Development of a standardized adsorbable organofluorine screening method for wastewaters with detection by combustion ion chromatography.

Per- and polyfluoroalkyl substances (PFAS) are man-made organofluorine chemicals that can contaminate environmental waters and have gained worldwide attention over the past two decades. PFAS are most frequently detected by mass spectrometric targeted analysis methods which may not detect all the PFAS in samples. This report describes the investigation of adsorbable organofluorine (AOF) with detection by combustion ion chromatography (CIC) for detection of PFAS in surface waters and wastewaters that adsorb to granular activated carbon (GAC) with the recognition that this technique measures more than just PFAS. Overall mean recoveries of 77-120% were obtained in 17 of the 18 tested surface water and wastewater matrices spiked with perfluoropentane sulfonate (PFPeS) and 55-119% mean recoveries were obtained in 11 of the 12 surface water and wastewater matrices spiked with a PFAS mixture. Poor method performance (34-39% mean recoveries) was observed in landfill leachate wastewater. Method detection limits of 1.4-2.2 µg L-1 were achieved using 100 mL sample volumes adsorbed onto commercially available GAC. This report demonstrates that this AOF technique can be a useful screening tool for estimating organofluorine concentrations when PFAS contamination is suspected.

Highlighting the promise of qPCR-based environmental monitoring: response of the ribosomal RNA:DNA ratio of calanoid copepods to toxic cyanobacteria.

Calanoid copepods are integral to aquatic food webs and may drive the bioaccumulation of toxins and heavy metals, spread of infectious diseases, and occurrence of toxic cyanobacterial harmful algal blooms (HABs) in freshwater aquatic systems. However, interrelationships between copepod and cyanobacterial population dynamics and ecophysiology remain unclear. Insights into these relationships are important to aquatic resource management, as they may help guide mitigation efforts. We developed a calanoid copepod qPCR assay to investigate how copepod abundance and physiological status relate to the abundance of cyanobacteria and the concentration of total microcystin in a HAB-prone freshwater multi-use eutrophic lake. Through in silico and in vitro validation of primers and analyses of time series, we demonstrate that our assay can be used as a reliable tool for environmental monitoring. Importantly, copepod RNA:DNA ratios on and shortly after the day when microcystin concentration was at its highest within the lake were not significantly lower (or higher) than before or after this period, suggesting that copepods may have been tolerant of microcystin levels observed and capable of perpetuating bloom events by consuming competitors of toxic cyanobacteria.

Use of qPCR and RT-qPCR for monitoring variations of microcystin producers and as an early warning system to predict toxin production in an Ohio inland lake.

Public concern over cyanobacterial blooms has increased due to their higher frequency of occurrence and their potential ecological and health impacts. Detection of microcystin (MC) producers (MCPs) using qPCR and RT-qPCR allows for the rapid identification of blooms by combining specificity and sensitivity with a relatively high throughput capability. Investigation of MCP population composition (correlation, dominance), toxin gene expression, and relationship to MC concentration was conducted using a panel of qPCR assays targeting mcyA, E and G on weekly and daily water samples collected from an Ohio inland reservoir lake. Further, these data were used to develop early warning thresholds for prediction of MC concentrations exceeding the US EPA Health Advisory cutoff value (>0.3 µg L-1) using receiver operating characteristic curves and tobit regression. MCP Microcystis genomic copy number made up approximately 35% of the total Microcystis spp. and was the dominant toxic subpopulation of MCPs. The expressed MCPs were 0.2% of the extant genomic copy numbers, while toxic Microcystis had higher expressed proportion (0.5%) than that of toxic Planktothrix (0.04%). Microcystis toxin genes increased in June and July but decreased in August and September along with similar trends of cell replication. Quantities of both RT-qPCR and qPCR followed the same trend and were highly correlated with MC-ADDA, while RT-qPCR not only reflected the active toxin genes or toxic species, but also indicated the beginning and ending of toxin production. A one-week early warning of MC exceedance over the EPA Health Advisory was based on signaling of qPCR and RT-qPCR using receiver operating characteristic curves. This study illustrates the potential use of qPCR or RT-qPCR as an early warning system of extant and MC producing potentials during a toxic algal bloom, with predictive powers of 50%-60% and 30%-40% (p < 0.001), respectively, and false positive rates of about 70% for both LC-MS/MS or ELISA.

Radiologic common data elements rates in pediatric mild traumatic brain injury.

OBJECTIVE: The nosology for classifying structural MRI findings following pediatric mild traumatic brain injury (pmTBI) remains actively debated. Radiologic common data elements (rCDE) were developed to standardize reporting in research settings. However, some rCDE are more specific to trauma (probable rCDE). Other more recently proposed rCDE have multiple etiologies (possible rCDE), and may therefore be more common in all children. Independent cohorts of patients with pmTBI and controls were therefore recruited from multiple sites (New Mexico and Ohio) to test the dual hypothesis of a higher incidence of probable rCDE (pmTBI > controls) vs similar rates of possible rCDE on structural MRI. METHODS: Patients with subacute pmTBI (n = 287), matched healthy controls (HC; n = 106), and orthopedically injured (OI; n = 71) patients underwent imaging approximately 1 week postinjury and were followed for 3-4 months. RESULTS: Probable rCDE were specific to pmTBI, occurring in 4%-5% of each sample, rates consistent with previous large-scale CT studies. In contrast, prevalence rates for incidental findings and possible rCDE were similar across groups (pmTBI vs OI vs HC). The prevalence of possible rCDE was also the only finding that varied as a function of site. Possible rCDE and incidental findings were not associated with postconcussive symptomatology or quality of life 3-4 months postinjury. CONCLUSION: Collectively, current findings question the trauma-related specificity of certain rCDE, as well how these rCDE are radiologically interpreted. Refinement of rCDE in the context of pmTBI may be warranted, especially as diagnostic schema are evolving to stratify patients with structural MRI abnormalities as having a moderate injury.

Integrated preservation and sample clean up procedures for studying water ingestion by recreational swimmers via urinary biomarker determination.

The use of cyanuric acid as a biomarker for ingestion of swimming pool water may lead to quantitative knowledge of the volume of water ingested during swimming, contributing to a better understanding of disease resulting from ingestion of environmental contaminants. When swimming pool water containing chlorinated cyanurates is inadvertently ingested, cyanuric acid is excreted quantitatively within 24 h as a urinary biomarker of ingestion. Because the volume of water ingested can be quantitatively estimated by calculation from the concentration of cyanuric acid in 24 h urine samples, a procedure for preservation, cleanup, and analysis of cyanuric acid was developed to meet the logistical demands of large scale studies. From a practical stand point, urine collected from swimmers cannot be analyzed immediately, given requirements of sample collection, shipping, handling, etc. Thus, to maintain quality control to allow confidence in the results, it is necessary to preserve the samples in a manner that ensures as quantitative analysis as possible. The preservation and clean-up of cyanuric acid in urine is complicated because typical approaches often are incompatible with the keto-enol tautomerization of cyanuric acid, interfering with cyanuric acid sample preparation, chromatography, and detection. Therefore, this paper presents a novel integration of sample preservation, clean-up, chromatography, and detection to determine cyanuric acid in 24 h urine samples. Fortification of urine with cyanuric acid (0.3-3.0 mg/L) demonstrated accuracy (86-93% recovery) and high reproducibility (RSD < 7%). Holding time studies in unpreserved urine suggested sufficient cyanuric acid stability for sample collection procedures, while longer holding times suggested instability of the unpreserved urine. Preserved urine exhibited a loss of around 0.5% after 22 days at refrigerated storage conditions of 4 °C.

Disclosing neuroimaging incidental findings: a qualitative thematic analysis of health literacy challenges.

BACKGROUND: Returning neuroimaging incidental findings (IF) may create a challenge to research participants' health literacy skills as they must interpret and make appropriate healthcare decisions based on complex radiology jargon. Disclosing IF can therefore present difficulties for participants, research institutions and the healthcare system. The purpose of this study was to identify the extent of the health literacy challenges encountered when returning neuroimaging IF. We report on findings from a retrospective survey and focus group sessions with major stakeholders involved in disclosing IF. METHODS: We surveyed participants who had received a radiology report from a research study and conducted focus groups with participants, parents of child participants, Institutional Review Board (IRB) members, investigators and physicians. Qualitative thematic analyses were conducted using standard group-coding procedures and descriptive summaries of health literacy scores and radiology report outcomes are examined. RESULTS: Although participants reported high health literacy skills (m = 87.3 on a scale of 1-100), 67 % did not seek medical care when recommended to do so; and many participants in the focus groups disclosed they could not understand the findings described in their report. Despite their lack of understanding, participants desire to have information about their radiology results, and the investigators feel ethically inclined to return findings. CONCLUSIONS: The language in clinically useful radiology reports can create a challenge for participants' health literacy skills and has the potential to negatively impact the healthcare system and investigators conducting imaging research. Radiology reports need accompanying resources that explain findings in lay language, which can help reduce the challenge caused by the need to communicate incidental findings.

COINSTAC: A Privacy Enabled Model and Prototype for Leveraging and Processing Decentralized Brain Imaging Data.

The field of neuroimaging has embraced the need for sharing and collaboration. Data sharing mandates from public funding agencies and major journal publishers have spurred the development of data repositories and neuroinformatics consortia. However, efficient and effective data sharing still faces several hurdles. For example, open data sharing is on the rise but is not suitable for sensitive data that are not easily shared, such as genetics. Current approaches can be cumbersome (such as negotiating multiple data sharing agreements). There are also significant data transfer, organization and computational challenges. Centralized repositories only partially address the issues. We propose a dynamic, decentralized platform for large scale analyses called the Collaborative Informatics and Neuroimaging Suite Toolkit for Anonymous Computation (COINSTAC). The COINSTAC solution can include data missing from central repositories, allows pooling of both open and "closed" repositories by developing privacy-preserving versions of widely-used algorithms, and incorporates the tools within an easy-to-use platform enabling distributed computation. We present an initial prototype system which we demonstrate on two multi-site data sets, without aggregating the data. In addition, by iterating across sites, the COINSTAC model enables meta-analytic solutions to converge to "pooled-data" solutions (i.e., as if the entire data were in hand). More advanced approaches such as feature generation, matrix factorization models, and preprocessing can be incorporated into such a model. In sum, COINSTAC enables access to the many currently unavailable data sets, a user friendly privacy enabled interface for decentralized analysis, and a powerful solution that complements existing data sharing solutions.

Development and Multi-laboratory Verification of US EPA Method 543 for the Analysis of Drinking Water Contaminants by Online Solid Phase Extraction-LC-MS-MS.

A drinking water method for seven pesticides and pesticide degradates is presented that addresses the occurrence monitoring needs of the US Environmental Protection Agency (EPA) for a future Unregulated Contaminant Monitoring Regulation (UCMR). The method employs online solid phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS-MS). Online SPE-LC-MS-MS has the potential to offer cost-effective, faster, more sensitive and more rugged methods than the traditional offline SPE approach due to complete automation of the SPE process, as well as seamless integration with the LC-MS-MS system. The method uses 2-chloroacetamide, ascorbic acid and Trizma to preserve the drinking water samples for up to 28 days. The mean recoveries in drinking water (from a surface water source) fortified with method analytes are 87.1-112% with relative standard deviations of <14%. Single laboratory lowest concentration minimum reporting levels of 0.27-1.7 ng/L are demonstrated with this methodology. Multi-laboratory data are presented that demonstrate method ruggedness and transferability. The final method meets all of the EPA's UCMR survey requirements for sample collection and storage, precision, accuracy, and sensitivity.

Evolution of universal review and disclosure of MRI reports to research participants.

BACKGROUND: Although incidental findings (IF) are commonly encountered in neuroimaging research, there is no consensus regarding what to do with them. Whether researchers are obligated to review scans for IF, or if such findings should be disclosed to research participants at all, is controversial. Objective data are required to inform reasonable research policy; unfortunately, such data are lacking in the published literature. This manuscript summarizes the development of a radiology review and disclosure system in place at a neuroimaging research institute and its impact on key stakeholders. METHODS: The evolution of a universal radiology review system is described, from inception to its current status. Financial information is reviewed, and stakeholder impact is characterized through surveys and interviews. RESULTS: Consistent with prior reports, 34% of research participants had an incidental finding identified, of which 2.5% required urgent medical attention. A total of 87% of research participants wanted their magnetic resonance imaging (MRI) results regardless of clinical significance and 91% considered getting an MRI report a benefit of study participation. A total of 63% of participants who were encouraged to see a doctor about their incidental finding actually followed up with a physician. Reasons provided for not following-up included already knowing the finding existed (14%), not being able to afford seeing a physician (29%), or being reassured after speaking with the institute's Medical Director (43%). Of those participants who followed the recommendation to see a physician, nine (38%) required further diagnostic testing. No participants, including those who pursued further testing, regretted receiving their MRI report, although two participants expressed concern about the excessive personal cost. The current cost of the radiology review system is about $23 per scan. CONCLUSIONS: It is possible to provide universal radiology review of research scans through a system that is cost-effective, minimizes investigator burden, and does not overwhelm local healthcare resources.

'Ethical responsibility' or 'a whole can of worms': differences in opinion on incidental finding review and disclosure in neuroimaging research from focus group discussions with participants, parents, IRB members, investigators, physicians and community members.

PURPOSE: To identify the specific needs, preferences and expectations of the stakeholders impacted by returning neuroimaging incidental findings to research participants. METHODS: Six key stakeholder groups were identified to participate in focus group discussions at our active neuroimaging research facility: Participants, Parents of child participants, Investigators, Institutional Review Board (IRB) Members, Physicians and Community Members. A total of 151 subjects attended these discussions. Transcripts were analysed using principles of Grounded Theory and group consensus coding. RESULTS: A series of similar and divergent themes were identified across our subject groups. Similarities included beliefs that it is ethical for researchers to disclose incidental findings as it grants certain health and emotional benefits to participants. All stakeholders also recognised the potential psychological and financial risks to disclosure. Divergent perspectives elucidated consistent differences between our 'Participant' subjects (Participants, Parents, Community Members) and our 'Professional' subjects (IRB Members, Investigators and Physicians). Key differences included (1) what results should be reported, (2) participants' autonomous right to research information and (3) the perception of the risk-benefit ratio in managing results. CONCLUSIONS: Understanding the perceived impact on all stakeholders involved in the process of disclosing incidental findings is necessary to determine appropriate research management policy. Our data further demonstrate the challenge of this task as different stakeholders evaluate the balance between risk and benefit related to their unique positions in this process. These findings offer some of the first qualitative insight into the expectations of the diverse stakeholders affected by incidental finding disclosure.

Stakeholder Opinions And Ethical Perspectives Support Complete Disclosure Of Incidental Findings In MRI Research.

How far does a researcher's responsibility extend when an incidental finding is identified? Balancing pertinent ethical principles such as beneficence, respect for persons, and duty to rescue is not always straightforward, particularly in neuroimaging research where empirical data that might help guide decision-making is lacking. We conducted a systematic survey of perceptions and preferences of 396 investigators, research participants and IRB members at our institution. Using the partial entrustment model as described by Richardson, we argue that our data supports universal reading by a neuroradiologist of all research MRI scans for incidental findings and providing full disclosure to all participants.

The MCIC collection: a shared repository of multi-modal, multi-site brain image data from a clinical investigation of schizophrenia.

Expertly collected, well-curated data sets consisting of comprehensive clinical characterization and raw structural, functional and diffusion-weighted DICOM images in schizophrenia patients and sex and age-matched controls are now accessible to the scientific community through an on-line data repository (coins.mrn.org). The Mental Illness and Neuroscience Discovery Institute, now the Mind Research Network (MRN, http://www.mrn.org/ ), comprised of investigators at the University of New Mexico, the University of Minnesota, Massachusetts General Hospital, and the University of Iowa, conducted a cross-sectional study to identify quantitative neuroimaging biomarkers of schizophrenia. Data acquisition across multiple sites permitted the integration and cross-validation of clinical, cognitive, morphometric, and functional neuroimaging results gathered from unique samples of schizophrenia patients and controls using a common protocol across sites. Particular effort was made to recruit patients early in the course of their illness, at the onset of their symptoms. There is a relatively even sampling of illness duration in chronic patients. This data repository will be useful to 1) scientists who can study schizophrenia by further analysis of this cohort and/or by pooling with other data; 2) computer scientists and software algorithm developers for testing and validating novel registration, segmentation, and other analysis software; and 3) educators in the fields of neuroimaging, medical image analysis and medical imaging informatics who need exemplar data sets for courses and workshops. Sharing provides the opportunity for independent replication of already published results from this data set and novel exploration. This manuscript describes the inclusion/exclusion criteria, imaging parameters and other information that will assist those wishing to use this data repository.

Sensory and sensorimotor gating deficits after neonatal ventral hippocampal lesions in rats.

Neonatal ventral hippocampal lesions (NVHLs) in rats lead to reduced prepulse inhibition (PPI) of startle and other behavioral deficits in adulthood that model abnormalities in schizophrenia patients. A neurophysiological deficit in schizophrenia patients and their first-degree relatives is reduced gating of the P50 event-related potential (ERP). N40 ERP gating in rats may be a cross-species analog of P50 gating, and is disrupted in experimental manipulations related to schizophrenia. Here, we tested whether N40 gating as well as PPI is disrupted after NVHLs, using contemporaneous measures of these two conceptually related phenomena. Male rat pups received sham or ibotenic acid NVHLs on postnatal day 7. PPI was tested on days 35 and 56, after which rats were equipped with cortical surface electrodes for ERP measurements. One week later, PPI and N40 gating were measured in a single test, using paired S1-S2 clicks spaced 500 ms apart to elicit N40 gating. Compared to sham-lesioned rats, those with NVHLs exhibited PPI deficits on days 35 and 56. NVHL rats also exhibited reduced N40 gating and reduced PPI, when measured contemporaneously at day 65. Deficits in PPI and N40 gating appeared most pronounced in rats with larger lesions, focused within the ventral hippocampus. In this first report of contemporaneous measures of two important schizophrenia-related phenotypes in NVHL rats, NVHLs reproduce both sensory (N40) and sensorimotor (PPI) gating deficits exhibited in schizophrenia. In this study, lesion effects were detected prior to pubertal onset, and were sustained well into adulthood.

Sensory and sensorimotor gating-disruptive effects of apomorphine in Sprague Dawley and Long Evans rats.

RATIONALE: Rat strains differ in sensitivity to the disruptive effects of dopamine agonists on sensorimotor gating, measured by prepulse inhibition (PPI) of startle. For example, Sprague Dawley (SD) rats are more sensitive to PPI-disruptive effects of apomorphine (APO) compared to Long Evans (LE) rats; F1 (SDxLE) and N2 generations exhibit intermediate phenotypes. We reported that APO increased S2/S1 ratios and reduced S1 amplitudes of the N40 event-related potential (ERP) in SD rats, suggesting that it reduced sensory gating and/or sensory registration. Here, we investigated whether SD and LE rats differ in sensitivity to APO effects on N40 gating or amplitude. METHODS: PPI and N40 gating were assessed contemporaneously in male SD and LE rats after APO, in a 4-day within-subject design. RESULTS: Compared to SD rats, LE rats were less sensitive to the PPI-disruptive effects of APO. APO increased S2/S1 ratios paralleled by a dose-dependent reduction in S1 amplitude; SD and LE rats did not differ significantly in this measure. No clear relationship was evident between APO effects on PPI and N40 gating, nor between APO effects on startle magnitude and S1 amplitude, across strains. CONCLUSION: SD and LE rats differ in their sensitivity to the disruptive effects of dopamine receptor activation on sensorimotor gating (PPI) but not sensory gating (N40 suppression) or sensory registration (S1 amplitude). These data suggest differences in both the neural and genetic regulation of dopamine agonist effects on these measures.

Human serum IgE reacts with a Metarhizium anisopliae fungal catalase.

BACKGROUND: Previous studies have demonstrated that Metarhizium anisopliae extract can induce responses characteristic of human allergic asthma in a mouse model. The study objectives were (1) to identify and characterize the M. anisopliae mycelia extract (MYC) proteins that are recognized by mouse serum IgE, (2) to determine if human serum IgE reacts with these proteins, and (3) to determine if these IgE-reactive proteins are found in other fungi. METHODS: Asthmatic human serum IgE, M. anisopliae crude antigen (MACA) immunized mouse serum IgE, and anti-catalase antibodies were used to probe one- and two-dimensional gel electrophoresis blots of MYC. RESULTS: Mass spectrometry analysis identified catalase as a mouse IgE-reactive protein. This identification was confirmed by assaying catalase activity in the extract and extract immunoblots probed with anti-catalase antibody. Six adult asthmatic sera contained IgE, but not IgG, that was reactive with mycelia extract proteins. A similar protein profile was seen when blots were probed with either mouse anti-MACA IgE or anti-bovine liver catalase antibodies. Furthermore, these mouse anti-MACA and anti-catalase antibodies were cross-reactive with other mold extracts (skin prick testing mix) and Aspergillus niger catalase. CONCLUSIONS: Some human asthmatics have developed IgE that reacts with an M. anisopliae catalase, most likely due to cross-reactivity (minimal IgG development). The cross-reactivity among fungal catalases suggests that IgE-reactive catalase might be useful for exposure assessment. Additionally, the similarity of protein profiles visualized with both human and mouse serum IgE suggests that allergy hazard identification can be facilitated using a mouse model.

Development of a U.S. EPA drinking water method for the analysis of selected perfluoroalkyl acids by solid-phase extraction and LC-MS-MS.

A drinking water method for perfluoroalkyl acids (PFAAs) is presented that addresses the occurrence monitoring needs of the U.S. Environmental Protection Agency (EPA) for a future unregulated contaminant monitoring regulation (UCMR). This paper describes the challenges associated with developing an analytical method for 14 PFAAs that will be used for drinking water occurrence monitoring. The method employs solid-phase extraction with analysis by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The final method preservation scheme requires that samples be stored in polypropylene bottles and that they be buffered and free chlorine removed with Trizma buffer. Mean recoveries of chlorinated surface water samples fortified with the PFAAs at 40-100 ng/L (except for the perfluorooctane-sulfonamido-acetic acids at 200 ng/L) are 85-112% with < 5% relative standard deviation. Single laboratory minimum reporting limits of 2.9-14 ng/L are demonstrated with this methodology. The final method meets all of the EPA UCMR survey requirements for sample collection and storage, precision, accuracy, and sensitivity and is expected to be proposed for use under a future UCMR.

LC/MS/MS structure elucidation of reaction intermediates formed during the TiO(2) photocatalysis of microcystin-LR.

Microcystin-LR (MC-LR), a cyanotoxin and emerging drinking water contaminant, was treated with TiO(2) photocatalysts immobilized on stainless steel plates as an alternative to nanoparticles in slurry. The reaction intermediates of MC-LR were identified with mass spectrometry (MS) at pH of Milli-Q water (pH(sq)=5.7). Eleven new [M+H](+) were observed in the liquid chromatography mass spectrometry (LC/MS) chromatogram with some of them giving multiple peaks. Most of these reaction intermediates have not been reported from previous studies employing TiO(2) nanoparticles at acidic conditions (pH=4.0). Investigating the effects of pH (for 3.0

Strain differences in the gating-disruptive effects of apomorphine: relationship to gene expression in nucleus accumbens signaling pathways.

BACKGROUND: Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is deficient in certain psychiatric disorders, including schizophrenia. Sprague Dawley (SD) rats are more sensitive to PPI-disruptive effects of apomorphine (APO) at long interstimulus intervals (ISIs) (60-120 msec) and less sensitive to PPI-enhancing effects of APO at short ISIs (10-30 msec) compared with Long Evans (LE) rats. METHODS: Prepulse inhibition was tested in SD and LE rats after APO (.5 mg/kg) or vehicle in a within- subject design and sacrificed 14 days later. Total RNA was extracted from the nucleus accumbens (NAC). Approximately 700 dopamine-relevant transcripts on the Affymetrix 230 2.0 microarray were analyzed. RESULTS: As previously reported, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared with LE rats. One hundred four genes exhibited significantly different NAC expression levels in these two strains. Pathway analysis revealed that many of these genes contribute to dopamine receptor signaling, synaptic long-term potentiation, or inositol phosphate metabolism. The expression of some genes significantly correlated with measures of APO-induced PPI sensitivity in either SD or LE rats. The expression of select genes was validated by real-time reverse transcription polymerase chain reaction (RT-PCR). CONCLUSIONS: Differences in PPI APO sensitivity in SD versus LE rats are robust and reproducible and may be related to strain differences in the expression of genes that regulate signal transduction in the NAC. These genes could facilitate the identification of targets for ameliorating heritable gating deficits in brain disorders such as schizophrenia.

A novel rat strain with enhanced sensitivity to the effects of dopamine agonists on startle gating.

BACKGROUND: Compared to outbred Sprague Dawley (SD) rats, inbred Brown Norway (BN) rats exhibit less prepulse inhibition of startle (PPI) at long prepulse intervals, and more PPI at short intervals. Sensitivity to dopaminergic drug effects on PPI differs substantially across strains, and is heritable within SD and other outbred strains. To further understand the heritability of PPI and its sensitivity to dopamine agonists, we assessed PPI and apomorphine sensitivity in SD, BN and F1 (SD x BN) rats. METHODS: PPI was measured in BN, SD and F1 rats under a variety of stimulus conditions, and after treatment with apomorphine. RESULTS: Findings confirmed significantly more PPI in BN compared to SD rats at short prepulse intervals, and significantly more PPI in SD compared to BN rats at long intervals. F1s were "supersensitive" to both the PPI-disruptive effects of apomorphine at longer intervals, and the PPI-enhancing effects of apomorphine at shorter intervals, compared to either parental strain. CONCLUSION: Differences in sensorimotor gating between SD and BN rats are robust, time-locked and consistent across studies. Unlike patterns in other strains, heritability of PPI apomorphine sensitivity phenotypes in SD x BN F1s cannot be easily explained by simple additive effects.