The future of pharmacology education: a global outlook

Pharmacology educators play a unique role in higher education, at the intersection of basic biological, and clinical sciences. They teach a on wide range of courses including undergraduate and postgraduate medicine, pharmacy, nursing, dentistry, physiotherapy, osteopathy, veterinary science and biomedical science [1]. Note that this is far from an exhaustive list. Significant changes have taken place in pharmacology education in response to advances in pharmacology, developments in educational approaches and learning technologies, changes in healthcare education delivery, and the massification and internationalization of higher education. These challenge the educator, whose role is increasingly recognized as encompassing teaching, leadership and scholarly activity [2]. The future of pharmacology education depends on our ability to navigate these changes. We argue that there are sets of interrelated knowledge, skill, and attribute competencies that pharmacology educators must master to ultimately enable their students to succeed, discussed in detail in the following sections

A riot of rhythms: neuronal and glial circadian oscillators in the mediobasal hypothalamus

Background: In mammals, the synchronized activity of cell autonomous clocks in the suprachiasmatic nuclei (SCN) enables this structure to function as the master circadian clock, coordinating daily rhythms in physiology and behavior. However, the dominance of this clock has been challenged by the observations that metabolic duress can over-ride SCN controlled rhythms, and that clock genes are expressed in many brain areas, including those implicated in the regulation of appetite and feeding. The recent development of mice in which clock gene/protein activity is reported by bioluminescent constructs (luciferase or luc) now enables us to track molecular oscillations in numerous tissues ex vivo. Consequently we determined both clock activities and responsiveness to metabolic perturbations of cells and tissues within the mediobasal hypothalamus (MBH), a site pivotal for optimal internal homeostatic regulation. Results: Here we demonstrate endogenous circadian rhythms of PER2::LUC expression in discrete subdivisions of the arcuate (Arc) and dorsomedial nuclei (DMH). Rhythms resolved to single cells did not maintain long-term synchrony with one-another, leading to a damping of oscillations at both cell and tissue levels. Complementary electrophysiology recordings revealed rhythms in neuronal activity in the Arc and DMH. Further, PER2::LUC rhythms were detected in the ependymal layer of the third ventricle and in the median eminence/pars tuberalis (ME/PT). A high-fat diet had no effect on the molecular oscillations in the MBH, whereas food deprivation resulted in an altered phase in the ME/PT. Conclusion: Our results provide the first single cell resolution of endogenous circadian rhythms in clock gene expression in any intact tissue outside the SCN, reveal the cellular basis for tissue level damping in extra-SCN oscillators and demonstrate that an oscillator in the ME/PT is responsive to changes in metabolism

Developing an international concept-based curriculum for pharmacology education: The promise of core concepts and concept inventories

\ua9 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond ‘know’ towards ‘know how to’. A concept-based approach will help educators prioritize and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities and improve application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified and unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts of Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realize these benefits, pharmacology educators must develop methods to teach and assess core concepts. Work to develop concept inventories is ongoing, including identifying student misconceptions of the core concepts and creating a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented

Neuropeptide Signaling Differentially Affects Phase Maintenance and Rhythm Generation in SCN and Extra-SCN Circadian Oscillators

Circadian rhythms in physiology and behavior are coordinated by the brain's dominant circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Vasoactive intestinal polypeptide (VIP) and its receptor, VPAC2, play important roles in the functioning of the SCN pacemaker. Mice lacking VPAC2 receptors (Vipr2−/−) express disrupted behavioral and metabolic rhythms and show altered SCN neuronal activity and clock gene expression. Within the brain, the SCN is not the only site containing endogenous circadian oscillators, nor is it the only site of VPAC2 receptor expression; both VPAC2 receptors and rhythmic clock gene/protein expression have been noted in the arcuate (Arc) and dorsomedial (DMH) nuclei of the mediobasal hypothalamus, and in the pituitary gland. The functional role of VPAC2 receptors in rhythm generation and maintenance in these tissues is, however, unknown. We used wild type (WT) and Vipr2−/− mice expressing a luciferase reporter (PER2::LUC) to investigate whether circadian rhythms in the clock gene protein PER2 in these extra-SCN tissues were compromised by the absence of the VPAC2 receptor. Vipr2−/− SCN cultures expressed significantly lower amplitude PER2::LUC oscillations than WT SCN. Surprisingly, in Vipr2−/− Arc/ME/PT complex (Arc, median eminence and pars tuberalis), DMH and pituitary, the period, amplitude and rate of damping of rhythms were not significantly different to WT. Intriguingly, while we found WT SCN and Arc/ME/PT tissues to maintain a consistent circadian phase when cultured, the phase of corresponding Vipr2−/− cultures was reset by cull/culture procedure. These data demonstrate that while the main rhythm parameters of extra-SCN circadian oscillations are maintained in Vipr2−/− mice, the ability of these oscillators to resist phase shifts is compromised. These deficiencies may contribute towards the aberrant behavior and metabolism associated with Vipr2−/− animals. Further, our data indicate a link between circadian rhythm strength and the ability of tissues to resist circadian phase resetting

Timed daily exercise remodels circadian rhythms in mice

Regular exercise is important for physical and mental health. An underexplored and intriguing property of exercise is its actions on the body’s 24 h or circadian rhythms. Molecular clock cells in the brain’s suprachiasmatic nuclei (SCN) use electrical and chemical signals to orchestrate their activity and convey time of day information to the rest of the brain and body. To date, the long-lasting effects of regular physical exercise on SCN clock cell coordination and communication remain unresolved. Utilizing mouse models in which SCN intercellular neuropeptide signaling is impaired as well as those with intact SCN neurochemical signaling, we examined how daily scheduled voluntary exercise (SVE) influenced behavioral rhythms and SCN molecular and neuronal activities. We show that in mice with disrupted neuropeptide signaling, SVE promotes SCN clock cell synchrony and robust 24 h rhythms in behavior. Interestingly, in both intact and neuropeptide signaling deficient animals, SVE reduces SCN neural activity and alters GABAergic signaling. These findings illustrate the potential utility of regular exercise as a long-lasting and effective non-invasive intervention in the elderly or mentally ill where circadian rhythms can be blunted and poorly aligned to the external world

Tissue-Specific Function of Period3 in Circadian Rhythmicity

The mammalian circadian system is composed of multiple central and peripheral clocks that are temporally coordinated to synchronize physiology and behavior with environmental cycles. Mammals have three homologs of the circadian Period gene (Per1, 2, 3). While numerous studies have demonstrated that Per1 and Per2 are necessary for molecular timekeeping and light responsiveness in the master circadian clock in the suprachiasmatic nuclei (SCN), the function of Per3 has been elusive. In the current study, we investigated the role of Per3 in circadian timekeeping in central and peripheral oscillators by analyzing PER2::LUCIFERASE expression in tissues explanted from C57BL/6J wild-type and Per3−/− mice. We observed shortening of the periods in some tissues from Per3−/− mice compared to wild-types. Importantly, the periods were not altered in other tissues, including the SCN, in Per3−/− mice. We also found that Per3-dependent shortening of endogenous periods resulted in advanced phases of those tissues, demonstrating that the in vitro phenotype is also present in vivo. Our data demonstrate that Per3 is important for endogenous timekeeping in specific tissues and those tissue-specific changes in endogenous periods result in internal misalignment of circadian clocks in Per3−/− mice. Taken together, our studies demonstrate that Per3 is a key player in the mammalian circadian system

Identification of a Circadian Clock-Controlled Neural Pathway in the Rabbit Retina

Background: Although the circadian clock in the mammalian retina regulates many physiological processes in the retina, it is not known whether and how the clock controls the neuronal pathways involved in visual processing. Methodology/Principal Findings: By recording the light responses of rabbit axonless (A-type) horizontal cells under darkadapted conditions in both the day and night, we found that rod input to these cells was substantially increased at night under control conditions and following selective blockade of dopamine D2, but not D1, receptors during the day, so that the horizontal cells responded to very dim light at night but not in the day. Using neurobiotin tracer labeling, we also found that the extent of tracer coupling between rabbit rods and cones was more extensive during the night, compared to the day, and more extensive in the day following D 2 receptor blockade. Because A-type horizontal cells make synaptic contact exclusively with cones, these observations indicate that the circadian clock in the mammalian retina substantially increases rod input to A-type horizontal cells at night by enhancing rod-cone coupling. Moreover, the clock-induced increase in D2 receptor activation during the day decreases rod-cone coupling so that rod input to A-type horizontal cells is minimal. Conclusions/Significance: Considered together, these results identify the rod-cone gap junction as a key site in mammals through which the retinal clock, using dopamine activation of D2 receptors, controls signal flow in the day and night fro

Constant light enhances synchrony among circadian clock cells and promotes behavioral rhythms in VPAC(2)-signaling deficient mice

Individual neurons in the suprachiasmatic nuclei (SCN) contain an intracellular molecular clock and use intercellular signaling to synchronize their timekeeping activities so that the SCN can coordinate brain physiology and behavior. The neuropeptide vasoactive intestinal polypeptide (VIP) and its VPAC2 receptor form a key component of intercellular signaling systems in the SCN and critically control cellular coupling. Targeted mutations in either the intracellular clock or intercellular neuropeptide signaling mechanisms, such as VIP-VPAC2 signaling, can lead to desynchronization of SCN neuronal clocks and loss of behavioral rhythms. An important goal in chronobiology is to develop interventions to correct deficiencies in circadian timekeeping. Here we show that extended exposure to constant light promotes synchrony among SCN clock cells and the expression of ~24 h rhythms in behavior in mice in which intercellular signaling is disrupted through loss of VIP-VPAC2 signaling. This study highlights the importance of SCN synchrony for the expression of rhythms in behavior and reveals how non-invasive manipulations in the external environment can be used to overcome neurochemical communication deficits in this important brain system