The role of the NK1 receptor in impulsive and perseverative behaviour in the mouse

The neurokinin-1 receptor (NK1) knockout mouse (NK1R-/-) has a hyperactive phenotype that is attenuated by psychostimulant treatment. This finding led to the NK1R-/- mouse being proposed as a model for Attention Deficit Hyperactivity Disorder (ADHD). The three core diagnostic symptoms of ADHD, hyperactivity, inattention and impulsivity have been investigated in the NK1R-/- mice alongside wildtype controls. Circular corridor apparatus was used to monitor activity over a 48-hour period, during which there was no overall difference in activity, but NK1R-/- mice displayed significantly higher levels of activity in the hour after lights out than wildtype mice. The 5-choice serial reaction time-task (5-CSRTT) is used to measure levels of attention and impulsivity (the other core features of ADHD) in wildtype and NK1R-/- mice. Both genotypes were able to learn the task to the pre-determined baseline level, but when the difficulty of the task was increased, the NK1R /- mice displayed impulsivity and deficits in attention. Interestingly, the NK1R-/- mice consistently made more perseverative responses compared to wildtype controls. This experiment was extended to test whether the phenotype of the NK1R-/- mice could be replicated with NK1 receptor antagonist treatment in wildtype animals. The NK1 receptor antagonist RP 67580 increased premature responding in wildtype animals, but did not effect omissions or perseveration. Because of the robust nature of the perseverative phenotype of the NK1R-/- at all stages of the 5-CSRTT, marble burying and burrowing tests were used as alternative behavioural paradigms to measure perseveration. In these ‘species-typical’ behavioural tests no robust difference in behaviour was noted between wildtype and NK1R-/- animals. These findings highlight the multifarious nature of perseverative behaviour and provide evidence for differential neural circuitry for perseverative behaviour in a cued task versus repetitive motor movement. Using an atlas of the distribution of the NK1 receptor and its preferred ligand substance P, this thesis concludes with explanations of the underlying neurobiology that may be responsible for these observations

Performance Deficits of NK1 Receptor Knockout Mice in the 5-Choice Serial Reaction-Time Task: Effects of d-Amphetamine, Stress and Time of Day

Background: The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon.Methods and Results: The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning.Conclusion: In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

The influence of test experience and NK1 receptor antagonists on the performance of NK1R-/- and wildtype mice in the 5 Choice Serial Reaction Time Task

Genetically-altered mice, lacking functional NK1 receptors (NK1R-/-), express abnormal behaviours that are prominent in Attention Deficit Hyperactivity Disorder: namely, inattentiveness and impulsivity (indicated by their greater %omissions and premature responses in the 5 Choice Serial Reaction Time Task: ‘5 CSRTT’) and locomotor hyperactivity. Here, we investigated how behaviour in the 5 CSRTT is affected by repeated testing and whether the abnormalities expressed by NK1R-/- mice are mimicked by treating wildtypes with an NK1R antagonist (L 733060 or RP 67580; 5 or 10 mg/kg). Repeated testing with a variable (VITI) or fixed, prolonged (LITI) intertrial interval reduced %omissions. Premature responses also declined, but only in NK1R /- mice in the VITI test. By contrast, perseveration increased in both genotypes. RP 67580 (10 mg/kg) increased the %omissions in both genotypes in the VITI, an action which cannot be attributed to NK1R antagonism. Neither drug affected perseveration. However, for premature responses, the profile of the response suggests that the low and high doses of RP 67580 (VITI) and L 733060 (LITI) have opposing effects on this behaviour. We infer that the effect of NK1R antagonists in the 5 CSRTT is confounded by animals’ test experience and non-specific drug effects at sites other than NK1R, possibly L type Ca2+v channels

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.Peer reviewe

Research cardiac magnetic resonance imaging in end stage renal disease - incidence, significance and implications of unexpected incidental findings

Objectives: Left ventricular mass (LVM) at cardiac magnetic resonance imaging (CMR) is a frequent end point in clinical trials in nephrology. Trial participants with end stage renal disease (ESRD) may have a greater frequency of incidental findings (IF). We retrospectively investigated prevalence of IF in previous research CMR and reviewed their subsequent impact on participants. Methods: Between 2002 and 2006, 161 ESRD patients underwent CMR in a transplant assessment study. Images were used to assess LV mass and function. In the current study a radiologist reviewed the scans for IF. Review of patient records determined the subsequent clinical significance of IF. Results: There were 150 IF in 95 study participants. Eighty-four (56 %) were new diagnoses. One hundred and two were non-cardiac. Fifteen were suspicious of malignancy. There was a clinically significant IF for 14.9 % of the participants. In six cases earlier identification of an IF may have improved quality of life or survival. Conclusions: Without radiology support clinically important IF may be missed on CMR. Patients undergoing CMR in trials should be counselled about the frequency and implications of IF. Patients with ESRD have a higher prevalence of IF than reported in other populations. Nephrology studies require mechanisms for radiologist reporting and strategies for dealing with IF

Informing HIV prevention efforts targeting Liberian youth: a study using the PLACE method in Liberia

BACKGROUND: Preventing HIV infection among young people is a priority for the Liberian government. Data on the young people in Liberia are scarce but needed to guide HIV programming efforts. METHODS: We used the Priorities for Local AIDS Control Efforts (PLACE) method to gather information on risk behaviors that young people (ages 14 to 24) engage in or are exposed to that increase their vulnerability for HIV infection. Community informants identified 240 unique venues of which 150 were visited and verified by research staff. 89 of the 150 venues comprised our sampling frame and 571 females and 548 males were interviewed in 50 venues using a behavioral survey. RESULTS: Ninety-one percent of females and 86% of males reported being sexually active. 56% of females and 47% of males reported they initiated sexual activity before the age of 15. Among the sexually active females, 71% reported they had received money or a gift for sex and 56% of males reported they had given money or goods for sex. 20% of females and 6% males reported that their first sexual encounter was forced and 15% of females and 6% of males reported they had been forced to have sex in the past year. Multiple partnerships were common among both sexes with 81% females and 76% males reporting one or more sex partners in the past four weeks. Less than 1% reported having experiences with injecting drugs and only 1% of males reporting have sex with men. While knowledge of HIV/AIDS was high, prevention behaviors including HIV testing and condom use were low. CONCLUSION: Youth-focused HIV efforts in Liberia need to address transactional sex and multiple and concurrent partnerships. HIV prevention interventions should include efforts to meet the economic needs of youth

SSR and AFLP based genetic diversity of soybean germplasm differing in photoperiod sensitivity

Forty-four soybean genotypes with different photoperiod response were selected after screening of 1000 soybean accessions under artificial condition and were profiled using 40 SSR and 5 AFLP primer pairs. The average polymorphism information content (PIC) for SSR and AFLP marker systems was 0.507 and 0.120, respectively. Clustering of genotypes was done using UPGMA method for SSR and AFLP and correlation was 0.337 and 0.504, respectively. Mantel's correlation coefficients between Jaccard's similarity coefficient and the cophenetic values were fairly high in both the marker systems (SSR = 0.924; AFLP = 0.958) indicating very good fit for the clustering pattern. UPGMA based cluster analysis classified soybean genotypes into four major groups with fairly moderate bootstrap support. These major clusters corresponded with the photoperiod response and place of origin. The results indicate that the photoperiod insensitive genotypes, 11/2/1939 (EC 325097) and MACS 330 would be better choice for broadening the genetic base of soybean for this trait

Indigenous biosecurity: Māori responses to kauri dieback and myrtle rust in Aotearoa New Zealand

It is widely acknowledged that Indigenous peoples have traditional knowledge relevant to modern environmental management. By asserting roles within associated science and policy networks, such Indigenous Knowledge (IK) can be seen as part of the resistance to colonisation that includes protest, treaty making, political and economic empowerment, legislation, cultural renaissance and regulatory influence. In New Zealand, these achievements inform attempts by Māori (the Indigenous people of New Zealand) to manage forest ecosystems and cultural keystone species. This chapter presents two case studies of how indigenous participation in modern biosecurity through the example of Māori asserting and contributing to forest management. While progress is often frustratingly slow for indigenous participants, significant gains in acceptance of Māori cultural frameworks have been achieved

Genetics of VEGF Serum Variation in Human Isolated Populations of Cilento: Importance of VEGF Polymorphisms

Vascular Endothelial Growth Factor (VEGF) is the main player in angiogenesis. Because of its crucial role in this process, the study of the genetic factors controlling VEGF variability may be of particular interest for many angiogenesis-associated diseases. Although some polymorphisms in the VEGF gene have been associated with a susceptibility to several disorders, no genome-wide search on VEGF serum levels has been reported so far. We carried out a genome-wide linkage analysis in three isolated populations and we detected a strong linkage between VEGF serum levels and the 6p21.1 VEGF region in all samples. A new locus on chromosome 3p26.3 significantly linked to VEGF serum levels was also detected in a combined population sample. A sequencing of the gene followed by an association study identified three common single nucleotide polymorphisms (SNPs) influencing VEGF serum levels in one population (Campora), two already reported in the literature (rs3025039, rs25648) and one new signal (rs3025020). A fourth SNP (rs41282644) was found to affect VEGF serum levels in another population (Cardile). All the identified SNPs contribute to the related population linkages (35% of the linkage explained in Campora and 15% in Cardile). Interestingly, none of the SNPs influencing VEGF serum levels in one population was found to be associated in the two other populations. These results allow us to exclude the hypothesis that the common variants located in the exons, intron-exon junctions, promoter and regulative regions of the VEGF gene may have a causal effect on the VEGF variation. The data support the alternative hypothesis of a multiple rare variant model, possibly consisting in distinct variants in different populations, influencing VEGF serum levels