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L-type calcium channels (LTCCs), including the Ca

In this issue of Neuron, Nguyen and colleagues (Nguyen et al., 2021) investigate nicotine's effects on diverse midbrain dopamine neurons. Their findings provide new understanding of the functional role of ventral tegmental area (VTA) dopamine neurons and reveal topographically distinct, pathway-specific, and opposite dopaminergic responses to nicotine that likely mediate reward and anxiety, respectively.

Acetylcholine is an important neuromodulator of the mesolimbic dopamine (DA) system, which itself is a mediator of motivated behavior. Motivated behavior can be described by two primary components, termed directional and activational motivation, both of which can be examined and dissociated using effort-choice tasks. The directional component refers to motivated behavior directed towards reinforcing stimuli and away from aversive stimuli. Behaviors characterized by increased vigor, persistence, and work output are considered to reflect activational components of motivation. Disruption of DA signaling has been shown to decrease activational components of motivation, while leaving directional features intact. Facilitation of DA release promotes the activational aspects of motivated behavior. In this review, we discuss cholinergic and DA regulation of motivated behaviors. We place emphasis on effort-choice processes and the ability of effort-choice tasks to examine and dissociate changes of motivated behavior in the context of substance use and mood disorders. Furthermore, we consider how altered cholinergic transmission impacts motivated behavior across disease states, and the possible role of cholinergic dysregulation in the etiology of these illnesses. Finally, we suggest that treatments targeting cholinergic activity may be useful in ameliorating motivational disruptions associated with substance use and comorbid substance use and mood disorders.

Although e-cigarette use among youth is recognized as an epidemic, there is limited understanding regarding nicotine's orosensory and chronic use effects in youth, and how fruit e-cigarette flavorings may influence nicotine's effects. We aimed to characterize the orosensory and chronic use effects of nicotine in adolescent rats. We also determined the acute and chronic effects of benzaldehyde, a cherry/berry/almond flavoring, on nicotine's taste, consumption, withdrawal, and reinstatement. Rats were examined for their acute taste responses to the different nicotine concentrations. The effects of chronic exposure on nicotine's taste, withdrawal, and reinstatement were also determined. In addition, impact of benzaldehyde on these nicotine use behaviors was evaluated. While taste responses to low nicotine concentrations did not differ from water, high nicotine concentrations induced aversion. Aversive responses to nicotine that were observed in naïve animals vanished after chronic nicotine exposure, indicating the development of tolerance to nicotine's aversive taste. Additionally, nicotine abstinence after chronic exposure induced withdrawal. Following abstinence, animals reinstated nicotine use. Further, animals showed higher preference to nicotine after reinstatement, compared to preference values before nicotine withdrawal. Benzaldehyde did not alter nicotine's taste reactivity, withdrawal, and reinstatement experiments. Some sex differences were found in benzaldehyde's taste response and choice behavior experiments.

Background: Tobacco use in humans is a long-standing public health concern. Flavors are common additives in tobacco and alternative tobacco products, added to mask nicotine’s harsh orosensory effects and increase the appeal of these products. Animal models are integral for investigating nicotine use and addiction and are helpful for understanding the effects of flavor additives on the use of nicotine delivery products. Objective: This review focuses on preclinical models to evaluate the contribution of flavor additives to nicotine addiction. Materials and Methods: An electronic literature search was conducted by authors up to May 2022. Original articles were selected. Results: The behavioral models of rodents described here capture multiple dimensions of human flavored nicotine use behaviors, including advantages and disadvantages. Conclusion: The consensus of the literature search was that human research on nicotine use behavior has not caught up with fast-changing product innovations, marketing practices, and federal regulations. Animal models are therefore needed to investigate mechanisms underlying nicotine use and addiction. This review provides a comprehensive overview of animal models that can be used to investigate the effects of flavors on nicotine use behaviors.

How can academics and community practitioners better collaborate to overcome the existing barriers? What role can intersectoral research collaboratives play in supporting, enhancing, and sustaining the impact of community-engaged research? In response to these broad questions, this paper shares insights from the Food: Locally Embedded, Globally Engaged (FLEdGE) community-engaged research network, a collaborative, interdisciplinary group of scholars and practitioners that crossed sectors, scales, and geographies. The FLEdGE research program ran from 2015 to 2021, and built on over a decade of academic and community partnerships to assess the current and potential role of food initiatives as pillars for sustainable transformation. Our mixed-methods study draws on data from a social network analysis survey, summary reports, semi-structured interviews, and reflections from the authors who were all active members of the network. Our findings reveal that beyond making theoretical and practical contributions to food systems scholarship and initiatives in the participating regions, FLEdGE played an important role in building food movements across Canada and beyond. We describe this as a modular approach, an organizational structure in which multiple units (or modules) operate independently while also sharing enough commonalities that allow them to be interrelated, modified, and reconfigured in diverse and dynamic ways. We argue that intersectoral research networks adopting a modular approach require interdisciplinarity and collaborative methodologies, but also flexibility and critical reflexivity. In addition, we underscore that setting objectives, both overarching and tactical, requires a negotiated approach, particularly when budgetary administration resides within an institutional partner.

Introduction Tobacco product flavors may change the sensory properties of nicotine, such as taste and olfactory cues, which may alter nicotine reward and aversion and nicotine taking behavior. The hedonic or aversive value of a taste stimulus can be evaluated by examining affective orofacial movements in rodents. Aims and Methods We characterized taste responses to various oral nicotine concentrations using the taste reactivity test in rats. We also evaluated the impact of menthol and benzaldehyde (cherry, almond) flavorants on both ingestive and aversive responses to oral nicotine. Adult Sprague-Dawley rats (n = 5–10 per sex per group) were implanted with intraoral catheters and received 20 infusions (200 µl/ea). Nicotine (1–100 µg/mL) was evaluated in taste reactivity test to determine taste responses to nicotine. Later, the effects of menthol (50 µg/mL) and benzaldehyde (100 µg/mL) on the taste responses to nicotine were determined. Results Nicotine at low concentrations (3 µg/mL in males, 1 µg/mL in females) elicited significantly greater ingestive responses compared with water, whereas higher nicotine concentrations (≥30 µg/mL in males, ≥10 µg/mL in females) elicited significant aversive reactions. Thus, intraoral nicotine induced both hedonic and aversive responses in a concentration- and sex-dependent manner. Females were more sensitive to nicotine’s concentration. The addition of menthol or benzaldehyde significantly increased the hedonic responses to nicotine, and significantly decreased the aversive nicotine responses. Conclusions Oral nicotine induces both hedonic and aversive taste responses, which may represent liking and disliking. Menthol and benzaldehyde can alter the orosensory experience of nicotine, which may influence nicotine’s abuse liability. Implications Our work represents a model to study impact of flavors on oral nicotine liking and disliking responses in rats. Moreover, our findings show that menthol and benzaldehyde alter the orosensory experience of nicotine, suggesting that both could influence nicotine’s abuse liability.

Drug relapse after periods of abstinence is a common feature of substance abuse. Moreover, anxiety and other mood disorders are often co-morbid with substance abuse. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate drug-seeking and anxiety-related behavior in rodent models. However, it is unclear if overlapping VTA cholinergic mechanisms mediate drug relapse and anxiety-related behaviors associated with drug abstinence. We examined the effects of VTA cholinergic receptor blockade on cue-induced cocaine seeking and anxiety during cocaine abstinence. Male Sprague–Dawley rats were trained to self-administer intravenous cocaine (~ 0.5 mg/kg/infusion, FR1 schedule) for 10 days, followed by 14 days of forced abstinence. VTA infusion of the non-selective nicotinic acetylcholine receptor antagonist mecamylamine (0, 10, and 30 μg/side) or the non-selective muscarinic receptor antagonist scopolamine (0, 2.4 and 24 μg /side) significantly decreased cue-induced cocaine seeking. In cocaine naive rats, VTA mecamylamine or scopolamine also led to dose-dependent increases in open arm time in the elevated plus maze (EPM). In contrast, rats that received I.V. cocaine, compared to received I.V. saline rats, displayed an anxiogenic response on day 14 of abstinence as reflected by decreased open arm time in the EPM. Furthermore, low doses of VTA mecamylamine (10 μg /side) or scopolamine (2.4 μg /side), that did not alter EPM behavior in cocaine naive rats, were sufficient to reverse the anxiogenic effects of cocaine abstinence. Together, these data point to an overlapping role of VTA cholinergic mechanisms to regulate relapse and mood disorder-related responses during cocaine abstinence.

Phasic dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens plays a pivotal role in reward processing and reinforcement learning. Understanding how the diverse neuronal inputs into the VTA control phasic DA release can provide a better picture of the circuitry that controls reward processing and reinforcement learning. Here, we describe a method that combines intra-VTA cannula infusions of pharmacological agonists and antagonists with stimulation-evoked phasic DA release (combined infusion and stimulation, or CIS) as measured by in vivo fast-scan cyclic voltammetry (FSCV). Using CIS-FSCV in anesthetized rats, a phasic DA response can be evoked by electrically stimulating the VTA with a bipolar electrode fitted with a cannula while recording in the nucleus accumbens core. Pharmacological agonists or antagonists can be infused directly at the stimulation site to investigate specific VTA receptors' roles in driving phasic DA release. A major benefit of CIS-FSCV is that VTA receptor function can be studied in vivo, building on in vitro studies.

Previous preclinical and clinical investigations have focused on the L-type calcium channel (LTCC) as a potential therapeutic target for substance abuse. While some clinical studies have examined the ability of LTCC blockers to alter cocaine’s subjective effects, very few LTCC studies have examined cocaine relapse. Here, we examined whether ventral tegmental area (VTA)-specific or systemic administration of the LTCC inhibitor, isradipine, altered cocaine-seeking behavior in a rat model. Male Sprague-Dawley rats first received 10 days of cocaine self-administration training (2 h sessions), where active lever depression resulted in delivery of a ∼0.5 mg/kg cocaine infusion paired with a tone + light cue. Rats then underwent 10 days of forced abstinence, without access to cocaine or cocaine cues. Rats were then returned to the opertant chamber for the cue-induced cocaine-seeking test, where active lever depression in the original training context resulted in tone + light cue presentation. We found VTA specific or systemic isradipine administration robustly attenuated cocaine-seeking, without altering cocaine-taking nor natural reward seeking. Dopamine (DA) signaling in the nucleus accumbens (NAc) core is necessary and sufficient for cue-induced drug-seeking. Surprisingly in our study, isradipine enhanced tonic and phasic DA signaling in cocaine abstinent rats, with no change in sucrose abstinent nor naïve rats. Strikingly, isradipine’s behavioral effects were dependent upon NAc core DA receptor activation. Together, our findings reveal a novel mechanism by which the FDA-approved drug, isradipine, could act to decrease cocaine relapse.

Multi-stakeholder partnerships (MSPs) have become a widespread means for deploying policies in a whole of society strategy to address the complex problem of childhood obesity. However, decision-making in MSPs is fraught with challenges, as decision-makers are faced with complexity, and have to reconcile disparate conceptualizations of knowledge across multiple sectors with diverse sets of indicators and data. These challenges can be addressed by supporting MSPs with innovative tools for obtaining, organizing and using data to inform decision-making. The purpose of this paper is to describe and analyze the development of a knowledge-based infrastructure to support MSP decision-making processes. The paper emerged from a study to define specifications for a knowledge-based infrastructure to provide decision support for community-level MSPs in the Canadian province of Quebec. As part of the study, a process assessment was conducted to understand the needs of communities as they collect, organize, and analyze data to make decisions about their priorities. The result of this process is a “portrait”, which is an epidemiological profile of health and nutrition in their community. Portraits inform strategic planning and development of interventions, and are used to assess the impact of interventions. Our key findings indicate ambiguities and disagreement among MSP decision-makers regarding causal relationships between actions and outcomes, and the relevant data needed for making decisions. MSP decision-makers expressed a desire for easy-to-use tools that facilitate the collection, organization, synthesis, and analysis of data, to enable decision-making in a timely manner. Findings inform conceptual modeling and ontological analysis to capture the domain knowledge and specify relationships between actions and outcomes. This modeling and analysis provide the foundation for an ontology, encoded using OWL 2 Web Ontology Language. The ontology is developed to provide semantic support for the MSP process, defining objectives, strategies, actions, indicators, and data sources. In the future, software interacting with the ontology can facilitate interactive browsing by decision-makers in the MSP in the form of concepts, instances, relationships, and axioms. Our ontology also facilitates the integration and interpretation of community data, and can help in managing semantic interoperability between different knowledge sources. Future work will focus on defining specifications for the development of a database of indicators and an information system to help decision-makers to view, analyze and organize indicators for their community. This work should improve MSP decision-making in the development of interventions to address childhood obesity.

As the global health agenda shifts from the Millennium Development Goals (MDGs) to Sustainable Development Goals (SDGs), the need for effective preventive health efforts has gained prominence, particularly in low-income regions with poor health and nutrition outcomes. To address needs in communities with limited access to health services and personnel, it is important to develop strategies that can improve the effectiveness of nurses as they interact with the populations they serve. We contribute to informing such strategies by explaining how mothers' "reflective trust" in community health nurses develops as a key influencer in their health-related decision-making and behavior. Between December 2012 and June 2013, our ethnographic study gathered data in three adjacent rural and semi-rural communities in Ghana's Eastern Region, using interviews with 39 nursing mothers, three focus groups - with mothers, health-workers, and community leaders - as well as 941 h of participant observation. We focused on interactions between mothers and nurses, highlighting tensions between communities' traditions and messages that nurses bring, which are often based on modern science. We also investigated how mothers come to exhibit reflective trust in the nurses to make sense of traditional and scientific knowledge on infant feeding, and integrate them into their own feeding decisions. Our findings have global implications for effectively sustaining and scaling health and nutrition efforts through community approaches.

PURPOSE To develop a retrospective nonrigid motion-correction method based on 3D image-based navigators (iNAVs) for free-breathing whole-heart coronary magnetic resonance angiography (MRA). METHODS The proposed method detects global rigid-body motion and localized nonrigid motion from 3D iNAVs and compensates them with an autofocusing algorithm. To model the global motion, 3D rotation and translation are estimated from the 3D iNAVs. Two sets of localized nonrigid motions are obtained from deformation fields between 3D iNAVs and reconstructed binned images, respectively. A bank of motion-corrected images is generated and the final image is assembled pixel-by-pixel by selecting the best focused pixel from this bank. In vivo studies with six healthy volunteers were conducted to compare the performance of the proposed method with 3D translational motion correction and no correction. RESULTS In vivo studies showed that compared to no correction, 3D translational motion correction and the proposed method increased the vessel sharpness by 13% ± 13% and 19% ± 16%, respectively. Out of 90 vessel segments, 75 segments showed improvement with the proposed method compared to 3D translational correction. CONCLUSION We have developed a nonrigid motion-correction method based on 3D iNAVs and an autofocusing algorithm that improves the vessel sharpness of free-breathing whole-heart coronary MRA. Magn Reson Med 77:1884-1893, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose To develop a method for acquiring whole-heart 3D image-based navigators (iNAVs) with isotropic resolution for tracking and correction of localized motion in coronary magnetic resonance angiography (CMRA). Methods To monitor motion in all regions of the heart during a free-breathing scan, a variable-density cones trajectory was designed to collect a 3D iNAV every heartbeat in 176 ms with 4.4 mm isotropic spatial resolution. The undersampled 3D iNAV data were reconstructed with efficient self-consistent parallel imaging reconstruction (ESPIRiT). 3D translational and nonrigid motion-correction methods using 3D iNAVs were compared to previous translational and nonrigid methods using 2D iNAVs. Results Five subjects were scanned with a 3D cones CMRA sequence, accompanied by both 2D and 3D iNAVs. The quality of the right and left anterior descending coronary arteries was assessed on 2D and 3D iNAV-based motion-corrected images using a vessel sharpness metric and qualitative reader scoring. This assessment showed that nonrigid motion correction based on 3D iNAVs produced results that were noninferior to correction based on 2D iNAVs. Conclusion The ability to acquire isotropic-resolution 3D iNAVs every heartbeat during a CMRA scan was demonstrated. Such iNAVs enabled direct measurement of localized motion for nonrigid motion correction in free-breathing whole-heart CMRA. Magn Reson Med 77:1874-1883, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Acetylcholine is implicated in mood disorders including depression and anxiety. Increased cholinergic tone in humans and rodents produces pro-depressive and anxiogenic-like effects. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate these responses in male rats, as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and the forced swim test (FST). However, these effects have not been examined in females, and the VTA muscarinic receptor subtype(s) mediating the pro-depressive and anxiogenic-like behavioral effects of increased cholinergic tone are unknown. We first examined the behavioral effects of increased VTA cholinergic tone in male and female rats, and then determined whether VTA muscarinic M5 receptors were mediating these effects. VTA infusion of the acetylcholinesterase inhibitor physostigmine (0.5 μg, 1 μg and 2 μg/side) in males and females produced anhedonic-like, anxiogenic, pro-depressive-like responses on the SPT, EPM, and FST. In females, VTA administration of the muscarinic M5 selective negative allosteric modulator VU6000181 (0.68 ng, 2.3 ng, 6.8 ng/side for a 3 μM, 10 μM, 30 μM/side infusion) did not alter SPT, EPM nor FST behavior. However, in males intra-VTA infusion of VU6000181 alone reduced time spent immobile on the FST. Furthermore, co-infusion of VU6000181 with physostigmine, in male and female rats, attenuated the pro-depressive and anxiogenic-like behavioral responses induced by VTA physostigmine alone, in the SPT, EPM, and FST. Together, these data reveal a critical role of VTA M5 receptors in mediating the anhedonic, anxiogenic, and depressive-like behavioral effects of increased cholinergic tone in the VTA.

Tobacco-related morbidity and mortality continue to be a significant public health concern. Unfortunately, current FDA-approved smoking cessation pharmacotherapies have limited efficacy and are associated with high rates of relapse. Therefore, a better understanding of the neurobiological and neurophysiological mechanisms that promote smoking relapse is needed to develop novel smoking cessation medications. Here, we review preclinical studies focused on identifying the neurotransmitter and neuromodulator systems that mediate nicotine relapse, often modeled in laboratory animals using the reinstatement paradigm, as well as the plasticity-dependent neurophysiological mechanisms that facilitate nicotine reinstatement. Particular emphasis is placed on how these neuroadaptations relate to smoking relapse in humans. We also highlight a number of important gaps in our understanding of the neural mechanisms underlying nicotine reinstatement and critical future directions, which may lead toward the development of novel, target pharmacotherapies for smoking cessation.

Sustainable solutions for complex societal problems, like poverty, require informing stakeholders about progress and changes needed as they collaborate. Yet, inter-organizational collaboration researchers highlight monumental challenges in measuring seemingly intangible factors during collective impact processes. We grapple with the question: How can decision-makers coherently conceptualize and measure seemingly intangible factors to sustain partnerships for the emergence of collective impact? We conducted an inductive process case study to address this question, analyzing data from documents, observations, and interviews of 24 philanthropy leaders and multiple stakeholders in a decades-long partnership involving Canada’s largest private family foundation, government and community networks, and during which a “collective impact project” emerged in Quebec Province, Canada. The multidimensional proximity framework provided an analytical lens. During the first phase of the partnership studied, there was a lack of baseline measurement of largely qualitative factors—conceptualized as cognitive, social, and institutional proximity between stakeholders—which evaluations suggested were important for explaining which community networks successfully brought about desired outcomes. Non-measurement of these factors was a problem in providing evidence for sustained engagement of stakeholders, such as government and local businesses. We develop a multidimensional proximity model that coherently conceptualizes qualitative proximity factors, for measuring their change over time.

Purpose To develop a 3D cones steady-state free precession sequence with improved robustness to respiratory motion while mitigating eddy current artifacts for free-breathing whole-heart coronary magnetic resonance angiography. Method The proposed sequence collects cone interleaves using a phyllotaxis pattern, which allows for more distributed k-space sampling for each heartbeat compared to a typical sequential collection pattern. A Fibonacci number of segments is chosen to minimize eddy current effects with the trade-off of an increased number of acquisition heartbeats. For verification, phyllotaxis-cones is compared to sequential-cones through simulations, phantom studies, and in vivo coronary scans with 8 subjects using 2D image-based navigators for retrospective motion correction. Results Simulated point spread functions and moving phantom results show less coherent motion artifacts for phyllotaxis-cones compared to sequential-cones. Assessment of the right and left coronary arteries using reader scores and the image edge profile acutance vessel sharpness metric indicate superior image quality and sharpness for phyllotaxis-cones. Conclusion Phyllotaxis 3D cones results in improved qualitative image scores and coronary vessel sharpness for free-breathing whole-heart coronary magnetic resonance angiography compared to standard sequential ordering when using a steady-state free precession sequence.

Background: Ghana has been the testing ground for many teaching and learning initiatives over the past 15–20 years. These initiatives, largely funded by donors, have sought to improve learning by introducing and reinforcing valuable teaching skills, materials and approaches, most of them child-friendly, learner-centred and involving activity-based learning (ABL). However, a problem in Ghana, also true of other countries in sub-Saharan Africa, is that whereas efforts over the past few decades have improved access to basic education in both pupil enrolment rates and teacher numbers, educational quality as measured by standardised test scores in key subject areas remains rather low.Purpose: This article reports on an aspect of a DfID (Ghana) – sponsored research project which examined how the quality of teaching and learning in Ghanaian basic schools could be improved through the utilisation of ABL pedagogy. The current article examines three overarching themes relative to ABL pedagogy, namely how participan...

The mesolimbic dopamine (DA) system is known to play a role in cue-mediated reward-seeking for natural rewards and drugs of abuse. Specifically, cholinergic and glutamatergic receptors in the ventral tegmental area (VTA) have been shown to regulate cue-induced drug-seeking. However, the potential role of these VTA receptors in regulating cue-induced reward seeking for natural rewards is unknown. Here, we examined whether blockade of VTA acetylcholine receptors (AChRs) and N-methyl-d-aspartate receptors (NMDARs) would alter cue-induced sucrose seeking in male Sprague-Dawley rats. Subjects underwent 10 days of sucrose self-administration training (fixed ratio 1 schedule) followed by 7 days of forced abstinence. On withdrawal day 7, rats received bilateral VTA infusion of vehicle, the muscarinic AChR antagonist scopolamine (2.4 or 24 μg/side), the nicotinic AChR antagonist mecamylamine (3 or 30 μg/side), or the NMDAR antagonist AP-5 (0.1 or 1 μg/side) immediately prior to examination of cue-induced sucrose-seeking. Scopolamine infusion led to robust attenuation, but did not completely block, sucrose-seeking behavior. In contrast, VTA administration of mecamylamine or AP-5 did not alter cue-induced sucrose-seeking. Together, the data suggest that VTA muscarinic AChRs, but not nicotinic AChRs nor NMDARs, facilitate the ability of food-associated cues to drive seeking behavior for a food reward.

Purpose To improve the spatial/temporal resolution of whole-heart coronary MR angiography by developing a variable-density (VD) 3D cones acquisition suitable for image reconstruction with parallel imaging and compressed sensing techniques. Methods A VD 3D cones trajectory design incorporates both radial and spiral trajectory undersampling techniques to achieve higher resolution. This design is used to generate a VD 3D cones trajectory with 0.8 mm/66 ms isotropic spatial/temporal resolution, using a similar number of readouts as our previous fully sampled cones trajectory (1.2 mm/100 ms). Scans of volunteers and patients are performed to evaluate the performance of the VD trajectory, using non-Cartesian L1-ESPIRiT for high-resolution image reconstruction. Results With gridding reconstruction, the high-resolution scans experience an expected drop in signal-to-noise and contrast-to-noise ratios, but with L1-ESPIRiT, the apparent noise is substantially reduced. Compared with 1.2 mm images, in each volunteer, the L1-ESPIRiT 0.8 mm images exhibit higher vessel sharpness values in the right and left anterior descending arteries. Conclusion Coronary MR angiography with isotropic submillimeter spatial resolution and high temporal resolution can be performed with VD 3D cones to improve the depiction of coronary arteries. Magn Reson Med 74:614–621, 2015. © 2015 Wiley Periodicals, Inc.

Purpose To develop a magnetization preparation sequence for simultaneous outer volume suppression (OVS) and T2 weighting in whole-heart coronary magnetic resonance angiography. Methods A combined OVS and T2 preparation sequence (OVS-T2 Prep) was designed with a nonselective adiabatic 90° tipdown pulse, two adiabatic 180° refocusing pulses, and a 2D spiral −90° tipup pulse. The OVS-T2 Prep preserves the magnetization inside an elliptic cylinder with T2 weighting, while saturating the magnetization outside the cylinder. Its performance was tested on phantoms and on 13 normal subjects with coronary magnetic resonance angiography using 3D cones trajectories. Results Phantom studies showed expected T2-dependent signal amplitude in the spatial passband and suppressed signal in the spatial stopband. In vivo studies with full-field-of-view cones yielded a passband-to-stopband signal ratio of 3.18 ± 0.77 and blood-myocardium contrast-to-noise ratio enhancement by a factor of 1.43 ± 0.20 (P

The 20th century saw accelerated human and economic development, with increased convergence in income, wealth, and living standards around the world. For a large part, owing to the well-entrenched Western-centric linear and siloed industrialization pattern, this positive transformation has also been associated with complex societal challenges at the nexus of agricultural, industrial, and health sectors. Efforts at cross-sectoral policy coherence have been deployed with limited success. To go beyond what has been possible thus far, the whole-of-society (WoS) paradigm for human and economic development proposes a 21st century convergence where, instead of the rest (of the world) converging with the West, sectoral and cross-sectoral efforts converge in their single and collective policy and action on a common target of human and economic development. In this paper, we first review and discuss contributions and limitations of policy coherence approaches. We then elaborate the institutional foundation of the WoS paradigm, taking as an anchor the well-established model of polycentric governance that views individuals, and state, market, and community, forming society as part of the same complex adaptive system. Actors within such systems self-organize into nested hierarchies that operate at multiple scales and move toward 21st century convergence of human and economic development.

In adopting a whole-of-society (WoS) approach that engages multiple stakeholders in public health policies across contexts, the authors propose that effective governance presents a challenge. The purpose of this paper is to highlight a case for how polycentric governance underlying the WoS approach is already functioning, while outlining an agenda to enable adaptive learning for improving such governance processes. Drawing upon a case study from Quebec, Canada, we employ empirically developed concepts from extensive, decades-long work of the 2009 Nobel laureate Elinor Ostrom in the governance of policy in nonhealth domains to analyze early efforts at polycentric governance in policies around overnutrition, highlighting interactions between international, domestic, state and nonstate actors and processes. Using information from primary and secondary sources, we analyze the emergence of the broader policy context of Quebec's public health system in the 20th century. We present a microsituational analysis of the WoS approach for Quebec's 21st century policies on healthy lifestyles, emphasizing the role of governance at the community level. We argue for rethinking prescriptive policy analysis of the 20th century, proposing an agenda for diagnostic policy analysis, which explicates the multiple sets of actors and interacting variables shaping polycentric governance for operationalizing the WoS approach to policymaking in specific contexts.

OBJECTIVES: Cohabiting but previously divorced women may be at increased risk of food insecurity. This study explored women's perceptions of how current and prior marital status could influence food security status. METHODS: Nine focus group (FG) discussions were held with mothers of young children who participated in a nutrition-sensitive agriculture intervention (Nutrition Links) in rural Ghana. Nine of 13 intervention communities were purposively selected to participate. Each FG had 5 to 9 women who were asked about the support they received from their partners regarding food for the household, entrepreneurship activities, and their children's healthcare. How this support changed with marital status, and from where else women could get support was further probed. Translated transcriptions of FG were thematically analyzed. RESULTS: Most women reported that men helped with money for food for the household or food stuff from farm. Divorced women would not receive that kind of support. The only support women agreed that men provided independent of marital status was for children's healthcare. Often, the main support network women counted on was that of their immediate family. Co-habiting women would be “pampered” by their partners. However, they would receive little support to develop their own business because men feared that a woman might leave if she were successful. FG participants complained about the lack of freedom married women had, but most of them agreed that married women had a better economic and social standing and had more support from their husband's family than non-married women. FG women reported that married men were more likely to support their wives’ business - assuming that they would also benefit - but a man would hinder his wife's entrepreneurial growth out of jealousy if he perceived that she was moving ahead of him. CONCLUSIONS: Marital status might affect the support women receive for food security in complex ways. Divorced women do not receive economic support from their ex-husbands and cohabiting women do not receive support to develop their business. As previous studies suggested, focusing solely on female household headship might not be enough to identify the most vulnerable individuals. Thus, interventions and policies targeting maternal and child nutrition should consider women's marital status as well as their support networks. FUNDING SOURCES: 1. International Development Research Centre (IDRC). 2. Global Affairs Canada. 3. McGill University. 4. World Vision. 5. University of Ghana.

Purpose To implement a nonrigid autofocus motion correction technique to improve respiratory motion correction of free-breathing whole-heart coronary magnetic resonance angiography acquisitions using an image-navigated 3D cones sequence. Methods 2D image navigators acquired every heartbeat are used to measure superior-inferior, anterior-posterior, and right-left translation of the heart during a free-breathing coronary magnetic resonance angiography scan using a 3D cones readout trajectory. Various tidal respiratory motion patterns are modeled by independently scaling the three measured displacement trajectories. These scaled motion trajectories are used for 3D translational compensation of the acquired data, and a bank of motion-compensated images is reconstructed. From this bank, a gradient entropy focusing metric is used to generate a nonrigid motion-corrected image on a pixel-by-pixel basis. The performance of the autofocus motion correction technique is compared with rigid-body translational correction and no correction in phantom, volunteer, and patient studies. Results Nonrigid autofocus motion correction yields improved image quality compared to rigid-body-corrected images and uncorrected images. Quantitative vessel sharpness measurements indicate superiority of the proposed technique in 14 out of 15 coronary segments from three patient and two volunteer studies. Conclusion The proposed technique corrects nonrigid motion artifacts in free-breathing 3D cones acquisitions, improving image quality compared to rigid-body motion correction. Magn Reson Med 72:347–361, 2014. © 2013 Wiley Periodicals, Inc.

Reeves, C; Carnoy, M; Addy, N. (2013). Comparing opportunity to learn and student achievement gains in southern African primary schools: a new approach. International Journal of Educational Development , 33, 5. 2013. p. 426-435, DOI:10.1016/j.ijedudev.2012.12.006

Published articles permit mapping international and comparative education research. We reviewed 605 articles published 2004–2008 in four major journals. Using title, abstract, and entire text we explored thematic focus, geographic focus, level/type of education studied, method, and funding. The economic, political, and social context of education receives far more attention than its content. Comparative and international education research reflects more diversity than convergence in approach, theory, and methodology. The research community moves in multiple directions simultaneously, insisting that understanding education requires studying not only what happens within schools but also where the schools sit and who enters their doors.

Cholinergic and dopaminergic mechanisms within the mesolimbic dopamine system are suggested to play a role in the manifestation of depression and anxiety-related disorders. However, despite the fact that cholinergic mechanisms in the ventral tegmental area (VTA) highly regulate dopamine activity, the role of VTA cholinergic mechanisms in depression-related behaviors is relatively unknown. Here we sought to determine whether enhancing cholinergic tone in the VTA would alter depression and anxiety-related behavior in the forced swim test (FST), elevated plus maze (EPM) and sucrose preference test (SPT). Adult Sprague Dawley male rats received VTA infusion of the acetylcholinesterase inhibitor, physostigmine (0, 1, 2 μg/side), immediately prior to the FST, EPM, or SPT. Physostigmine administration increased immobility time in the FST, decreased time spent on open arms in the EPM, and decreased sucrose preference. In a separate cohort of rats, we also examined whether activation of VTA muscarinic receptors was sufficient to alter behavior in the FST and EPM. Similar to physostigmine, VTA infusion of the muscarinic receptor agonist, pilocarpine (0, 3, 30 μg/side), increased immobility time in the FST and decreased time spent on open arms in the EPM. These data suggest that enhanced VTA cholinergic tone promotes pro-depressive and anxiogenic-like effects and demonstrate that specific activation of VTA muscarinic receptors is also sufficient to induce pro-depressive and anxiogenic responses. Together, these findings reveal a novel role of VTA cholinergic, and specifically muscarinic receptor, mechanisms in mediating responses to stress and anxiety.

The influence of micronutrients on dopamine systems is not well defined. Using mice, we show a potential role for reduced dietary vitamin D3 (cholecalciferol) in promoting diet-induced obesity (DIO), food intake, and drug consumption while on a high fat diet. To complement these deficiency studies, treatments with exogenous fully active vitamin D3 (calcitriol, 10 µg/kg, i.p.) were performed. Nondeficient mice that were made leptin resistant with a high fat diet displayed reduced food intake and body weight after an acute treatment with exogenous calcitriol. Dopamine neurons in the midbrain and their target neurons in the striatum were found to express vitamin D3 receptor protein. Acute calcitriol treatment led to transcriptional changes of dopamine-related genes in these regions in naive mice, enhanced amphetamine-induced dopamine release in both naive mice and rats, and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.). Alternatively, mice that were chronically fed either the reduced D3 high fat or chow diets displayed less activity after acute amphetamine treatment compared with their respective controls. Finally, high fat deficient mice that were trained to orally consume liquid amphetamine (90 mg/L) displayed increased consumption, while nondeficient mice treated with calcitriol showed reduced consumption. Our findings suggest that reduced dietary D3 may be a contributing environmental factor enhancing DIO as well as drug intake while eating a high fat diet. Moreover, these data demonstrate that dopamine circuits are modulated by D3 signaling, and may serve as direct or indirect targets for exogenous calcitriol.

This chapter reviews the seminal findings and advances that have contributed to the field's understanding of the neurobiological processes that underlie substance use disorders (SUDs). Much of the current understanding has been facilitated by investigations that have identified drug-mediated changes in neurotransmitter signaling, synaptic physiology, intracellular signaling, and subsequent neurophysiological, morphological, and genetic adaptations that occur within specific neuronal circuits and pathways. The chapter also reviews the progress of ongoing studies that are identifying genes associated with susceptibility to SUD and the role of genetic and epigenetic processes in mediating SUD-related behaviors. The chapter closes by discussing how advances in our knowledge of genetic mechanisms can inform understanding of abuse susceptibility, as well as the implications of such knowledge for the successful treatment of SUD.

Fast imaging trajectories are used in MRI to speed up the acquisition process, but imperfections in the gradient system create artifacts in the reconstructed images. Artifacts result from the deviation between k-space trajectories achieved on the scanner and their original prescription. Measuring or approximating actual k-space trajectories with predetermined gradient timing delays reduces the artifacts, but are generally based on a specific trajectory and scan orientation. A single linear time-invariant characterization of the gradient system provides a method to predict k-space trajectories scanned in arbitrary orientations through convolution. This is done efficiently, by comparing the Fourier transforms of the input and measured waveforms of a single high-bandwidth test gradient waveform. This new method is tested for spiral, interleaved echo-planar, and three-dimensional cones imaging, demonstrating its ability to reduce reconstructed image artifacts for various k-space trajectories. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.

Repeated cocaine exposure and withdrawal leads to long-term changes, including behavioral and dopamine sensitization to an acute cocaine challenge, that are most pronounced after long withdrawal periods. However, the changes in dopamine neurotransmission after short withdrawal periods are less well defined. To study dopamine neurotransmission after 1-day withdrawal, we used fast-scan cyclic voltammetry (FSCV) to determine whether repeated cocaine alters rapid dopamine release and uptake in the nucleus accumbens (NAc) core and shell. FSCV was performed in urethane anesthetized male Sprague-Dawley rats that had previously received one or seven daily injections of saline or cocaine (15 mg/kg, ip). In response to acute cocaine, subjects showed increased dopamine overflow that resulted from both increased dopamine release and slowed dopamine uptake. One-day cocaine pre-exposure, however, did not alter dopaminergic responses to a subsequent cocaine challenge. In contrast, 7-day cocaine-treated subjects showed a potentiated rapid dopamine response in both the core and shell after an acute cocaine challenge. In addition, kinetic analysis during the cocaine challenge showed a greater increase in apparent Km of 7-day cocaine exposed subjects. Together, the data provide the first in vivo demonstration of rapid dopamine sensitization in the NAc core and shell after a short withdrawal period. In addition, the data clearly delineate cocaine's release and uptake effects and suggest that the observed sensitization results from greater uptake inhibition in cocaine pre-exposed subjects.

Cocaine administration in rats increases locomotor activity as a result of underlying changes in neurotransmitter dynamics and intracellular signaling. The serine/ threonine phosphatase, calcineurin, is known to modulate several signaling proteins that can influence behavioral responses to cocaine.This study aimed to determine whether calcineurin plays a role in locomotor responses associated with acute and repeated cocaine exposure. Second, we examined cocaine-mediated changes in intracellular signaling to identify potential mechanism underlying the ability of calcineurin to influence cocaine-mediated behavior.Locomotor activity was assessed over 17 days in male Sprague-Dawley rats (n = 48) that received daily administration of cocaine (15 mg/kg, s.c.) or saline in the presence or absence of the calcineurin inhibitor, cyclosporine (15 mg/kg, i.p.). Non-cocaine-treated animals from this initial experiment (n = 24) also received an acute cocaine challenge on day 18 of testing.Daily cyclosporine administration potentiated the locomotor response to repeated cocaine 5 min after cocaine injection and attenuated the sustained locomotor response 15 to 40 min after cocaine. Furthermore, cyclosporine pretreatment for 17 days augmented the acute locomotor response to acute cocaine 5 to 30 min after cocaine injection. Finally, repeated exposure to either cocaine or cyclosporine for 22 days increased synapsin I phosphorylation at the calcineurin-sensitive Ser 62/67 site, demonstrating a common downstream target for both calcineurin and cocaine.Our results suggest that calcineurin inhibition augments locomotor responses to cocaine and mimics cocaine-mediated phosphorylation of synapsin I.

Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs). An ongoing controversy in the field is to what extent the behavioral effects of nicotine result from activation of nAChRs, and to what extent receptor desensitization is involved in these behavioral processes. Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of nicotine in the brain, and these experiments have provided cellular mechanisms that could underlie the contribution of both of these processes to nicotine-mediated behaviors. For instance, desensitization of nAChRs may contribute to the salience of environmental cues associated with smoking behavior and activation and desensitization of nAChRs may contribute to both primary and conditioned drug reward. Similarly, studies of the antidepressant-like effects of nicotinic agents have revealed a balance between activation and desensitization of nAChRs. This review will examine the evidence for the contribution of these two very different consequences of nicotine administration to behaviors related to nicotine addiction, including processes related to drug reinforcement and affective modulation. We conclude that there are effects of nAChR activation and desensitization on drug reinforcement and affective behavior, and that both processes are important in the behavioral consequences of nicotine in tobacco smoking.

Rapid, phasic dopamine (DA) release in the mammalian brain plays a critical role in reward processing, reinforcement learning, and motivational control. Fast scan cyclic voltammetry (FSCV) is an electrochemical technique with high spatial and temporal (sub-second) resolution that has been utilized to examine phasic DA release in several types of preparations. In vitro experiments in single-cells and brain slices and in vivo experiments in anesthetized rodents have been used to identify mechanisms that mediate dopamine release and uptake under normal conditions and in disease models. Over the last 20 years, in vivo FSCV experiments in awake, freely moving rodents have also provided insight of dopaminergic mechanisms in reward processing and reward learning. One major advantage of the awake, freely moving preparation is the ability to examine rapid DA fluctuations that are time-locked to specific behavioral events or to reward or cue presentation. However, one limitation of combined behavior and voltammetry experiments is the difficulty of dissociating DA effects that are specific to primary rewarding or aversive stimuli from co-occurring DA fluctuations that mediate reward-directed or other motor behaviors. Here, we describe a combined method using in vivo FSCV and intra-oral infusion in an awake rat to directly investigate DA responses to oral tastants. In these experiments, oral tastants are infused directly to the palate of the rat – bypassing reward-directed behavior and voluntary drinking behavior – allowing for direct examination of DA responses to tastant stimuli.

Stimuli paired with rewards acquire reinforcing properties to promote reward-seeking behavior. Previous work supports the role of ventral tegmental area (VTA) nicotinic acetylcholine receptors (nAChRs) in mediating conditioned reinforcement elicited by drug-associated cues. However, it is not known whether these cholinergic mechanisms are specific to drug-associated cues or whether VTA cholinergic mechanisms also underlie the ability of cues paired with natural rewards to act as conditioned reinforcers. Burst firing of VTA dopamine (DA) neurons and the subsequent phasic DA release in the nucleus accumbens (NAc) plays an important role in cue-mediated behavior and in the ability of cues to acquire reinforcing properties. In the VTA, both AChRs and N-methyl-d-aspartate receptors (NMDARs) regulate DA burst firing and phasic DA release. Here, we tested the role of VTA nAChRs, muscarinic AChRs (mAChRs), and NMDARs in the conditioned reinforcement elicited by a food-associated, natural reward cue. Subjects received 10 consecutive days of Pavlovian conditioning training where lever extension served as a predictive cue for food availability. On day 11, rats received bilateral VTA infusion of saline, AP-5 (0.1 or 1μg), mecamylamine (MEC: 3 or 30μg) or scopolamine (SCOP: 3 or 66.7μg) immediately prior to the conditioned reinforcement test. During the test, nosepoking into the active (conditioned reinforced, CR) noseport produced a lever cue while nosepoking on the inactive (non-conditioned reinforced, NCR) noseport had no consequence. AP-5 robustly attenuated conditioned reinforcement and blocked discrimination between CR and NCR noseports at the 1-μg dose. MEC infusion decreased responding for both CR and NCR while 66.7-μg SCOP disrupted the subject's ability to discriminate between CR and NCR. Together, our data suggest that VTA NMDARs and mAChRs, but not nAChRs, play a role in the ability of natural reward-associated cues to act as conditioned reinforcers.

The adducin family of proteins interacts with the actin cytoskeleton and the plasma membrane in a calcium- and cAMP-dependent manner. Thus, adducins may be involved in changes in cytoskeletal organization resulting from synaptic stimulation. β-Adducin knock-out mice were examined in physiological and behavioral paradigms related to synaptic plasticity to elucidate the role the adducin family plays in processes underlying learning and memory.In situhybridization for α- and β-adducin demonstrates that these mRNAs are found throughout the brain, with high levels of expression in the hippocampus. Schaffer collateral-CA1 tetanic long-term potentiation decayed rapidly in acute hippocampal slices from β-adducin knock-out mice, although baseline spine morphology and postsynaptic density were normal. Interestingly, the input-output relationship was significantly increased in hippocampal slices from β-adducin knock-out mice. Furthermore, β-adducin knock-out mice were impaired in performance of fear conditioning and the water maze paradigm. The current results indicate that β-adducin may play an important role in the cellular mechanisms underlying activity-dependent synaptic plasticity associated with learning and memory.

Clozapine is an effective antipsychotic drug, but its effects on cognitive function are unclear. Previously, we found that clozapine caused a working memory deficit, which was reversed by nicotine. Hippocampal systems are important in determining clozapine effect on memory. In the current study, the memory effects of clozapine and nicotine administration were determined in rats with lesions of the fimbria-fornix, a fiber bundle which carries cholinergic and other projections between the septum and the hippocampus. Female Sprague-Dawley rats were trained on a win-shift procedure in the radial-arm maze, in which each arm entry was rewarded once per session. Then, 13 rats received bilateral knife-cut lesions of the fimbria-fornix, while 14 rats underwent sham surgery. The rats were tested after subcutaneous injections with combinations of clozapine (0 and 1.25 mg/kg) and nicotine (0, 0.2, and 0.4 mg/kg). In sham-operated rats, clozapine caused a significant (P

Nicotinic acetylcholine and NMDA glutamate receptors play critical roles in memory function. The brain areas involved in their interaction are still under investigation. One likely area is the hippocampus. Ventral hippocampal administration of nicotinic antagonists impair memory. Hippocampal administration of NMDA antagonists also cause memory impairments. We evaluated the importance of ventral hippocampal NMDA receptors for nicotinic actions on memory by testing the impact of systemic nicotine on memory with and without administration of the NMDA antagonist dizocilpine into the ventral hippocampus. Sprague-Dawley rats (N=11) trained on the 16-arm radial maze were bilaterally implanted with local infusion cannulae in the ventral hippocampus. The effects on memory function of ventral hippocampal infusions of 0, 2, 6 and 18 microg per side of dizocilpine were examined with and without acute systemic nicotine administration (0 or 0.4 mg/kg). The dizocilpine doses tested did not cause memory deficits by themselves but only did so when given in combination with systemic nicotine. Blocking NMDA ventral hippocampal actions revealed an impairing action of nicotine on memory. Nicotine effects on other non-NMDA hippocampal receptor systems or extra-hippocampal systems may have been left unchecked by the diminished nicotinic effect on ventral hippocampal NMDA receptors.

Nicotine has been shown to improve working memory. The neural mechanisms underlying this effect are still being determined. The ventral hippocampus is critical for nicotinic effects on memory. Local ventral hippocampal infusions of either the nicotinic alpha7 nicotinic receptor antagonist methyllycaconitine (MLA) or the alpha4beta2 nicotinic receptor antagonist dihydro-beta-erythroidine (DHbetaE) caused working memory impairments, but no additive effects were seen. Other areas, such as the amygdala, also likely play important roles in nicotinic effects on memory. Amygdalar lesions cause memory impairment and there is a dense concentration of nicotinic receptors in the basolateral amygdala. The current study used local basolateral amygdalar infusions of the nicotinic antagonists MLA and DHbetaE to determine the involvement of alpha7 and alpha4beta2 nicotinic receptors in spatial working and reference memory. Rats (n=8) were trained in the 16-arm radial maze and were implanted with bilateral infusion cannulae into the basolateral amygdala. Acute infusions of MLA (6.75 micro g/side, P0.0005) or DHbetaE (3.38 micro g/side, P0.025) caused significant working memory impairments. When given together MLA and DHbetaE did not produce an additive effect. In fact, the 6.75 micro g/kg dose of DHbetaE produced a significant (P0.0005) attenuation of the MLA-induced working memory impairment. Significant effects were not seen with reference memory or response latency. Nicotinic systems in the basolateral amygdala, as in the ventral hippocampus, are important for spatial working memory. In both the basolateral amygdala and the ventral hippocampus, MLA and DHbetaE individually caused working memory impairments. The lowest effective dose of DHbetaE was lower in the basolateral amygdala than in the ventral hippocampus. In both the basolateral amygdala and the ventral hippocampus, combined MLA and DHbetaE treatment did not produce additive working memory deficits. Unlike in the ventral hippocampus, the addition of DHbetaE to MLA in the basolateral amygdala significantly reduced the MLA-induced working memory deficit.