Measuring Motivation and Reward-Related Decision Making in the Rodent Operant Touchscreen System.

This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/0471142301.ns0834s74This unit is designed to facilitate implementation of the fixed and progressive ratio paradigms and the effort-related choice task in the rodent touchscreen apparatus to permit direct measurement of motivation and reward-related decision making in this equipment. These protocols have been optimized for use in the mouse and reliably yield stable performance levels that can be enhanced or suppressed by systemic pharmacological manipulation. Instructions are also provided for the adjustment of task parameters to permit use in mouse models of neurodegenerative disease. These tasks expand the utility of the rodent touchscreen apparatus beyond the currently available battery of cognitive assessment paradigms.The protocols presented in this Unit were developed and optimized as part of a research program funded by Wellcome Trust grant 089703/Z/09/Z awarded to TJB and LMS. TJB and LMS also received funding from the Innovative Medicine Initiative Joint Undertaking under grant agreement n° 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007- 2013). TJB and LMS consult for Campden Instruments Ltd

Examining Individualism in College Student Retention Theory and Practice

College student retention and completion rates correlate with the production of societal benefits such as community engagement, human capital, diverse campus communities, and social mobility. While ideas vary, most contemporary retention practices and strategies rely on foundational studies that focus on individualism, the student-institution relationship, and inhibiting factors to student integration into a collegiate environment. This meta-synthesis examines the individualistic nature of foundational historic and contemporary retention theories and practices as well as recommends a collectivist, culturally-responsive alternative paradigm for retention theory and strategy development moving forward

Interrelationships between depressive symptoms and positive and negative symptoms of recent onset schizophrenia spectrum disorders:A network analytical approach

Objective: There is a need to better understand the interrelationships between positive and negative symptoms of recent-onset schizophrenia spectrum disorders (SSD) and co-occurring depressive symptoms. Aims were to determine: (1) whether depressive symptoms are best conceptualised as distinct from, or intrinsic to, positive and negative symptoms; and (2) bridging symptoms. Methods: Network analysis was applied to data from 198 individuals with depressive and psychotic symptoms in SSD from the Psychosis Recent Onset GRoningen Survey (PROGR-S). Measures were: Montgomery-Asberg Depression Rating Scale and Positive and Negative Syndrome Scale. Results: Positive symptoms were just as likely to be associated with depressive and negative symptoms, and had more strong associations with depressive than negative symptoms. Negative symptoms were more likely to be associated with depressive than positive symptoms, and had more strong associations with depressive than positive symptoms. Suspiciousness and stereotyped thinking bridged between positive and depressive symptoms, and apparent sadness and lassitude between negative and depressive symptoms. Conclusions: Depressive symptoms might be best conceptualised as intrinsic to positive and negative symptoms pertaining to deficits in motivation and interest in the psychotic phase of SSD. Treatments targeting bridges between depressive and positive symptoms, and depressive and such negative symptoms, might prevent or improve co-occurring depressive symptoms, or vice-versa, in the psychotic phase of SSD

Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.

Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5-10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction

Selective effects of 5-HT2C receptor modulation on performance of a novel valence-probe visual discrimination task and probabilistic reversal learning in mice.

RATIONALE: Dysregulation of the serotonin (5-HT) system is a pathophysiological component in major depressive disorder (MDD), a condition closely associated with abnormal emotional responsivity to positive and negative feedback. However, the precise mechanism through which 5-HT tone biases feedback responsivity remains unclear. 5-HT2C receptors (5-HT2CRs) are closely linked with aspects of depressive symptomatology, including abnormalities in reinforcement processes and response to stress. Thus, we aimed to determine the impact of 5-HT2CR function on response to feedback in biased reinforcement learning. METHODS: We used two touchscreen assays designed to assess the impact of positive and negative feedback on probabilistic reinforcement in mice, including a novel valence-probe visual discrimination (VPVD) and a probabilistic reversal learning procedure (PRL). Systemic administration of a 5-HT2CR agonist and antagonist resulted in selective changes in the balance of feedback sensitivity bias on these tasks. RESULTS: Specifically, on VPVD, SB 242084, the 5-HT2CR antagonist, impaired acquisition of a discrimination dependent on appropriate integration of positive and negative feedback. On PRL, SB 242084 at 1 mg/kg resulted in changes in behaviour consistent with reduced sensitivity to positive feedback. In contrast, WAY 163909, the 5-HT2CR agonist, resulted in changes associated with increased sensitivity to positive feedback and decreased sensitivity to negative feedback. CONCLUSIONS: These results suggest that 5-HT2CRs tightly regulate feedback sensitivity bias in mice with consequent effects on learning and cognitive flexibility and specify a framework for the influence of 5-HT2CRs on sensitivity to reinforcement

Pyrimidine salvage enzymes are essential for de novo biosynthesis of Deoxypyrimidine nucleotides in Trypanosoma brucei

© 2016 Leija et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The human pathogenic parasite Trypanosoma brucei possess both de novo and salvage routes for the biosynthesis of pyrimidine nucleotides. Consequently, they do not require salvageable pyrimidines for growth. Thymidine kinase (TK) catalyzes the formation of dTMP and dUMP and is one of several salvage enzymes that appear redundant to the de novo pathway. Surprisingly, we show through analysis of TK conditional null and RNAi cells that TK is essential for growth and for infectivity in a mouse model, and that a catalytically active enzyme is required for its function. Unlike humans, T. brucei and all other kinetoplastids lack dCMP deaminase (DCTD), which provides an alternative route to dUMP formation. Ectopic expression of human DCTD resulted in full rescue of the RNAi growth phenotype and allowed for selection of viable TK null cells. Metabolite profiling by LC-MS/MS revealed a buildup of deoxypyrimidine nucleosides in TK depleted cells. Knockout of cytidine deaminase (CDA), which converts deoxycytidine to deoxyuridine led to thymidine/deoxyuridine auxotrophy. These unexpected results suggested that T. brucei encodes an unidentified 5'-nucleotidase that converts deoxypyrimidine nucleotides to their corresponding nucleosides, leading to their dead-end buildup in TK depleted cells at the expense of dTTP pools. Bioinformatics analysis identified several potential candidate genes that could encode 5'-nucleotidase activity including an HD-domain protein that we show catalyzes dephosphorylation of deoxyribonucleotide 5'-monophosphates. We conclude that TK is essential for synthesis of thymine nucleotides regardless of whether the nucleoside precursors originate from the de novo pathway or through salvage. Reliance on TK in the absence of DCTD may be a shared vulnerability among trypanosomatids and may provide a unique opportunity to selectively target a diverse group of pathogenic single-celled eukaryotes with a single drug.This work was supported by National Institutes of Health (grants AI078962 and AI034432) to MAP (https://www.niaid.nih.gov) and (grant GM007062) to CL (https://www.nigms.nih. gov), the Welch Foundation (grant I-1257) to MAP and (grant I-1686) to JJK (http://www.welch1.org), and Fundac ̧ão para a Ciência e Tecnologia (FCT, Portugal) SFRH/BD/51286/2010 (http://www.fct.pt) to FRF.info:eu-repo/semantics/publishedVersio

Review of gynaecological cancer among Aboriginal and/or Torres Strait Islander people in Australia

Gynaecological cancers bear a significant burden on the health of Australians. Whilst Australia has made great strides in reducing the overall gynaecological cancer burden nationally, Aboriginal and/or Torres Strait Islander women continue to experience disproportionately high rates of gynaecological cancers. This review focuses on the social, cultural, and historical contexts that contribute to inequitable gynaecological cancer rates among Aboriginal and/or Torres Strait Islander women. An in-depth discussion on cervical cancer, ovarian cancer, and uterine cancer are described; including the incidence, mortality, survival, and management of these diseases for Aboriginal and/or Torres Strait Islander women. It highlights both the persistent barriers and facilitators relating to Aboriginal and/or Torres Strait Islander women’s uptake of preventative measures and treatments, including their use of services and programs relating to the management of gynaecological cancers. This review summarises past and current policies and strategies implemented by the Australian Government and other cancer related peak bodies that aim to address this health issue. It recommends that critical attention be given to risk reduction, participation in cancer screening programs, and improved access to culturally appropriate, high quality primary health care and tertiary specialist services. This would address inequitable differences faced by Aboriginal and/or Torres Strait Islander people and reduce the overall burden of gynaecological cancers

Coexistence of perseveration and apathy in the TDP-43Q331K knock-in mouse model of ALS-FTD.

Funder: Motor Neurone Disease Association (MNDA); doi: https://doi.org/10.13039/501100000406Funder: the Lady Edith Wolfson Fellowship Fund, the van Geest FoundationPerseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43Q331K mouse, an ALS-FTD model with a human-equivalent mutation (TDP-43Q331K) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS-FTD patients. The TDP-43Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS-FTD

High Healthcare Utilization at the Onset of Medically Unexplained Symptoms

Objective: Patients with medically unexplained syndromes (MUS) often do not receive appropriate healthcare. A critical time for effective healthcare is the inception of MUS. The current study examined data from a prospective longitudinal study of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans to understand the relationship of increasing physical symptom burden to healthcare utilization. Methods: Data was examined from a prospective study of OEF/OIF veterans assessed before and one year after deployment (n=335). Physical symptom burden was measured with the Patient Health Questionnaire (PHQ-15). Analyses were conducted with polynomial regression and response surface analysis (RSA). Results: Increases in physical symptom burden predicted greater healthcare utilization one year after deployment: primary care practitioner (slope = -0.26, F=4.07, p=0.04), specialist (slope = -.43, t=8.67, p=0.003), allied health therapy (e.g., physical therapy) (slope = -.41, t=5.71, p=0.02) and mental health (slope = -.32, F=4.04, p=0.05). There were no significant difference in utilization between those with consistently high levels and those with increases in physical symptom burden. Conclusion: This is the first prospective study to examine, and show, a relationship between onset of clinically significant physical symptoms and greater healthcare utilization. Our data suggest that patients with increasing physical symptom burden have the same level of healthcare as patients with chronic physical symptom burden. Needed next steps are to better understand the quality of care at inception and determine how to intervene so that recommended approaches to care are provided from the onset