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Many neurons exhibit regular firing that is limited to the duration and intensity of depolarizing stimuli. However, some neurons exhibit all-or-nothing plateau potentials that, once elicited, can lead to prolonged activity that is independent of stimulus intensity or duration. To better understand this diversity of information processing, we compared the voltage-gated and Ca 2+ -gated currents of three identified neurons from hermaphroditic Aplysia californica Two of these neurons, B51 and B64, generated plateau potentials and a third neuron, B8, exhibited regular firing and was incapable of generating a plateau potential. With the exception of the Ca 2+ -gated potassium current ( I KCa ), all three neuron types expressed a similar array of outward and inward currents, but with distinct voltage-dependent properties for each neuron type. Inhibiting voltage-gated Ca 2+ channels with Ni + prolonged the plateau potential, indicating I KCa is important for plateau potential termination. In contrast, inhibiting persistent Na + ( I NaP ) blocked plateau potentials, empirically and in simulations. Surprisingly, the properties and level of expression of I NaP were similar in all three neurons, indicating that the presence of I NaP does not distinguish between regular-firing neurons and neurons capable of generating plateau potentials. Rather, the key distinguishing factor is the relationship between I NaP and outward currents such as the delayed outward current ( I D ), and I KCa We then demonstrated a technique for predicting complex physiological properties such as plateau duration, plateau amplitude, and action potential duration as a function of parameter values, by fitting a curve in parameter space and projecting the curve beyond the tested values. SIGNIFICANCE STATEMENT Plateau potentials are intrinsic properties of neurons that are important for information processing in a wide variety of nervous systems. We examined three identified neurons in Aplysia californica with different propensities to generate a plateau potential. No single conductance was found to distinguish plateau generating neurons. Instead, plateau generation depended on the ratio between persistent Na + current ( I NaP ), which favored plateaus, and outward currents such as I KCa , which facilitated plateau termination. Computational models revealed a relationship between the individual currents that predicted the features of simulated plateau potentials. These results provide a more solid understanding of the conductances that mediate plateau generation., (Copyright © 2023 the authors.)

Background: Learning requires the activation of protein kinases with distinct temporal dynamics. In Aplysia , nonassociative learning can be enhanced by a computationally designed learning protocol with intertrial intervals (ITIs) that maximize the interaction between fast-activated PKA (protein kinase A) and slow-activated ERK (extracellular signal-regulated kinase). Whether a similar strategy can enhance associative learning in mammals is unknown., Methods: We simulated 1000 training protocols with varying ITIs to predict an optimal protocol based on empirical data for PKA and ERK dynamics in rat hippocampus. Adult male rats received the optimal protocol or control protocols in auditory fear conditioning and fear extinction experiments. Immunohistochemistry was performed to evaluate pCREB (phosphorylated cAMP response element binding)\protein levels in brain regions that have been implicated in fear acquisition., Results: Rats exposed to the optimal conditioning protocol with irregular ITIs exhibited impaired extinction memory acquisition within the session using a standard footshock intensity, and stronger fear memory retrieval and spontaneous recovery with a weaker footshock intensity, compared with rats that received massed or spaced conditioning protocols with fixed ITIs. Rats exposed to the optimal extinction protocol displayed improved extinction of contextual fear memory and reduced spontaneous recovery compared with rats that received standard extinction protocols. Moreover, the optimal conditioning protocol increased pCREB levels in the dentate gyrus of the dorsal hippocampus, suggesting enhanced induction of long-term potentiation., Conclusions: These findings demonstrate that a computational model-driven behavioral intervention can enhance associative learning in mammals and may provide insight into strategies to improve cognition in humans., (© 2023 The Authors.)

Background: The analyses of neuronal circuits require high-throughput technologies for stimulating and recording many neurons simultaneously with single-neuron precision. Voltage-sensitive dyes (VSDs) have enabled the monitoring of membrane potentials of many (10-100 s) neurons simultaneously. Carbon fiber electrode (CFE) arrays allow for stimulation and recording of many neurons simultaneously, including intracellularly., New Method: Combining CFE with VSD leverages the advantages of both technologies, allowing for stimulation of single neurons while recording the activity of the entire network. 3-D printing technology was used to develop a chamber to simultaneously perform VSD imaging, CFE array recording, and extracellular recording from individual glass electrodes., Results: Aplysia buccal ganglia were stained with VSD and imaged while also recording using a CFE array and extracellular nerve electrodes. Coincident spiking activity was recorded by VSD, CFE, and extracellular nerve electrodes. Current injection with CFE electrodes could activate and inhibit individual neurons as detected by VSD and nerve recordings., Comparison to Existing Methods: The large size of traditional manipulators limits the number of electrodes used and the number of neurons recorded during an experiment. Here we present a method to build a 3-D printed recording chamber that includes a 3-axis micromanipulator to position a CFE array and eight 2-axis manipulators to position eight extracellular electrodes., Conclusions: 3-D printing technology can be used to build a custom recording chamber and micromanipulators. Combining these technologies allows for the direct modulation of the activity of neurons while recording the activity of 100 s of neurons simultaneously., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: Selection and use of personal protective equipment (PPE) to prevent non-percutaneous body fluid exposure (NP BFE) is determined by a clinical assessment of risk. The aim of this study was to explore the selection and use of PPE, particularly masks and eye protection to prevent NP BFE, by nurses., Methods: This quantitative single-site two-phased study was guided by the Health Belief Model (HBM). Phase 1 was a retrospective electronic database audit of body fluid exposure surveillance data. Phase 2 included a cross-sectional survey., Results: The highest incidence of reported NP BFE to non-intact skin and mucous membranes during the study period were identified in the emergency department (ED) at 51.3% (20/39), intensive care unit (ICU) at 30.8% (12/39), operating theatre (OT) with 12.9% (5/39), and inpatient renal ward with 5.1% (2/39). Reported PPE use during NP BFE was: 0% face shields or masks, 10% gown/apron, and 15% goggles. Survey results related to Prevention of mucocutaneous exposures were similar across all high-risk units, though ED nurses reported poorer compliance with the use of PPE to prevent exposure. Risk assessment for prevention of NP BFE was reported, yet there was a lack of compliance. The ICU results indicated a positive safety culture in contrast to the ED., Conclusion: The findings are consistent with research identifying inadequate prevention of NP BFE, although nurses are aware of the importance of risk assessment. The HBM has the potential to increase understanding of the differences in nurses' perceptions of risk in safety culture., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Empirical and computational methods were combined to examine whether individual or dual-drug treatments can restore the deficit in long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse observed in a cellular model of Coffin-Lowry syndrome (CLS). The model was produced by pharmacological inhibition of p90 ribosomal S6 kinase (RSK) activity. In this model, coapplication of an activator of the mitogen-activated protein kinase (MAPK) isoform ERK and an activator of protein kinase A (PKA) resulted in enhanced phosphorylation of RSK and enhanced LTF to a greater extent than either drug alone and also greater than their additive effects, which is termed synergism. The extent of synergism appeared to depend on another MAPK isoform, p38 MAPK. Inhibition of p38 MAPK facilitated serotonin (5-HT)-induced RSK phosphorylation, indicating that p38 MAPK inhibits activation of RSK. Inhibition of p38 MAPK combined with activation of PKA synergistically activated both ERK and RSK. Our results suggest that cellular models of disorders that affect synaptic plasticity and learning, such as CLS, may constitute a useful strategy to identify candidate drug combinations, and that combining computational models with empirical tests of model predictions can help explain synergism of drug combinations., (© 2022 Liu et al.; Published by Cold Spring Harbor Laboratory Press.)

Phosphorylation of the MAPK family member extracellular signal-regulated kinase (ERK) is required to induce long-term synaptic plasticity, but little is known about its persistence. We examined ERK activation by three protocols that induce long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse - the standard protocol (five 5-min pulses of 5-HT with interstimulus intervals (ISIs) of 20 min), the enhanced protocol (five pulses with irregular ISIs, which induces greater and longer-lasting LTF) and the two-pulse protocol (two pulses with ISI 45 min). Immunofluorescence revealed complex ERK activation. The standard and two-pulse protocols immediately increased active, phosphorylated ERK (pERK), which decayed within 5 h. A second wave of increased pERK was detected 18 h post-treatment for all protocols. This late phase was blocked by inhibitors of protein kinase A, TrkB and TGF-β. These results suggest that complex interactions among kinase pathways and growth factors contribute to the late increase of pERK. ERK activity returned to basal 24 h after the standard or two-pulse protocols, but remained elevated 24 h for the enhanced protocol. This 24-h elevation was also dependent on PKA and TGF-β, and partly on TrkB. These results begin to characterize long-lasting ERK activation, plausibly maintained by positive feedback involving growth factors and PKA, that appears essential to maintain LTF and LTM. Because many processes involved in LTF and late LTP are conserved among Aplysia and mammals, these findings highlight the importance of examining the dynamics of kinase cascades involved in vertebrate long-term memory., Competing Interests: None declared., (© The Author(s) 2022. Published by Oxford University Press.)

Key features of long-term memory (LTM), such as its stability and persistence, are acquired during processes collectively referred to as consolidation. The dynamics of biological changes during consolidation are complex. In adult rodents, consolidation exhibits distinct periods during which the engram is more or less resistant to disruption. Moreover, the ability to consolidate memories differs during developmental periods. Although the molecular mechanisms underlying consolidation are poorly understood, the initial stages rely on interacting signaling pathways that regulate gene expression, including brain-derived neurotrophic factor (BDNF) and Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) dependent feedback loops. We investigated the ways in which these pathways may contribute to developmental and dynamical features of consolidation. A computational model of molecular processes underlying consolidation following inhibitory avoidance (IA) training in rats was developed. Differential equations described the actions of CaMKIIα, multiple feedback loops regulating BDNF expression, and several transcription factors including methyl-CpG binding protein 2 (MeCP2), histone deacetylase 2 (HDAC2), and SIN3 transcription regulator family member A (Sin3a). This model provides novel explanations for the (apparent) rapid forgetting of infantile memory and the temporal progression of memory consolidation in adults. Simulations predict that dual effects of MeCP2 on the expression of bdnf, and interaction between MeCP2 and CaMKIIα, play critical roles in the rapid forgetting of infantile memory and the progress of memory resistance to disruptions. These insights suggest new potential targets of therapy for memory impairment., Competing Interests: The authors have declared that no competing interests exist.

Despite numerous studies examining the mechanisms of operant conditioning (OC), the diversity of OC plasticity loci and their synergism have not been examined sufficiently. In the well-characterized feeding neural circuit of Aplysia , in vivo and in vitro appetitive OC increases neuronal excitability and electrical coupling among several neurons leading to an increase in expression of ingestive behavior. Here, we used the in vitro analog of OC to investigate whether OC reduces the excitability of a neuron, B4, whose inhibitory connections decrease expression of ingestive behavior. We found OC decreased the excitability of B4. This change appeared intrinsic to B4 because it could be replicated with an analog of OC in isolated cultures of B4 neurons. In addition to changes in B4 excitability, OC decreased the strength of B4's inhibitory connection to a key decision-making neuron, B51. The OC-induced changes were specific without affecting the excitability of another neuron critical for feeding behavior, B8, or the B4-to-B8 inhibitory connection. A conductance-based circuit model indicated that reducing the B4-to-B51 synapse, or increasing B51 excitability, mediated the OC phenotype more effectively than did decreasing B4 excitability. We combined these modifications to examine whether they could act synergistically. Combinations including B51 synergistically enhanced feeding. Taken together, these results suggest modifications of diverse loci work synergistically to mediate OC and that some neurons are well suited to work synergistically with plasticity in other loci. SIGNIFICANCE STATEMENT The ways in which synergism of diverse plasticity loci mediate the change in motor patterns in operant conditioning (OC) are poorly understood. Here, we found that OC was in part mediated by decreasing the intrinsic excitability of a critical neuron of Aplysia feeding behavior, and specifically reducing the strength of one of its inhibitory connections that targets a key decision-making neuron. A conductance-based computational model indicated that the known plasticity loci showed a surprising level of synergism to mediate the behavioral changes associated with OC. These results highlight the importance of understanding the diversity, specificity and synergy among different types of plasticity that encode memory. Also, because OC in Aplysia is mediated by dopamine (DA), the present study provides insights into specific and synergistic mechanisms of DA-mediated reinforcement of behaviors., (Copyright © 2022 the authors.)

Learning engages a high-dimensional neuronal population space spanning multiple brain regions. However, it remains unknown whether it is possible to identify a low-dimensional signature associated with operant conditioning, a ubiquitous form of learning in which animals learn from the consequences of behavior. Using single-neuron resolution voltage imaging, here we identify two low-dimensional motor modules in the neuronal population underlying Aplysia feeding. Our findings point to a temporal shift in module recruitment as the primary signature of operant learning. Our findings can help guide characterization of learning signatures in systems in which only a smaller fraction of the relevant neuronal population can be monitored., (© 2022. The Author(s).)

Kinases play critical roles in synaptic and neuronal changes involved in the formation of memory. However, significant gaps exist in the understanding of how interactions among kinase pathways contribute to the mechanistically distinct temporal domains of memory ranging from short-term memory to long-term memory (LTM). Activation of protein kinase A (PKA) and mitogen-activated protein kinase (MAPK)-ribosomal S6 kinase (RSK) pathways are critical for long-term enhancement of neuronal excitability (LTEE) and long-term synaptic facilitation (LTF), essential processes in memory formation. This study provides new insights into how these pathways contribute to the temporal domains of memory, using empirical and computational approaches. Empirical studies of Aplysia sensory neurons identified a positive feedforward loop in which the PKA and ERK pathways converge to regulate RSK, and a negative feedback loop in which p38 MAPK inhibits the activation of ERK and RSK. A computational model incorporated these findings to simulate the dynamics of kinase activity produced by different stimulus protocols and predict the critical roles of kinase interactions in the dynamics of these pathways. These findings may provide insights into the mechanisms underlying aberrant synaptic plasticity observed in genetic disorders such as RASopathies and Coffin-Lowry syndrome., (© 2021. The Author(s).)

Objective: ED avoidance strategies including In-Event Health Service (IEHS) processes during mass gathering events (MGEs), such as 'Schoolies week', may be important for EDs, ambulance services, the local population, and attendees. The aim of the present study was to provide a longitudinal description of emergency care requirements for young adults (16-18 years old); focussing on the impact of the Schoolies MGEs., Methods: This retrospective observational study included youth (16-18 years) presentations made (i) to local public EDs during Schoolies week in 2008-2014 and (ii) to local EDs over a 3-week period (pre, during, post-Schoolies week) and the IEHS in 2015 and 2016. Descriptive and inferential statistics were undertaken., Results: Youth presentations (n = 4256) were included. Presentation rates/1000 fluctuated over time (range 6.2-21.2). The IEHS provided care for 167 and 288 youth during 2015 and 2016 Schoolies week, respectively. Demographic factors (gender, age, region domiciled) and episode of care factors (time of presentation, mode of arrival, urgency, time to triage, time to be seen by a clinician and length of stay) between 2008 and 2016 varied by year. Toxicology (alcohol and other drugs), trauma, and mental health concerns were the most common diagnoses., Conclusions: The IEHS, operational during Schoolies, appeared to reduce pressures on local EDs by offering rapid, targeted care for potentially vulnerable youth; decrease requirements for hospital transport and minimise impacts on care provision for the local community. Given increases in ED crowding and pressures on ambulance services, such care models may be worth considering for other types of MGEs and in other locations., (© 2020 Australasian College for Emergency Medicine.)

Objective . Accurate inference of functional connectivity is critical for understanding brain function. Previous methods have limited ability distinguishing between direct and indirect connections because of inadequate scaling with dimensionality. This poor scaling performance reduces the number of nodes that can be included in conditioning. Our goal was to provide a technique that scales better and thereby enables minimization of indirect connections. Approach . Our major contribution is a powerful model-free framework, graphical directed information (GDI), that enables pairwise directed functional connections to be conditioned on the activity of substantially more nodes in a network, producing a more accurate graph of functional connectivity that reduces indirect connections. The key technology enabling this advancement is a recent advance in the estimation of mutual information (MI), which relies on multilayer perceptrons and exploiting an alternative representation of the Kullback-Leibler divergence definition of MI. Our second major contribution is the application of this technique to both discretely valued and continuously valued time series. Main results . GDI correctly inferred the circuitry of arbitrary Gaussian, nonlinear, and conductance-based networks. Furthermore, GDI inferred many of the connections of a model of a central pattern generator circuit in Aplysia , while also reducing many indirect connections. Significance . GDI is a general and model-free technique that can be used on a variety of scales and data types to provide accurate direct connectivity graphs and addresses the critical issue of indirect connections in neural data analysis., (Creative Commons Attribution license.)

Objective: Busy, high-stress EDs prompt many work-based interventions to address staff wellness, with mixed success. The aim of the present study was to enable ED clinicians to systematically identify core components of a work-based strategy to improve their working environment and/or coping., Methods: Purposively sampled ED doctors and nurses from one health service were invited to participate in modified nominal group technique. Participants identified, from a pre-defined list, a key ED stressor and then discussed and ratified proposed core components of a work-based strategy to address or ameliorate this stressor., Results: Two nominal group technique sessions were held with a total of 10 participants (n = 7 nurses and n = 3 doctors). Participants proposed several strategies aimed at both individual and organisational levels to address occupational stress and coping, and support staff well-being in the workplace. These included mobile/web-based applications, group counselling sessions, yoga, social activities, team building activities and debriefing. Participants described three key components to promote staff wellness and hence enhance their ability to buffer negative aspects of occupational stress: (i) increased individual and team support; (ii) development of professional resilience; and (iii) maximising opportunities for social connection., Conclusions: Ensuring appropriate systems, services and support for ED staff should be a priority at local departmental, wider organisational and governmental levels. ED clinicians are ideally placed to identify such systems, services and supports. Managers and policy makers can use these findings to inform the implementation of interventions in EDs., (© 2020 Australasian College for Emergency Medicine.)

Purpose: Fertility is a quality of life outcome adversely affected by cancer therapy. Many childhood cancer patients, however, are not offered options to preserve their fertility. Providers acknowledge difficulty discussing impaired fertility to patients due to lack of knowledge of available options. Our objective was to review the impact of a pediatric multidisciplinary fertility preservation program on providers' fertility preservation counseling and discussion of options., Methods: A retrospective medical chart review was conducted for pediatric cancer patients prior to and following program establishment. Fertility preservation discussions, consults, and incidence were noted. Following filtering and stratification, 198 and 237 patients were seen prior to and following program establishment, respectively., Results: Following program establishment, provider-patient discussions of impaired fertility (p = 0.007), fertility preservation consults (p = 0.01), and incidence of fertility preservation procedures (p < 0.001) increased among patients. Furthermore, the number of patients who received fertility preservation consults after receiving gonadotoxic treatment decreased (p < 0.001). This trend was particularly noted in pre-pubertal and female patients, for whom fertility preservation options are limited without an established program., Conclusion: The establishment of a formal program greatly improved access to fertility preservation consults and procedures in children with cancer.

Genetic disorders such as Rubinstein-Taybi syndrome (RTS) and Coffin-Lowry syndrome (CLS) cause lifelong cognitive disability, including deficits in learning and memory. Can pharmacological therapies be suggested that improve learning and memory in these disorders? To address this question, we simulated drug effects within a computational model describing induction of late long-term potentiation (L-LTP). Biochemical pathways impaired in these and other disorders converge on a common target, histone acetylation by acetyltransferases such as CREB binding protein (CBP), which facilitates gene induction necessary for L-LTP. We focused on four drug classes: tropomyosin receptor kinase B (TrkB) agonists, cAMP phosphodiesterase inhibitors, histone deacetylase inhibitors, and ampakines. Simulations suggested each drug type alone may rescue deficits in L-LTP. A potential disadvantage, however, was the necessity of simulating strong drug effects (high doses), which could produce adverse side effects. Thus, we investigated the effects of six drug pairs among the four classes described above. These combination treatments normalized impaired L-LTP with substantially smaller individual drug 'doses'. In addition three of these combinations, a TrkB agonist paired with an ampakine and a cAMP phosphodiesterase inhibitor paired with a TrkB agonist or an ampakine, exhibited strong synergism in L-LTP rescue. Therefore, we suggest these drug combinations are promising candidates for further empirical studies in animal models of genetic disorders that impair histone acetylation, L-LTP, and learning.

A fundamental neuroscience question is how memories are maintained from days to a lifetime, given turnover of proteins that underlie expression of long-term synaptic potentiation (LTP) or "tag" synapses as eligible for LTP. A likely solution relies on synaptic positive feedback loops, prominently including persistent activation of Ca 2+ /calmodulin kinase II (CaMKII) and self-activated synthesis of protein kinase M ζ (PKMζ). Data also suggest positive feedback based on recurrent synaptic reactivation within neuron assemblies, or engrams, is necessary to maintain memories. The relative importance of these mechanisms is controversial. To explore the likelihood that each mechanism is necessary or sufficient to maintain memory, we simulated maintenance of LTP with a simplified model incorporating persistent kinase activation, synaptic tagging, and preferential reactivation of strong synapses, and analyzed implications of recent data. We simulated three model variants, each maintaining LTP with one feedback loop: autonomous, self-activated PKMζ synthesis (model variant I); self-activated CamKII (model variant II); and recurrent reactivation of strengthened synapses (model variant III). Variant I predicts that, for successful maintenance of LTP, either 1) PKMζ contributes to synaptic tagging, or 2) a low constitutive tag level persists during maintenance independent of PKMζ, or 3) maintenance of LTP is independent of tagging. Variant II maintains LTP and suggests persistent CaMKII activation could maintain PKMζ activity, a feedforward interaction not previously considered. However, we note data challenging the CaMKII feedback loop. In Variant III synaptic reactivation drives, and thus predicts, recurrent or persistent activation of CamKII and other necessary kinases, plausibly contributing to persistent elevation of PKMζ levels. Reactivation is thus predicted to sustain recurrent rounds of synaptic tagging and incorporation of plasticity-related proteins. We also suggest (model variant IV) that synaptic reactivation and autonomous kinase activation could synergistically maintain LTP. We propose experiments that could discriminate these maintenance mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Smolen, Baxter and Byrne.)

Operant reward learning of feeding behavior in Aplysia increases the frequency and regularity of biting, as well as biases buccal motor patterns (BMPs) toward ingestion-like BMPs (iBMPs). The engram underlying this memory comprises cells that are part of a central pattern generating (CPG) circuit and includes increases in the intrinsic excitability of identified cells B30, B51, B63, and B65, and increases in B63-B30 and B63-B65 electrical synaptic coupling. To examine the ways in which sites of plasticity (individually and in combination) contribute to memory expression, a model of the CPG was developed. The model included conductance-based descriptions of cells CBI-2, B4, B8, B20, B30, B31, B34, B40, B51, B52, B63, B64, and B65, and their synaptic connections. The model generated patterned activity that resembled physiological BMPs, and implementation of the engram reproduced increases in frequency, regularity, and bias. Combined enhancement of B30, B63, and B65 excitabilities increased BMP frequency and regularity, but not bias toward iBMPs. Individually, B30 increased regularity and bias, B51 increased bias, B63 increased frequency, and B65 decreased all three BMP features. Combined synaptic plasticity contributed primarily to regularity, but also to frequency and bias. B63-B30 coupling contributed to regularity and bias, and B63-B65 coupling contributed to all BMP features. Each site of plasticity altered multiple BMP features simultaneously. Moreover, plasticity loci exhibited mutual dependence and synergism. These results indicate that the memory for operant reward learning emerged from the combinatoric engagement of multiple sites of plasticity., (© 2020 Costa et al.; Published by Cold Spring Harbor Laboratory Press.)

Multiple kinases converge on the transcription factor cAMP response element-binding protein (CREB) to enhance the expression of proteins essential for long-term synaptic plasticity and memory. The p90 ribosomal S6 kinase (RSK) is one of these kinases, although its role is poorly understood. The present study exploited the technical advantages of the Aplysia sensorimotor culture system to examine the role of RSK in long-term synaptic facilitation (LTF) and long-term enhancement of neuronal excitability (LTEE), two correlates of long-term memory (LTM). Inhibition of RSK expression or RSK activity both significantly reduced CREB1 phosphorylation, LTF, and LTEE, suggesting RSK is required for learning-related synaptic plasticity and enhancement in neuronal excitability. In addition, knock down of RSK by RNAi in Aplysia sensory neurons impairs LTF, suggesting that this may be a useful single-cell system to study aspects of defective synaptic plasticity in Coffin-Lowry Syndrome (CLS), a cognitive disorder that is caused by mutations in rsk2 and associated with deficits in learning and memory. We found that the impairments in LTF and LTEE can be rescued by a computationally designed spaced training protocol, which was previously demonstrated to augment normal LTF and LTM.

With memory encoding reliant on persistent changes in the properties of synapses, a key question is how can memories be maintained from days to months or a lifetime given molecular turnover? It is likely that positive feedback loops are necessary to persistently maintain the strength of synapses that participate in encoding. Such feedback may occur within signal-transduction cascades and/or the regulation of translation, and it may occur within specific subcellular compartments or within neuronal networks. Not surprisingly, numerous positive feedback loops have been proposed. Some posited loops operate at the level of biochemical signal-transduction cascades, such as persistent activation of Ca 2+ /calmodulin kinase II (CaMKII) or protein kinase Mζ. Another level consists of feedback loops involving transcriptional, epigenetic and translational pathways, and autocrine actions of growth factors such as BDNF. Finally, at the neuronal network level, recurrent reactivation of cell assemblies encoding memories is likely to be essential for late maintenance of memory. These levels are not isolated, but linked by shared components of feedback loops. Here, we review characteristics of some commonly discussed feedback loops proposed to underlie the maintenance of memory and long-term synaptic plasticity, assess evidence for and against their necessity, and suggest experiments that could further delineate the dynamics of these feedback loops. We also discuss crosstalk between proposed loops, and ways in which such interaction can facilitate the rapidity and robustness of memory formation and storage., (© 2019 Smolen et al.; Published by Cold Spring Harbor Laboratory Press.)

The transition from early long-term potentiation (E-LTP) to late long-term potentiation (L-LTP) is a multistep process that involves both protein synthesis and degradation. The ways in which these two opposing processes interact to establish L-LTP are not well understood, however. For example, L-LTP is attenuated by inhibiting either protein synthesis or proteasome-dependent degradation prior to and during a tetanic stimulus (e.g., Huang et al., 1996; Karpova et al., 2006), but paradoxically, L-LTP is not attenuated when synthesis and degradation are inhibited simultaneously (Fonseca et al., 2006). These paradoxical results suggest that counter-acting 'positive' and 'negative' proteins regulate L-LTP. To investigate the basis of this paradox, we developed a model of LTP at the Schaffer collateral to CA1 pyramidal cell synapse. The model consists of nine ordinary differential equations that describe the levels of both positive- and negative-regulator proteins (PP and NP, respectively) and the transitions among five discrete synaptic states, including a basal state (BAS), three states corresponding to E-LTP (EP1, EP2, and ED), and a L-LTP state (LP). An LTP-inducing stimulus: 1) initiates the transition from BAS to EP1 and from EP1 to EP2; 2) initiates the synthesis of PP and NP; and finally; 3) activates the ubiquitin-proteasome system (UPS), which in turn, mediates transitions of EP1 and EP2 to ED and the degradation of NP. The conversion of E-LTP to L-LTP is mediated by the PP-dependent transition from ED to LP, whereas NP mediates reversal of EP2 to BAS. We found that the inclusion of the five discrete synaptic states was necessary to simulate key empirical observations: 1) normal L-LTP, 2) block of L-LTP by either proteasome inhibitor or protein synthesis inhibitor alone, and 3) preservation of L-LTP when both inhibitors are applied together. Although our model is abstract, elements of the model can be correlated with specific molecular processes. Moreover, the model correctly captures the dynamics of protein synthesis- and degradation-dependent phases of LTP, and it makes testable predictions, such as a unique synaptic state (ED) that precedes the transition from E-LTP to L-LTP, and a well-defined time window for the action of the UPS (i.e., during the transitions from EP1 and EP2 to ED). Tests of these predictions will provide new insights into the processes and dynamics of long-term synaptic plasticity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The ongoing challenges of managing large student enrolments and increasing demand from students for online learning platforms and teaching strategies has helped drive tertiary implementation of asynchronous online discussion boards (AOD). However, supporting and assessing students in such a forum remains contentious., Methods: This explorative, mixed methods study examined and evaluated the usage and perceptions of a unique form of AOD used in a postgraduate nursing course. Student survey and semi-structured interviews with staff (n = 3) were used to explore the structures, processes and outcomes of inclusion of an AOD in this online course. Triangulation of themes emerging from the staff interviews, survey outcomes, and student free text responses enabled appraisal of AOD, focusing primarily on its contribution to course content and assessment., Results: Students' survey responses (approx. 24% of the cohort; n = 34) were largely positive. Themes that arose from the qualitative data included i) AOD to build a sense of student community, ii) AOD to encourage interaction with and deliberation of course content, iii) stimuli and challenges around assessing the discussion board, and iv) easy to use IT interface made it a more positive experience. Student responses suggested that scaffolding, feedback and sufficient time allocation were required. Many factors impacted on student interaction with the AOD, including a lack of time due to paid work and other coursework and assessments., Discussion: Overall, staff and students reported the assessed AOD was a positive course component. It encouraged engagement with staff, other students and the subtleties of complex course content, critical appraisal and discussion of evidence, and application to clinical practice. Exemplars and explicit marking criteria setting out the need for informed contributions were considered crucial by all stakeholders., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Introduction: Physical activity (PA) has diverse benefits for physical and mental health and can reduce symptoms of mental illness. Adults with mental illness face practical, psychosocial and socioeconomic barriers to adopting and maintaining PA, and it is unclear how to effectively promote PA in this group. Supervised exercise interventions provide high support but may not promote autonomous motivation, which is important for PA maintenance. The aim of this study is to compare the effectiveness of two interventions to promote PA in adults with mental illness., Methods and Analysis: This is a randomised controlled trial of two interventions to promote PA: (1) supervised exercise and gym membership and (2) motivational discussions and self-monitoring of PA using fitness trackers. The intervention duration is 16 weeks, including 8 weeks of weekly supervised group sessions, and 8 weeks of access to the gym or fitness tracker unsupervised. Participants are community-dwelling adults recruited from outpatient clinics of public mental health services. The primary outcome is PA adoption assessed using GENEActiv accelerometers worn continuously over 8 weeks. Secondary outcomes measured at baseline, postintervention (8 weeks) and follow-up (16 weeks), include exercise motivation, psychological distress and self-reported PA assessed using self-administered questionnaires and indicators of physical health measured by a researcher blinded to allocation (blood pressure, weight, waist circumference, 6 min walk test). Participant experiences will be assessed using qualitative focus groups with analysis informed by a theoretical model of behaviour (COM-B)., Ethics and Dissemination: Ethics approval has been obtained from the Royal Brisbane and Women's Hospital (HREC/17/QRBW/302). We plan to submit a manuscript on protocol development from pilot work, and a manuscript of the results to a peer-reviewed journal. Results will be presented at conferences, community and consumer forums and hospital grand rounds., Trial Registration Number: ACTRN12617001017314; Pre-results., Competing Interests: Competing interests: The lead author is employed as a Program Manager at PCYC Queensland where he oversees implementation of the Healthy Bodies, Healthy Minds (HBHM) programme. The exercise protocol used in the HBHM programme is one of the intervention conditions of this study., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A key issue in neuroscience is understanding the ways in which neuromodulators such as dopamine modify neuronal activity to mediate selection of distinct motor patterns. We addressed this issue by applying either low or high concentrations of l-DOPA (40 or 250 μM) and then monitoring activity of up to 130 neurons simultaneously in the feeding circuitry of Aplysia using a voltage-sensitive dye (RH-155). l-DOPA selected one of two distinct buccal motor patterns (BMPs): intermediate (low l-DOPA) or bite (high l-DOPA) patterns. The selection of intermediate BMPs was associated with shortening of the second phase of the BMP (retraction), whereas the selection of bite BMPs was associated with shortening of both phases of the BMP (protraction and retraction). Selection of intermediate BMPs was also associated with truncation of individual neuron spike activity (decreased burst duration but no change in spike frequency or burst latency) in neurons active during retraction. In contrast, selection of bite BMPs was associated with compression of spike activity (decreased burst latency and duration and increased spike frequency) in neurons projecting through specific nerves, as well as increased spike frequency of protraction neurons. Finally, large-scale voltage-sensitive dye recordings delineated the spatial distribution of neurons active during BMPs and the modification of that distribution by the two concentrations of l-DOPA.

A major challenge in neuroscience is to develop effective tools that infer the circuit connectivity from large-scale recordings of neuronal activity patterns. In this study, context tree maximizing (CTM) was used to estimate directed information (DI), which measures causal influences among neural spike trains in order to infer putative synaptic connections. In contrast to existing methods, the method presented here is data driven and can readily identify both linear and nonlinear relations between neurons. This CTM-DI method reliably identified circuit structures underlying simulations of realistic conductance-based networks. It also inferred circuit properties from voltage-sensitive dye recordings of the buccal ganglion of Aplysia. This method can be applied to other large-scale recordings as well. It offers a systematic tool to map network connectivity and to track changes in network structure such as synaptic strengths as well as the degrees of connectivity of individual neurons, which in turn could provide insights into how modifications produced by learning are distributed in a neural network. NEW & NOTEWORTHY This study brings together the techniques of voltage-sensitive dye recording and information theory to infer the functional connectome of the feeding central pattern generating network of Aplysia. In contrast to current statistical approaches, the inference method developed in this study is data driven and validated by conductance-based model circuits, can distinguish excitatory and inhibitory connections, is robust against synaptic plasticity, and is capable of detecting network structures that mediate motor patterns., (Copyright © 2017 the American Physiological Society.)

Doxorubicin (DOX), a common chemotherapeutic agent, impairs synaptic plasticity. DOX also causes a persistent increase in basal neuronal excitability, which occludes serotonin-induced enhanced excitability. Therefore, we sought to characterize and reverse DOX-induced physiological changes and modulation of molecules implicated in memory induction using sensory neurons from the marine mollusk Aplysia californica. DOX produced two mechanistically distinct phases of extracellular signal-regulated kinase (ERK) activation, an early and a late phase. Inhibition of MEK (mitogen-activated protein kinase (MAPK)/ERK kinase) after DOX treatment reversed the late ERK activation. MEK inhibition during treatment enhanced the late ERK activation possibly through prolonged downregulation of MAPK phosphatase-1 (MKP-1). Unexpectedly, the late ERK activation negatively correlated with excitability. MEK inhibition during DOX treatment simultaneously enhanced the late activation of ERK and blocked the increase in basal excitability. In summary, we report DOX-mediated biphasic activation of ERK and the reversal of the associated changes in neurons, a potential strategy for reversing the deleterious effects of DOX treatment.

Developing treatment strategies to enhance memory is an important goal of neuroscience research. Activation of multiple biochemical signaling cascades, such as the protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) pathways, is necessary to induce long-term synaptic facilitation (LTF), a correlate of long-term memory (LTM). Previously, a computational model was developed which correctly predicted a novel enhanced training protocol that augmented LTF by searching for the protocol with maximal overlap of PKA and ERK activation. The present study focused on pharmacological approaches to enhance LTF. Combining an ERK activator, NSC, and a PKA activator, rolipram, enhanced LTF to a greater extent than did either drug alone. An even greater increase in LTF occurred when rolipram and NSC were combined with the Enhanced protocol. These results indicate superior memory can be achieved by enhanced protocols that take advantage of the structure and dynamics of the biochemical cascades underlying memory formation, used in conjunction with combinatorial pharmacology., (© 2017 Liu et al.; Published by Cold Spring Harbor Laboratory Press.)

The MAPK isoforms ERK and p38 MAPK are believed to play opposing roles in long-term synaptic facilitation (LTF) induced by serotonin (5-HT) in Aplysia . To fully understand their roles, however, it is necessary to consider the dynamics of ERK and p38 MAPK activation. Previous studies determined that activation of ERK occurred ∼45 min after a 5-min pulse of 5-HT treatment. The dynamics of p38 MAPK activation following 5-HT are yet to be elucidated. Here, the activity of p38 MAPK was examined at different times after 5-HT, and the interaction between the ERK and p38 MAPK pathways was investigated. A 5-min pulse of 5-HT induced a transient inhibition of p38 MAPK, followed by a delayed activation between 25 and 45 min. This activation was blocked by a MAPK kinase inhibitor, suggesting that similar pathways are involved in activation of ERK and p38 MAPK. ERK activity decreased shortly after the activation of p38 MAPK. A p38 MAPK inhibitor blocked this decrease in ERK activity, suggesting a causal relationship. The p38 MAPK activity ∼45 min after different stimulus protocols was also characterized. These data were incorporated into a computational model for the induction of LTF. Simulations and empirical data suggest that p38 MAPK, together with ERK, contributes to the efficacy of spaced stimulus protocols to induce LTF, a correlate of long-term memory (LTM). For example, decreased p38 MAPK activity ∼45 min after the first of two sensitizing stimuli might be an important determinant of an optimal interstimulus interval (ISI) for LTF induction.

Inhibitory avoidance (IA) training in rodents initiates a molecular cascade within hippocampal neurons. This cascade contributes to the transition of short- to long-term memory (i.e., consolidation). Here, a differential equation-based model was developed to describe a positive feedback loop within this molecular cascade. The feedback loop begins with an IA-induced release of brain-derived neurotrophic factor (BDNF), which in turn leads to rapid phosphorylation of the cAMP response element-binding protein (pCREB), and a subsequent increase in the level of the β isoform of the CCAAT/enhancer binding protein (C/EBPβ). Increased levels of C/EBPβ lead to increased bdnf expression. Simulations predicted that an empirically observed delay in the BDNF-pCREB-C/EBPβ feedback loop has a profound effect on the dynamics of consolidation. The model also predicted that at least two independent self-sustaining signaling pathways downstream from the BDNF-pCREB-C/EBPβ feedback loop contribute to consolidation. Currently, the nature of these downstream pathways is unknown., (© 2016 Zhang et al.; Published by Cold Spring Harbor Laboratory Press.)

With increasing knowledge of the materials science of bulk metallic glasses (BMGs) and improvements in their properties and processing, they have started to become candidate materials for biomedical devices. A dichotomy in the types of medical applications has also emerged, in which some families of BMGs are being developed for permanent devices whilst another family - of Mg-based alloys - is showing promise in bioabsorbable implants. The current status of these metallurgical and technological developments is summarized., (© 2016 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

For many types of learning, spaced training, which involves repeated long inter-trial intervals, leads to more robust memory formation than does massed training, which involves short or no intervals. Several cognitive theories have been proposed to explain this superiority, but only recently have data begun to delineate the underlying cellular and molecular mechanisms of spaced training, and we review these theories and data here. Computational models of the implicated signalling cascades have predicted that spaced training with irregular inter-trial intervals can enhance learning. This strategy of using models to predict optimal spaced training protocols, combined with pharmacotherapy, suggests novel ways to rescue impaired synaptic plasticity and learning.