Crosstalk between biochemical signalling network architecture and trafficking governs AMPAR dynamics in synaptic plasticity.

Synaptic plasticity involves modification of both biochemical and structural components of neurons. Many studies have revealed that the change in the number density of the glutamatergic receptor AMPAR at the synapse is proportional to synaptic weight update; an increase in AMPAR corresponds to strengthening of synapses while a decrease in AMPAR density weakens synaptic connections. The dynamics of AMPAR are thought to be regulated by upstream signalling, primarily the calcium-CaMKII pathway, trafficking to and from the synapse, and influx from extrasynaptic sources. Previous work in the field of deterministic modelling of CaMKII dynamics has assumed bistable kinetics, while experiments and rule-based modelling have revealed that CaMKII dynamics can be either monostable or ultrasensitive. This raises the following question: how does the choice of model assumptions involving CaMKII dynamics influence AMPAR dynamics at the synapse? To answer this question, we have developed a set of models using compartmental ordinary differential equations to systematically investigate contributions of different signalling and trafficking variations, along with their coupled effects, on AMPAR dynamics at the synaptic site. We find that the properties of the model including network architecture describing different stability features of CaMKII and parameters that capture the endocytosis and exocytosis of AMPAR significantly affect the integration of fast upstream species by slower downstream species. Furthermore, we predict that the model outcome, as determined by bound AMPAR at the synaptic site, depends on (1) the choice of signalling model (bistable CaMKII or monostable CaMKII dynamics), (2) trafficking versus influx contributions and (3) frequency of stimulus. KEY POINTS: The density of AMPA receptors (AMPARs) at the postsynaptic density of the synapse provides a readout of synaptic plasticity, which involves crosstalk between complex biochemical signalling networks including CaMKII dynamics and trafficking pathways including exocytosis and endocytosis. Here we build a model that integrates CaMKII dynamics and AMPAR trafficking to explore this crosstalk. We compare different models of CaMKII that result in monostable or bistable kinetics and their impact on AMPAR dynamics. Our results show that AMPAR density depends on the coupling between aspects of biochemical signalling and trafficking. Specifically, assumptions regarding CaMKII dynamics and its stability features can alter AMPAR density at the synapse. Our model also predicts that the kinetics of trafficking versus influx of AMPAR from the extrasynaptic space can further impact AMPAR density. Thus, the contributions of both signalling and trafficking should be considered in computational models.

Spatiotemporal modelling reveals geometric dependence of AMPAR dynamics on dendritic spine morphology.

The modification of neural circuits depends on the strengthening and weakening of synaptic connections. Synaptic strength is often correlated to the density of the ionotropic, glutamatergic receptors, AMPARs, (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) at the postsynaptic density (PSD). While AMPAR density is known to change based on complex biological signalling cascades, the effect of geometric factors such as dendritic spine shape, size and curvature remain poorly understood. In this work, we developed a deterministic, spatiotemporal model to study the dynamics of AMPARs during long-term potentiation (LTP). This model includes a minimal set of biochemical events that represent the upstream signalling events, trafficking of AMPARs to and from the PSD, lateral diffusion in the plane of the spine membrane, and the presence of an extrasynaptic AMPAR pool. Using idealized and realistic spine geometries, we show that the dynamics and increase of bound AMPARs at the PSD depends on a combination of endo- and exocytosis, membrane diffusion, the availability of free AMPARs and intracellular signalling interactions. We also found non-monotonic relationships between spine volume and the change in AMPARs at the PSD, suggesting that spines restrict changes in AMPARs to optimize resources and prevent runaway potentiation. KEY POINTS: Synaptic plasticity involves dynamic biochemical and physical remodelling of small protrusions called dendritic spines along the dendrites of neurons. Proper synaptic functionality within these spines requires changes in receptor number at the synapse, which has implications for downstream neural functions, such as learning and memory formation. In addition to being signalling subcompartments, spines also have unique morphological features that can play a role in regulating receptor dynamics on the synaptic surface. We have developed a spatiotemporal model that couples biochemical signalling and receptor trafficking modalities in idealized and realistic spine geometries to investigate the role of biochemical and biophysical factors in synaptic plasticity. Using this model, we highlight the importance of spine size and shape in regulating bound AMPA receptor dynamics that govern synaptic plasticity, and predict how spine shape might act to reset synaptic plasticity as a built-in resource optimization and regulation tool.

Correction to: Public Health Approaches to Type 2 Diabetes Prevention: the US National Diabetes Prevention Program and Beyond.

The sentence should read: "Average weight loss and physical activity minutes per week were calculated among participants who attended ≥ 3 sessions in the first 6 months and whose time from first session attended to last session attended was ≥ 9 months.

Public Health Approaches to Type 2 Diabetes Prevention: the US National Diabetes Prevention Program and Beyond.

PURPOSE OF REVIEW: This article highlights foundational evidence, translation studies, and current research behind type 2 diabetes prevention efforts worldwide, with focus on high-risk populations, and whole-population approaches as catalysts to global prevention. RECENT FINDINGS: Continued focus on the goals of foundational lifestyle change program trials and their global translations, and the targeting of those at highest risk through both in-person and virtual modes of program delivery, is critical. Whole-population approaches (e.g., socioeconomic policies, healthy food promotion, environmental/systems changes) and awareness raising are essential complements to efforts aimed at high-risk populations. Successful type 2 diabetes prevention strategies are being realized in the USA through the National Diabetes Prevention Program and elsewhere in the world. A multi-tiered approach involving appropriate risk targeting and whole-population efforts is essential to curb the global diabetes epidemic.

Biophysical Modeling of Synaptic Plasticity.

Dendritic spines are small, bulbous compartments that function as postsynaptic sites and undergo intense biochemical and biophysical activity. The role of the myriad signaling pathways that are implicated in synaptic plasticity is well studied. A recent abundance of quantitative experimental data has made the events associated with synaptic plasticity amenable to quantitative biophysical modeling. Spines are also fascinating biophysical computational units because spine geometry, signal transduction, and mechanics work in a complex feedback loop to tune synaptic plasticity. In this sense, ideas from modeling cell motility can inspire us to develop multiscale approaches for predictive modeling of synaptic plasticity. In this article, we review the key steps in postsynaptic plasticity with a specific focus on the impact of spine geometry on signaling, cytoskeleton rearrangement, and membrane mechanics. We summarize the main experimental observations and highlight how theory and computation can aid our understanding of these complex processes.Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Electrical signals in the ER are cell type and stimulus specific with extreme spatial compartmentalization in neurons.

The endoplasmic reticulum (ER) is a tortuous organelle that spans throughout a cell with a continuous membrane containing ion channels, pumps, and transporters. It is unclear if stimuli that gate ER ion channels trigger substantial membrane potential fluctuations and if those fluctuations spread beyond their site of origin. Here, we visualize ER membrane potential dynamics in HEK cells and cultured rat hippocampal neurons by targeting a genetically encoded voltage indicator specifically to the ER membrane. We report the existence of clear cell-type- and stimulus-specific ER membrane potential fluctuations. In neurons, direct stimulation of ER ryanodine receptors generates depolarizations that scale linearly with stimulus strength and reach tens of millivolts. However, ER potentials do not spread beyond the site of receptor activation, exhibiting steep attenuation that is exacerbated by intracellular large conductance K+ channels. Thus, segments of ER can generate large depolarizations that are actively restricted from impacting nearby, contiguous membrane.

Membrane mechanics dictate axonal morphology and function.

Axons are thought to be ultrathin membrane cables of a relatively uniform diameter, designed to conduct electrical signals, or action potentials. Here, we demonstrate that unmyelinated axons are not simple cylindrical tubes. Rather, axons have nanoscopic boutons repeatedly along their length interspersed with a thin cable with a diameter of ∼60 nm like pearls-on-a-string. These boutons are only ∼200 nm in diameter and do not have synaptic contacts or a cluster of synaptic vesicles, hence non-synaptic. Our in silico modeling suggests that axon pearling can be explained by the mechanical properties of the membrane including the bending modulus and tension. Consistent with modeling predictions, treatments that disrupt these parameters like hyper- or hypo-tonic solutions, cholesterol removal, and non-muscle myosin II inhibition all alter the degree of axon pearling, suggesting that axon morphology is indeed determined by the membrane mechanics. Intriguingly, neuronal activity modulates the cholesterol level of plasma membrane, leading to shrinkage of axon pearls. Consequently, the conduction velocity of action potentials becomes slower. These data reveal that biophysical forces dictate axon morphology and function and that modulation of membrane mechanics likely underlies plasticity of unmyelinated axons.

Dendritic spine morphology regulates calcium-dependent synaptic weight change.

Dendritic spines act as biochemical computational units and must adapt their responses according to their activation history. Calcium influx acts as the first signaling step during postsynaptic activation and is a determinant of synaptic weight change. Dendritic spines also come in a variety of sizes and shapes. To probe the relationship between calcium dynamics and spine morphology, we used a stochastic reaction-diffusion model of calcium dynamics in idealized and realistic geometries. We show that despite the stochastic nature of the various calcium channels, receptors, and pumps, spine size and shape can modulate calcium dynamics and subsequently synaptic weight updates in a deterministic manner. Through a series of exhaustive simulations and analyses, we found that the calcium dynamics and synaptic weight change depend on the volume-to-surface area of the spine. The relationships between calcium dynamics and spine morphology identified in idealized geometries also hold in realistic geometries, suggesting that there are geometrically determined deterministic relationships that may modulate synaptic weight change.

Operationalising a modified Delphi study to progress quality care process nursing metrics for acute care.

Background: Despite representing the largest occupational group within the healthcare workforce, evidence suggests that due to the complexity of nursing practice, nurses' contribution remains 'invisible'. Quality Care Metrics aligned to standards can offer valuable numerical information that quantify input, output and dimensions of nursing care processes in complex clinical and interprofessional milieus. Aims and objectives: Progress an evidence-based metric system to measure the quality and clinical safety of nursing care within acute care in Ireland. The objectives were to: classify quality care process nursing metrics and corresponding indicators pertinent to acute care; reach agreement on a selected set of robust metrics and corresponding indicators; and implement the findings of the study. Design: A modified four-round Delphi study. Methods: The modified Delphi study integrated a four-round survey of 422 nurses, face-to-face meetings with a patient representative and key stakeholders within acute services with a final consensus meeting inclusive of a panel of 26 expert nurse clinicians. Results: There was consensus on 11 quality care process nursing metrics and 53 corresponding indicators for the acute care setting. Despite the rating of 'critical' in the Delphi rounds, a concern was reported by participants on the subjective nature of three of the developed metrics: 'patient experience', 'patient engagement' and 'professional and ethical approach to care' based on the absence of objective measurement tools that include patient input. Conversely, this led to the conundrum for the panel of experts at the final consensus meeting who were divided in their views on objectively observing, recording and subsequent auditing of those three developed metrics in real-time clinical practice. Conclusion: This paper describes the operationalisation of a modified Delphi technique that progressed a set of 11 quality care process metrics and 53 corresponding indicators. The challenge now is the implementation of these quality care process metrics so that nurses' contribution to patient-centred care is tangible in acute care.

Mechanical Principles Governing the Shapes of Dendritic Spines.

Dendritic spines are small, bulbous protrusions along the dendrites of neurons and are sites of excitatory postsynaptic activity. The morphology of spines has been implicated in their function in synaptic plasticity and their shapes have been well-characterized, but the potential mechanics underlying their shape development and maintenance have not yet been fully understood. In this work, we explore the mechanical principles that could underlie specific shapes using a minimal biophysical model of membrane-actin interactions. Using this model, we first identify the possible force regimes that give rise to the classic spine shapes-stubby, filopodia, thin, and mushroom-shaped spines. We also use this model to investigate how the spine neck might be stabilized using periodic rings of actin or associated proteins. Finally, we use this model to predict that the cooperation between force generation and ring structures can regulate the energy landscape of spine shapes across a wide range of tensions. Thus, our study provides insights into how mechanical aspects of actin-mediated force generation and tension can play critical roles in spine shape maintenance.

Gαq-mediated calcium dynamics and membrane tension modulate neurite plasticity.

The formation and disruption of synaptic connections during development are a fundamental step in neural circuit formation. Subneuronal structures such as neurites are known to be sensitive to the level of spontaneous neuronal activity, but the specifics of how neurotransmitter-induced calcium activity regulates neurite homeostasis are not yet fully understood. In response to stimulation by neurotransmitters such as acetylcholine, calcium responses in cells are mediated by the Gαq/phospholipase Cß (PLCß)/phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) signaling pathway. Here, we show that prolonged Gαq stimulation results in the retraction of neurites in PC12 cells and the rupture of neuronal synapses by modulating membrane tension. To understand the underlying cause, we dissected the behavior of individual components of the Gαq/PLCß/PI(4,5)P2 pathway during retraction and correlated these with the retraction of the membrane and cytoskeletal elements impacted by calcium signaling. We developed a mathematical model that combines biochemical signaling with membrane tension and cytoskeletal mechanics to show how signaling events are coupled to retraction velocity, membrane tension, and actin dynamics. The coupling between calcium and neurite retraction is shown to be operative in the Caenorhabditis elegans nervous system. This study uncovers a novel mechanochemical connection between Gαq/PLCß /PI(4,5)P2 that couples calcium responses with neural plasticity.

Dendritic spine geometry and spine apparatus organization govern the spatiotemporal dynamics of calcium.

Dendritic spines are small subcompartments that protrude from the dendrites of neurons and are important for signaling activity and synaptic communication. These subcompartments have been characterized to have different shapes. While it is known that these shapes are associated with spine function, the specific nature of these shape-function relationships is not well understood. In this work, we systematically investigated the relationship between the shape and size of both the spine head and spine apparatus, a specialized endoplasmic reticulum compartment within the spine head, in modulating rapid calcium dynamics using mathematical modeling. We developed a spatial multicompartment reaction-diffusion model of calcium dynamics in three dimensions with various flux sources, including N-methyl-D-aspartate receptors (NMDARs), voltage-sensitive calcium channels (VSCCs), and different ion pumps on the plasma membrane. Using this model, we make several important predictions. First, the volume to surface area ratio of the spine regulates calcium dynamics. Second, membrane fluxes impact calcium dynamics temporally and spatially in a nonlinear fashion. Finally, the spine apparatus can act as a physical buffer for calcium by acting as a sink and rescaling the calcium concentration. These predictions set the stage for future experimental investigations of calcium dynamics in dendritic spines.

Establishing a 'train the trainer' education model for clinical skills development.

Demographic trends and service reform present healthcare providers with the challenge of developing appropriate resources to manage increasing numbers of sick and disabled older people. But these changes bring increased opportunities for nursing, and the expansion of the nursing role is crucial as health services strive to meet the changing needs of older people. Against a background of reforms in Ireland and backed by an education and training needs analysis of nursing staff, two stakeholders devised a model of education that would best meet identified demands. This article sets out a model for skill attainment that acknowledges the diversity of care settings and improves the sustainability of training provided. Advantages and disadvantages are discussed, and lessons learned are shared.

Real-time patient satisfaction survey and improvement process.

The purpose of this article is to describe how one multidisciplinary hospital responded to patient-satisfaction issues and improved communication throughout its organization by implementing a real-time assessment of patient and staff satisfaction for a faster and better-focused improvement process. The survey process is based on eliciting information from several different sources in a manner that allows corrective action plans to be made and implemented within 4 to 8 weeks of patient encounters. Organized groups can then review feedback from the implemented action plans within 9 to 16 weeks of patient encounters. This 4-month process is repeated on a quarterly basis, as lessons learned from the previous cycle are fed into the upcoming survey process for continuous patient-satisfaction improvement. Employees, faculty, and administrators have accepted the Real-Time Patient Satisfaction Survey and Improvement Process as a routine activity within the normal operating structure at the Moffitt Cancer Center. This activity of problem identification-action-feedback has been well integrated in the system and will continue to rotate throughout all patient care clinical services at the Moffitt Cancer Center. The program has become a method for goal-setting and establishing management accountability. As an adaptation of continuous quality improvement, The Real-Time Patient Satisfaction Survey and Improvement Process at the Moffitt Cancer Center is applicable for use in other hospitals and cancer centers in the United States. The general design, materials, and analysis plan can be directed toward the needs of the specific institution (and are available for distribution by contacting the authors).

The guinea pig syndrome: improving clinical trial participation among thoracic patients.

BACKGROUND: The purpose of the study was to examine lung cancer patients' knowledge, attitudes, and behavior regarding clinical trials and to develop an effective intervention for increasing patient knowledge and awareness of clinical trials for lung cancer patients. METHODS: Qualitative semistructured, in-depth interviews were conducted with (1) new patients who had not yet interacted with their physicians, (2) existing patients who had participated in a clinical trial, and (3) existing patients who had not been offered a trial. Findings from the interviews led to the creation of a letter that was sent to all new patients before their first appointment, explaining that offering a clinical trial at this hospital was the norm, to expect this discussion, and the option of standard treatment was always available. RESULTS: Results showed new patients and established patients had similar perceptions of trials--the fear of being a guinea pig, offering a trial meant no hope, and misconception of purpose. Existing patients who had participated in a trial expressed positive benefits of trial participation, even if their health did not improve. A year after the letter process was initiated, accrual rates increased 18% and approximately 81% of all eligible lung cancer patients were in a trial. CONCLUSIONS: The letter, addressing patient's preexisting fears about being offered a clinical trial, appears to show some initial success in improving clinical trial accrual.