Effects of polychlorinated biphenyl (PCB) exposure on response perseveration and ultrasonic vocalization emission in rat during development

The 3 major symptoms of autistic spectrum disorders include 1) social behavioral alterations, 2) problems in communication and 3) higher-order motoric deficits of perseveration and stereotyped movements. Previous work has shown that early developmental exposure to polychlorinated biphenyls (PCBs) alters rat pup social motivation and juvenile rat social recognition/investigation. The present work extends this previous research by examining how perinatal PCB exposure alters motoric functions and communication abilities at different stages of development. Action perseveration was examined using performance measures from a T-maze environment. Communication abilities were evaluated by monitoring ultrasound emission in rat pups during a brief isolation from the litter. T-maze learning and performance were significantly impaired in PCB exposed animals. Additionally, PCB exposure led to reduced ultrasound emission rates during brief isolation from the natal group. When combined with the previous work using the same developmental exposure regimen, it seems clear that PCB exposure at moderate doses can lead to alterations in 1) social behavior, 2) action choice and perseveration, and 3) communication abilities making it a potential candidate as an endocrine disruptor involved in the production of autistic spectrum disorder in the human population

Determining the Critical Window of Influence of PCB Perinatally on Behavioral and Hormonal Development in Sprague-Dawley Rat Pups

Polychlorinated biphenyls (PCB) had widespread use in the United States in commercial manufacturing in the United States until the late 1970s. Even though they were banned, measurable amounts can still be found in the environment and food sources. PCB has known effects on altering hormone development and behavior in the species Rattus norvegicus. To determine the most crucial developmental time of exposure to PCB in Sprague-Dawley rat pups, rat pups were exposed to PCB at differing weeks of either gestation period or the first postnatal week. Behavioral tests were performed for the different rat pups, as well as blood serum was analyzed for the concentration of thyroid hormone. This paper presents data for PCB exposed pups that were tested for play behavior on PND 22. Statistical tests were used to determine the week of PCB exposure with the greatest effects on the rat pups. The results are that exposure of PCB led to a significant increase in the play behavior of the pups. The dorsal contact play behavior was significantly altered by PCB, while the pin behavior was not significantly altered. The critical window for PCB exposure was not identified, but it can be seen that PCB alters dorsal contact behavior in exposed rat pups

Where does damage lead to enhanced food aversion: the ventral pallidum/substantia innominata or lateral hypothalamus?

It is well known that lesions of the lateral hypothalamus (LH) produce aphagia. Several previous studies have reported that lateral hypothalamus damage produces food aversion in addition to aphagia. However, damage to other regions near the LH also produce aphagia and enhanced aversion. The purpose of this study was to resolve where the site or sites for aversion-inducing lesions is/are located. Small, bilateral excitotoxin lesions (QUIN, 10 [mu]g in 1 [mu]l or IBO, 15 [mu]g in 1 [mu]l) or bilateral sham injections of vehicle were made into the globus pallidus (GP), the ventral pallidum/substantia innominata (VP/SI) or the lateral hypothalamus (LH). Affective reactions to taste were elicited by infusing sucrose solutions (1 M) into the mouth via chronic oral cannulae. The number of aversive responses (gapes, chin-rubbing, head-shaking and forelimb flails) emitted was tallied. Individual lesions were mapped and a single `necessary and sufficient' site for damage-induced aversion was identified (the area of overlapping damage common to all rats that showed enhanced aversive reactions). To identify the lesions, two lesion-mapping techniques were used: (1) a conventional neuron-counting procedure in which an attempt is made to count all neurons within a brain region, and (2) a new modified `fractionator' procedure consisting of exhaustive 400 x magnification counts at point locations within a brain region. Results indicated that aversive reactions to food are enhanced only following bilateral neuron loss (>70%) from the caudal ventromedial VP/SI alone. This shared site has a lateral diameter of 1.0 mm, a dorsoventral diameter of 0.5 mm and a rostrocaudal diameter of 1.0 mm. Damage restricted to the LH never produced enhanced aversion even when it produced aphagia. The crucial region for aversion is located ventral and medial to the globus pallidus and dorsal and lateral to the lateral hypothalamus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30517/1/0000147.pd

Mapping of globus pallidus and ventral pallidum lesions that produce hyperkinetic treading

The purpose of this study was to identify sites where striatopallidal lesions produce two distinct sensory-triggered hyperkinetic syndromes: (1) exaggerated forelimb treading alone to oral taste infusions and (2) sensorimotor exaggerated treading plus enhanced aversive reactions to taste infusions. The behavioral characteristics of these syndromes have been described previously (Berridge, K.C. and Cromwell, H.C., Behav. Neurosci., 104 (1990) 778-795). Bilateral excitotoxin lesions were made using quinolinic acid (10 [mu]g in 1 [mu]l) in the caudate/putamen, nucleus accumbens, globus pallidus or ventral pallidum/substantia innominata. In order to identify the precise center, borders, severity and size of lesion sites that caused these hyperkinetic treading syndromes, neuron counts (modified fractionator technique) and glial fibrillary acidic protein immunoreactivity (GFAP-IR) densitometry were used in a stereological mapping analysis. The site of lesions that produced the hyperkinetic treading syndrome without enhanced aversion was found to be restricted to the globus pallidus (GP). Damage exceeding 60% neuron loss bilaterally within a 0.8 x 1.0 x 1.0 mm subregion of the ventromedial GP produced this syndrome. The site of lesions that produced the combined syndrome of hyperkinetic treading and aversive enhancement was ventral to the globus pallidus, within the ventral pallidum/substantia innominata (VP/SI). Damage exceeding 70% neuron loss bilaterally within a 1.0 x 0.5 x 1.0 m diameter subregion of the ventromedial ventral pallidum/substantia innominata produced this syndrome. This subterritory was located immediately lateral to the border of the lateral hypothalamus. Bilateral lesions to the caudate/putamen or nucleus accumbens did not produce either hyperkinetic treading syndrome. These results are discussed in terms of the connectivity of the ventral pallidal/substantia innominata and globus pallidus regions and in terms of neuropathological models of hyperkinetic disorders.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31107/1/0000003.pd

Polychlorinated biphenyl exposure alters oxytocin receptor gene expression and maternal behavior in rat model

Polychlorinated biphenyl (PCB) is a persistent organic pollutant known to induce diverse molecular and behavioral alterations. Effects of PCB exposure could be transmitted to future generations via changes in behavior and gene expression. Previous work has shown that PCB-exposure can alter social behavior. The present study extends this work by examining a possible molecular mechanism for these changes. Pregnant rats (Sprague-Dawley) were exposed through diet to a combination of non-coplanar (PCB 47 - 2,20,4,40-tetrachlorobiphenyl) and coplanar (PCB 77 - 3,30,4,40- tetrachlorobiphenyl) congeners. Maternal care behaviors were examined by evaluating the rate and quality of nest building on the last 4 d of gestation and dam/pup interactions on postnatal days 1, 2, 4 and 6. On postnatal day 17, dams were euthanized and hypothalamic tissue was removed for expression analyses of the oxytocin receptor (OXTR) and cytochrome P450 1a1 (Cyp1a1). PCB altered nest building and maternal care behaviors. Specifically, there was a significant increase in time spent in low crouch and high crouch nursing posture on PND 4 and PND 6 respectively. Molecular analysis revealed that PCB exposure upregulated OXTR expression in the hypothalamus of dams. These results provide a possible molecular mechanism for PCB-induced changes in social interactions during early development

Fractionating Choice: A Study on Reward Discrimination, Preference, and Relative Valuation in the Rat (Rattus Norvegicus)

Choice behavior combines discrimination between distinctive outcomes, preference for specific outcomes and relative valuation of comparable outcomes. Previous work has focused on 1 component (i.e., preference) disregarding other influential processes that might provide a more complete understanding. Animal models of choice have been explored primarily utilizing extensive training, limited freedom for multiple decisions and sparse behavioral measures constrained to a single phase of motivated action. The present study used a paradigm that combines different elements of previous methods with the goal to distinguish among components of choice and explore how well components match predictions based on risk-sensitive foraging strategies. In order to analyze discrimination and relative valuation, it was necessary to have an option that shifted and an option that remained constant. Shifting outcomes among weeks included a change in single-option outcome (0 to 1 to 2 pellets) or a change in mixed-option outcome (0 or 5 to 0 or 3 to 0 or 1 pellets). Constant outcomes among weeks were also mixed-option (0 or 3 pellets) or single-option (1 pellet). Shifting single-option outcomes among weeks led to better discrimination, more robust preference and significant incentive contrast effects for the alternative outcome. Shifting multioptions altered choice components and led to dissociations among discrimination, preference, and reduced contrast effects. During extinction, all components were impacted with the greatest deficits during the shifting mixed-option outcome sessions. Results suggest choice behavior can be optimized for 1 component but suboptimal for others depending upon the complexity of alterations in outcome value between options

Concussion-related Alterations in Neural Activity During Emotion Recognition: Case Studies of Short-term and Residual Effects

Concussions have recently become an area of concern among the general public, but a clear understanding of their total consequence is still being developed. Symptoms of concussions are wide-ranging, encapsulating a plethora of cognitive and emotional abilities that could be affected. Concussions transiently disrupt neural activation as well as behavioral responses across multiple categories. Skills pertaining to various aspects of emotions are often affected yet have rarely been studied after concussions. We present two case studies of collegiate athletes with a history of multiple concussions. This paper highlights the case of a collegiate athlete who had obtained two previous concussions with the most recent being sustained sixteen days prior to neuroimaging. A second athlete with two lifetime concussions was tested one year after the most recent injury. The current study utilized a novel emotional recognition task to assess the behavioral and neural effects of this injury. A group of five controls responded with high accuracy rates and quick response times to the task. They showed activation in regions of the frontal lobe as well as facial recognition areas of the occipital lobe. The 16-day case subject was impaired in recognizing emotions relative to controls and showed little to no overlap in brain activity for regions involved in emotional face processing. The athlete with a longer post-concussion period also showed residual effects of neural activity alteration when compared to controls with few overlapping active regions. Specific brain regions were activated in this group but not in controls including the sensorimotor cortex, supramarginal gyrus, and lateral occipital cortex. By taking a more individual approach in examination of neural activity post-concussion, we may be able to gain a better understanding of this heterogeneous injury

Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI). METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate. FINDINGS: The highest globally observed HALE at birth for both women and men was in Singapore, at 75·2 years (95% uncertainty interval 71·9-78·6) for females and 72·0 years (68·8-75·1) for males. The lowest for females was in the Central African Republic (45·6 years [42·0-49·5]) and for males was in Lesotho (41·5 years [39·0-44·0]). From 1990 to 2016, global HALE increased by an average of 6·24 years (5·97-6·48) for both sexes combined. Global HALE increased by 6·04 years (5·74-6·27) for males and 6·49 years (6·08-6·77) for females, whereas HALE at age 65 years increased by 1·78 years (1·61-1·93) for males and 1·96 years (1·69-2·13) for females. Total global DALYs remained largely unchanged from 1990 to 2016 (-2·3% [-5·9 to 0·9]), with decreases in communicable, maternal, neonatal, and nutritional (CMNN) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). The exemplars, calculated as the five lowest ratios of observed to expected age-standardised DALY rates in 2016, were Nicaragua, Costa Rica, the Maldives, Peru, and Israel. The leading three causes of DALYs globally were ischaemic heart disease, cerebrovascular disease, and lower respiratory infections, comprising 16·1% of all DALYs. Total DALYs and age-standardised DALY rates due to most CMNN causes decreased from 1990 to 2016. Conversely, the total DALY burden rose for most NCDs; however, age-standardised DALY rates due to NCDs declined globally. INTERPRETATION: At a global level, DALYs and HALE continue to show improvements. At the same time, we observe that many populations are facing growing functional health loss. Rising SDI was associated with increases in cumulative years of life lived with disability and decreases in CMNN DALYs offset by increased NCD DALYs. Relative compression of morbidity highlights the importance of continued health interventions, which has changed in most locations in pace with the gross domestic product per person, education, and family planning. The analysis of DALYs and HALE and their relationship to SDI represents a robust framework with which to benchmark location-specific health performance. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform health policies, health system improvement initiatives, targeted prevention efforts, and development assistance for health, including financial and research investments for all countries, regardless of their level of sociodemographic development. The presence of countries that substantially outperform others suggests the need for increased scrutiny for proven examples of best practices, which can help to extend gains, whereas the presence of underperforming countries suggests the need for devotion of extra attention to health systems that need more robust support. FUNDING: Bill & Melinda Gates Foundation

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk–outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk–outcome pairs, and new data on risk exposure levels and risk–outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk–outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings In 2017, 34·1 million (95% uncertainty interval [UI] 33·3–35·0) deaths and 1·21 billion (1·14–1·28) DALYs were attributable to GBD risk factors. Globally, 61·0% (59·6–62·4) of deaths and 48·3% (46·3–50·2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10·4 million (9·39–11·5) deaths and 218 million (198–237) DALYs, followed by smoking (7·10 million [6·83–7·37] deaths and 182 million [173–193] DALYs), high fasting plasma glucose (6·53 million [5·23–8·23] deaths and 171 million [144–201] DALYs), high body-mass index (BMI; 4·72 million [2·99–6·70] deaths and 148 million [98·6–202] DALYs), and short gestation for birthweight (1·43 million [1·36–1·51] deaths and 139 million [131–147] DALYs). In total, risk-attributable DALYs declined by 4·9% (3·3–6·5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23·5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18·6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.

The Global Burden of Diseases, Injuries and Risk Factors 2017 includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. METHODS: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting