamma- tory cytokines with associated insulin resistance, resulting in increased nutrient supply to the fetus may contribute to this risk with compensatory fetal hyperinsulinemia, increased fetal adiposity, and lifelong increased cardiometabolic risk. Evidence in support of a programming effect on the offspring of obese women would suggest there is a resultant positive loop effect on the prevalence of obesity, increasing the mag- nitude of the health care challenges posed by obesity. In an age where obesity has been described as a new worldwide epidemic, further work to understand more about the effects of maternal obesity for offspring is crucial.
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Detecting Abnormal Behavior in Web Applications

Detecting Abnormal Behavior in Web Applications

This chapter presents a blog bot detection system, which leverages the behavioral differences be- tween human users and bots in their mouse and keystroke activities. Compared [r]

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Crowd Behavior Detection for Abnormal Conditions

Crowd Behavior Detection for Abnormal Conditions

The need to detect behavior of crowd is to address social issues and have safer and more secure society. The surveillance videos can be used for detecting abnormal behavior of crowd. People naturally run away from the place where unexpected event takes place. Based on this observation we propose a system which detects behavior of crowd automatically when unusual events happen. The proposed system performs appropriate detection of unexpected events. The proposed system is based on optical flow and detects the pattern in crowd motion. The system takes sequence of images i.e. video as input. Preprocessing of video is done. Then frames are extracted from video. Every frame is processed to remove the background and to extract foreground patches. Then features are extracted on the basis of position, magnitude and direction. These extracted features are given to proposed system for further processing. Optical flow is then calculated to find the pattern between frames. The system then detects behavior of crowd as normal or abnormal. The proposed system gives more accurate results then the existing system and identifies crowd behavior through real time videos.
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The genetic mechanism of selfishness and altruism in parent-offspring coadaptation

The genetic mechanism of selfishness and altruism in parent-offspring coadaptation

Fig. 1. Experimental design and expression heat map. (A) The transcriptomic screen for candidate genes underlying parent-offspring coadaptation was based on experimental manipulation of the presence and absence of egg attendance and posthatching parental care: No care (NC), eggs were removed upon the completion of oviposition. No nymph sample was used because of insufficient hatching success of untended eggs (fig. S1 and table S1). Egg care (EC), mothers tended their eggs for 20 days and were then sampled shortly before eggs hatched (2). Nymphs were kept for 6 days without tending females before they were sampled. Full care (FC), mothers tended their eggs until hatching and cared for their nymphs until 6 days after hatching when both were sampled. Antennae, head, abdomen, and ovaries from mothers and the whole body of nymphs were sampled in each treatment. On the basis of this screen, the expression of candidate genes was manipulated using in vivo RNAi to assess their causal effects on behavior and components of evolutionary fitness. (B) Venn diagram illustrating that only two genes with confirmed insect origin were differentially coexpressed in mothers and offspring when they behaviorally interacted according to our selection criterion (see main text). (C to G) Heat maps of differentially expressed genes in different tissues from mothers and the nymphs (P FDR < 0.01). Rows are genes, columns are samples. Samples were clustered according to expression
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Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult type Leydig cell development in male offspring

Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult type Leydig cell development in male offspring

Stereological analysis of the testes showed that total Leydig cell numbers per testis were increased at PND24 only in the DES treatment group (Figure 3f). By PND90, there were no notable differences between both treatment groups and controls. Immunological analysis of total testosterone and LH in peripheral blood showed no differences for any treatment at any time point (Figure 3c and 3d), although a trend towards higher values for LH was evident in the DES-treated group at PND10 (Figure 3d). The ratio of T to LH within individuals has been interpreted as a measure of total Leydig cell functional capa- city. 24,25 Although there was a major increase in this parameter (mean6s.e.m. for all groups combined; P,0.001) between PND24 (0.03760.031; n518) and PND90 (0.44360.482; n518), as the Leydig cells differentiate and the HPG axis attains its final mature status (Figure 3e), there were no differences between treatment groups at all time points. Figure 3g indicates the ratio of circulating INSL3 (see below) to Leydig cell numbers per testis for those individual rats where this was measured. As such, it therefore offers an indication of individual Leydig cell functional capacity. Importantly, what this figure shows is that in spite of increased Leydig cell numbers at PND24, treatment does not appear to have altered their individual capacity to generate INSL3. This is different at PND90, where in the control group, Leydig cells appear to have reduced their individual capacity to make INSL3, compared to PND24, though not in the two treated groups.
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Maternal Dietary Micronutrient Restriction During Preconception, Conception and Postnatal Life Predispose the Offspring to Insulin Resistance and Hypertension in Adult Life

Maternal Dietary Micronutrient Restriction During Preconception, Conception and Postnatal Life Predispose the Offspring to Insulin Resistance and Hypertension in Adult Life

To assess the effect of maternal dietary micronutrient restriction during preconception, conception and postnatal days on insulin resistance, fat metabolism and systolic blood pressure in offspring. Female weanling mice received a control or a 50% micronutrient restricted (MR) diet and mated with control males. Pups born to the dams on the restricted diet were weaned on to the restricted diet till postnatal day (PD) 360. At birth, pups from deficient dams had reduced birth weight and crown rump length. Increased fasting glucose, insulin, total cholesterol and triglycerides levels were observed in the offspring of MR group. At PD-120, MR restricted offspring had an elevated systolic blood pressure than controls. Compared with controls, total body electrical conductivity measurements indicated significantly higher body fat percentage, lower lean body mass and fat-free mass in MR offspring besides elevated plasma triacylglycerols. Maternal micronutrition restriction per se resulted in an increased body fat and in plasma triglycerides, free fatty acids and total cholesterol concentrations in the offspring. These changes seem to predispose the offspring to insulin resistance and hypertension in later life.
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Obesity; An outcome of abnormal eating behavior

Obesity; An outcome of abnormal eating behavior

concerned? Well, the first link between fitness and enhanced cognitive skills was established in a group of children (Clarke, 1958). An increased BMI in Childhood has been linked with a decline in cognitive functioning (Smith et al. 2011) poor performance in academics (Castelli et al., 2007) predisposition towards metabolic and cardiovascular disorders (Ebbelling et al., 2002) poor health and high risk of mortality (Must et al., 1992), suggesting that childhood obesity can actually be a greater concern than adult obesity.

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Poor maternal nutrition inhibits muscle development in ovine offspring

Poor maternal nutrition inhibits muscle development in ovine offspring

lambs. This is consistent with other work that suggests that secondary myofibers are preferentially affected by en- vironmental conditions, including nutrition [34]. The poor postnatal muscle growth observed in OVER lambs may be due to prenatally programmed changes in nutrient parti- tioning, resulting in decreased muscle mass and increased adiposity at 3 mo of age. Although not measured in the current study, changes in fibrosis may also result in de- creased muscle mass. Indeed, both maternal obesity and nutrient restriction result in increased collagen content and crosslinking in the muscle [35,36]. However, RES lambs exhibited increased lipid accumulation in the muscle at 1 d of age but decreased lipid content at 3 mo compared with CON lambs, indicating that the mecha- nisms by which poor maternal nutrition affects both muscle growth and fat deposition in the muscle is specific to the nutritional insult during gestation. In other studies, maternal obesity during gestation increased lipid content in fetal muscle and offspring at 22 mo of age [6,17] whereas nutrient restriction from 28 to 78 d of gestation increased intramuscular triglyceride content of the longis- simus muscle in offspring at 8 mo of age [5]. Differences between the current work and that of others may be due to differences in the timing and length of poor nutrition, the severity of over- or under-feeding, or strategies for postnatal feeding. In our study, lambs were removed from the ewe and bottle fed until weaning to remove the impact of changes in milk quantity and composition due to differ- ences in maternal dietary intake during gestation [37]. Im- portantly, the changes in muscle growth and fat deposition in the current experiment occurred in a flock representative of a production flock, which are heterogeneous for number and gender of the offspring.
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The Risk of Offspring Psychiatric Disorders in the Setting of Maternal Obesity and Diabetes

The Risk of Offspring Psychiatric Disorders in the Setting of Maternal Obesity and Diabetes

1.45; 95% CI = 1.35–1.56). Marked effects were found particularly for ASD and ADHD and/or conduct disorder. Mothers with PGDM and severe obesity had a sixfold higher risk of having a child with ASD (HR = 6.49; 95% CI = 3.08–13.69, Fig 1) or ADHD and/or conduct disorder (HR = 6.03; 95% CI = 3.23–11.24, Fig 2) compared with normal weight mothers without PGDM. In fact, PGDM implied an overrepresentation of all groups of F-diagnoses with onset in childhood or adolescence (F80–F98) in mothers with severe obesity, with the category F92 to F95 also revealing markedly increased risk (mixed disorders of emotions and conduct, disorders of social function, and tics; HR = 4.29; 95% CI = 2.14–8.60, Fig 3). In addition, PGDM in combination with ordinary obesity associated with increased offspring risk for ASD (HR = 3.64; 95% CI = 1.63–8.16). Also, the diagnosis group F20 to F45 (nonjuvenile psychosis and mood and anxiety disorders) were overrepresented in offspring to mothers with PGDM and obesity (HR = 3.08; 95% CI = 1.28–7.43), a twofold risk relative to those without PGDM (HR = 1.58; 95% CI = 1.36–1.85). Maternal GDM, on the other hand, had only a borderline statistically significant influence on the risk for psychiatric disorders (for mothers with severe obesity, HR GDM = 1.66; 95% CI = 1.55–1.77;
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A Review: Abnormal Crowd Behavior Detection Techniques

A Review: Abnormal Crowd Behavior Detection Techniques

Abstract: Abnormal crowd behavior detection is an important part in video surveillance system because of more concern with people safety in public places like sports stadium, shopping mall, train subway etc. Crowd congestion is not fixed in public places so due to heavy density and occlusion abnormal crowd behavior detection become challenging task. In crowd segmentation and tracking of every person is not possible and even it’s become difficult task so we require method which does not require tracking of every person individually. This paper presents several techniques for abnormal behavior Detection such as crowd running suddenly, congestion detection, fighting etc.
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Abnormal immune responses of Bloom's syndrome lymphocytes in vitro

Abnormal immune responses of Bloom's syndrome lymphocytes in vitro

stimulator cells. Lmyphoctes from the heterozgotes produced normal responses in these three systems. Distrubed immunity appears to be on of several major consequences of homozygosity for the Bloom's syndrome gene. Although the explanation for this pleiotropism is at present obscure, the idea was advanced that the aberrant immune function is, along with the major clincial feature-small body size, amanifestation of defect in cellular […]

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Moderate maternal separation mitigates the altered synaptic transmission and neuronal activation in amygdala by chronic stress in adult mice

Moderate maternal separation mitigates the altered synaptic transmission and neuronal activation in amygdala by chronic stress in adult mice

In summary, our results indicated that stress inocula- tion could mitigate CSDS-induced anxiety-like behavior by alleviating CSDS-induced enhancement of glutamate transmission and intrinsic excitability. Despite this, sev- eral important questions remain open. For example, al- though we demonstrated the synaptic and cellular mechanisms of stress inoculation in amygdala, the underlying molecular mechanism remains elusive. On the other hand, the neurons are extensively intermingled within amygdala; however, they differ drastically in terms of their connectivity and functionality [45]. Our recent studies demonstrated that chronic stress specifically reg- ulated the structural and functional changes of vHPC projecting (BLA → vHPC) but not dmPFC projecting (BLA → dmPFC) or NAc projecting (BLA → NAc) neu- rons in BLA [23, 34]. Thus, whether stress inoculation may have distinct effect on these BLA neurons project- ing to different brain regions (such as mPFC, NAc, vHPC, BNST) remains unclear at the synaptic and cellu- lar levels. Addressing these issues will help to under- stand the molecular and circuit mechanisms of stress inoculation in amygdala, and may provide a more pre- cise intervention approach for the prevention of stress- related disorders.
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Identifying Abnormal Behavior of Users in Recommender Systems

Identifying Abnormal Behavior of Users in Recommender Systems

According to the reviews, there are two general features to all of the shilling attacks. First, the rate of the target item is usually maximum or minimum. Second, all attacks occur in a short time interval. Hence, another class of detection methods called time series are presented. In these methods, abnormal intervals are detected through analysis of time series; then, the attacked items are found and the attacks are eliminated. Since in the basic models, the initial time window size was fixed and the detection rate depended on the time window size, a method has been proposed as dynamic partitioning over time series. This method focuses on finding the abnormal items through obtaining important points of the dynamic time series, but due to the variety of the items and the unpredictability of ascending or descending the rates, the false alarm rate of this method is high.
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