Integration of Parallel Opposing Memories Underlies Memory Extinction.

Accurately predicting an outcome requires that animals learn supporting and conflicting evidence from sequential experience. In mammals and invertebrates, learned fear responses can be suppressed by experiencing predictive cues without punishment, a process called memory extinction. Here, we show that extinction of aversive memories in Drosophila requires specific dopaminergic neurons, which indicate that omission of punishment is remembered as a positive experience. Functional imaging revealed co-existence of intracellular calcium traces in different places in the mushroom body output neuron network for both the original aversive memory and a new appetitive extinction memory. Light and ultrastructural anatomy are consistent with parallel competing memories being combined within mushroom body output neurons that direct avoidance. Indeed, extinction-evoked plasticity in a pair of these neurons neutralizes the potentiated odor response imposed in the network by aversive learning. Therefore, flies track the accuracy of learned expectations by accumulating and integrating memories of conflicting events.

A Complete Electron Microscopy Volume of the Brain of Adult Drosophila melanogaster.

Drosophila melanogaster has a rich repertoire of innate and learned behaviors. Its 100,000-neuron brain is a large but tractable target for comprehensive neural circuit mapping. Only electron microscopy (EM) enables complete, unbiased mapping of synaptic connectivity; however, the fly brain is too large for conventional EM. We developed a custom high-throughput EM platform and imaged the entire brain of an adult female fly at synaptic resolution. To validate the dataset, we traced brain-spanning circuitry involving the mushroom body (MB), which has been extensively studied for its role in learning. All inputs to Kenyon cells (KCs), the intrinsic neurons of the MB, were mapped, revealing a previously unknown cell type, postsynaptic partners of KC dendrites, and unexpected clustering of olfactory projection neurons. These reconstructions show that this freely available EM volume supports mapping of brain-spanning circuits, which will significantly accelerate Drosophila neuroscience. VIDEO ABSTRACT.

Network Architecture of Gap Junctional Coupling among Parallel Processing Channels in the Mammalian Retina.

Gap junctions are ubiquitous throughout the nervous system, mediating critical signal transmission and integration, as well as emergent network properties. In mammalian retina, gap junctions within the Aii amacrine cell-ON cone bipolar cell (CBC) network are essential for night vision, modulation of day vision, and contribute to visual impairment in retinal degenerations, yet neither the extended network topology nor its conservation is well established. Here, we map the network contribution of gap junctions using a high-resolution connectomics dataset of an adult female rabbit retina. Gap junctions are prominent synaptic components of ON CBC classes, constituting 5%-25% of all axonal synaptic contacts. Many of these mediate canonical transfer of rod signals from Aii cells to ON CBCs for night vision, and we find that the uneven distribution of Aii signals to ON CBCs is conserved in rabbit, including one class entirely lacking direct Aii coupling. However, the majority of gap junctions formed by ON CBCs unexpectedly occur between ON CBCs, rather than with Aii cells. Such coupling is extensive, creating an interconnected network with numerous lateral paths both within, and particularly across, these parallel processing streams. Coupling patterns are precise with ON CBCs accepting and rejecting unique combinations of partnerships according to robust rulesets. Coupling specificity extends to both size and spatial topologies, thereby rivaling the synaptic specificity of chemical synapses. These ON CBC coupling motifs dramatically extend the coupled Aii-ON CBC network, with implications for signal flow in both scotopic and photopic retinal networks during visual processing and disease.SIGNIFICANCE STATEMENT Electrical synapses mediated by gap junctions are fundamental components of neural networks. In retina, coupling within the Aii-ON CBC network shapes visual processing in both the scotopic and photopic networks. In retinal degenerations, these same gap junctions mediate oscillatory activity that contributes to visual impairment. Here, we use high-resolution connectomics strategies to identify gap junctions and cellular partnerships. We describe novel, pervasive motifs both within and across classes of ON CBCs that dramatically extend the Aii-ON CBC network. These motifs are highly specific with implications for both signal processing within the retina and therapeutic interventions for blinding conditions. These findings highlight the underappreciated contribution of coupling motifs in retinal circuitry and the necessity of their detection in connectomics studies.

History of cardiovascular disease and cardiovascular biomarkers are associated with 30-day mortality in patients with hip fracture.

Hip fractures are associated with increased mortality and it is important to identify risk factors. This study demonstrates that preexisting cardiovascular disease as well as cardiovascular biomarkers that are associated with increased 30-day mortality. These findings can be used to identify high-risk patients who might benefit from specialized care. INTRODUCTION: This study investigates the association between cardiovascular disease (CVD), cardiovascular biomarkers, and 30-day mortality following a hip fracture. METHODS: The Danish National Patient Registry was used to investigate the association between CVD and mortality following hip fracture in a nationwide population-based cohort study. In a subset of the included patients (n = 355), blood samples were available from a local biobank. These samples were used for analyzing the association between specific biochemical markers and mortality. The primary outcome was 30-day mortality. RESULTS: A total of 113,211 patients were included in the population-based cohort study. Among these, heart failure was present in 9.4%, ischemic heart disease in 15.9%, and ischemic stroke in 12.0%. Within 30 days after the hip fracture, 11,488 patients died, resulting in an overall 30-day mortality of 10.1%. The 30-day mortality was significantly increased in individuals with preexisting CVD with multivariably adjusted odds ratios of 1.69 (95% confidence interval, 1.60-1.78) for heart failure, 1.23 (1.17-1.29) for ischemic heart disease, and 1.06 (1.00-1.12) for ischemic stroke. In the local database including 355 patients, 41 (11.5%) died within 30 days. The multivariably adjusted odds ratio for 30-day mortality increased with increasing NT-proBNP (2.36 [1.53-3.64] per quartile) and decreased with increasing HDL cholesterol (0.58 [0.41-0.82] per quartile). On this basis, we established a model for predicting the probability of death based on the biochemical markers. CONCLUSION: Preexisting CVD was associated with increased 30-day mortality after a hip fracture. Furthermore, high levels of NT-proBNP and low levels of HDL cholesterol were associated with increased 30-day mortality.

Hyponatremia and hypernatremia are associated with increased 30-day mortality in hip fracture patients.

UNLABELLED: Using data from the Danish national registries on 7317 patients, this study shows that abnormal plasma sodium levels, in the form of hyponatremia and hypernatremia, are prevalent and associated with increased 30-day mortality in hip fracture patients. INTRODUCTION: The aim of this study was to examine the prevalence of hyponatremia and hypernatremia in patients admitted with a fractured hip as well as the association with 30-day in mortality in these patients. METHODS: A total of 7317 hip fracture patients (aged 60 years or above) with admission plasma sodium measurements were included. Data on comorbidity, medication, and death was retrieved from Danish national registries. The association between plasma sodium and mortality was examined using Cox proportional hazard models. RESULTS: The prevalence of hyponatremia and hypernatremia on admission was 19.0 and 1.7 %, respectively. Thirty-day mortality was increased for patients with hyponatremia (12.2 %, p = 0.005) and hypernatremia (15.5 %, p = 0.03) compared to normonatremic patients (9.6 %). After adjustment for possible confounding factors, hyponatremia (1.38 [1.16-1.64], p = 0.0003) and hypernatremia (1.71 [1.08-2.70], p = 0.02) were still associated with increased risk of death by 30 days. Looking at the association between changes in plasma sodium during admission and mortality, there was no difference between patients with normalized and persistent hyponatremia (10.4 vs 11.3 %, p = 0.6) while a lower mortality was found for normalized hypernatremia compared to persistent hypernatremia (12.4 vs 33.3 %, p = 0.03). CONCLUSIONS: This study shows that abnormal plasma sodium levels are prevalent in patients admitted with a fractured hip and that both hyponatremia and hypernatremia are associated with increased risk of death within 30 days of admission.

Trauma treatment in a role 1 medical facility in Afghanistan.

BACKGROUND: Most of the emergency care delivered in Afghanistan is currently provided by the military sector and non-governmental organisations. Main Operating Base (MOB) Price in Helmand Province has a small medical centre and due to its location provides critical care to civilians and military casualties and this article describes the patterns in trauma patient care at the MOB Price medical centre regarding the types of patients and injuries. MATERIALS AND METHODS: The study population consists of 64 consecutive critically injured patients treated in MOB Price during a 4-month period from September to December 2010. The outcomes were battle-related injuries, treatment received before arriving to MOB Price, types of injury and treatment. RESULTS: There were 35 civilians (12 children and 23 adults), 28 Afghan National Security Forces and one International Security Assistance Force soldier; they were divided into three groups (civilian adults, civilian children and military). 22% of the patients suffered fragmentation injuries and civilians were more likely to incur fragment injury than military personnel (OR (95% CI) 7.04 (1.4 to 34.8)). Regarding intubation, there was a trend towards more civilians needing it than military personnel and significantly more children than adults underwent intubation (OR (95% Cl) 51 (5.2 to 498.5)). Gunshot wounds (GSW) occurred in 30% of the patients. Civilians patients had a lower OR for GSWs than military patients (OR (95% CI) 0.35 (0.1 to 1.1)). Other trends in injury types and treatment were apparent but did not reach significance due to the small number of patients. CONCLUSIONS: Both civilians and military personnel benefitted from the in-theatre Role 1 medical facility treatment. The most frequent injuries were fragmentation damage and GSW.

Circuit reorganization in the Drosophila mushroom body calyx accompanies memory consolidation.

The formation and consolidation of memories are complex phenomena involving synaptic plasticity, microcircuit reorganization, and the formation of multiple representations within distinct circuits. To gain insight into the structural aspects of memory consolidation, we focus on the calyx of the Drosophila mushroom body. In this essential center, essential for olfactory learning, second- and third-order neurons connect through large synaptic microglomeruli, which we dissect at the electron microscopy level. Focusing on microglomeruli that respond to a specific odor, we reveal that appetitive long-term memory results in increased numbers of precisely those functional microglomeruli responding to the conditioned odor. Hindering memory consolidation by non-coincident presentation of odor and reward, by blocking protein synthesis, or by including memory mutants suppress these structural changes, revealing their tight correlation with the process of memory consolidation. Thus, olfactory long-term memory is associated with input-specific structural modifications in a high-order center of the fly brain.

Hip protectors: recommendations for conducting clinical trials--an international consensus statement (part II).

INTRODUCTION: While hip protectors are effective in some clinical trials, many, including all in community settings, have been unable to demonstrate effectiveness. This is due partly to differences in the design and analysis. The aim of this report is to develop recommendations for subsequent clinical research. METHODS: In November of 2007, the International Hip Protector Research Group met to address barriers to the clinical effectiveness of hip protectors. This paper represents a consensus statement from the group on recommended methods for conducting future clinical trials of hip protectors. RESULTS AND CONCLUSIONS: Consensus recommendations include the following: the use of a hip protector that has undergone adequate biomechanical testing, the use of sham hip protectors, the conduct of clinical trials in populations with annual hip fracture incidence of at least 3%, a run-in period with demonstration of adequate adherence, surveillance of falls and adherence, and the inclusion of economic analyses. Larger and more costly clinical trials are required to definitively investigate effectiveness of hip protectors.

Wiring patterns from auditory sensory neurons to the escape and song-relay pathways in fruit flies.

Many animals rely on acoustic cues to decide what action to take next. Unraveling the wiring patterns of the auditory neural pathways is prerequisite for understanding such information processing. Here, we reconstructed the first step of the auditory neural pathway in the fruit fly brain, from primary to secondary auditory neurons, at the resolution of transmission electron microscopy. By tracing axons of two major subgroups of auditory sensory neurons in fruit flies, low-frequency tuned Johnston's organ (JO)-B neurons and high-frequency tuned JO-A neurons, we observed extensive connections from JO-B neurons to the main second-order neurons in both the song-relay and escape pathways. In contrast, JO-A neurons connected strongly to a neuron in the escape pathway. Our findings suggest that heterogeneous JO neuronal populations could be recruited to modify escape behavior whereas only specific JO neurons contribute to courtship behavior. We also found that all JO neurons have postsynaptic sites at their axons. Presynaptic modulation at the output sites of JO neurons could affect information processing of the auditory neural pathway in flies.

The Neuroanatomical Ultrastructure and Function of a Biological Ring Attractor.

Neural representations of head direction (HD) have been discovered in many species. Theoretical work has proposed that the dynamics associated with these representations are generated, maintained, and updated by recurrent network structures called ring attractors. We evaluated this theorized structure-function relationship by performing electron-microscopy-based circuit reconstruction and RNA profiling of identified cell types in the HD system of Drosophila melanogaster. We identified motifs that have been hypothesized to maintain the HD representation in darkness, update it when the animal turns, and tether it to visual cues. Functional studies provided support for the proposed roles of individual excitatory or inhibitory circuit elements in shaping activity. We also discovered recurrent connections between neuronal arbors with mixed pre- and postsynaptic specializations. Our results confirm that the Drosophila HD network contains the core components of a ring attractor while also revealing unpredicted structural features that might enhance the network's computational power.

Hip protectors: recommendations for biomechanical testing--an international consensus statement (part I).

INTRODUCTION: Hip protectors represent a promising strategy for preventing fall-related hip fractures. However, clinical trials have yielded conflicting results due, in part, to lack of agreement on techniques for measuring and optimizing the biomechanical performance of hip protectors as a prerequisite to clinical trials. METHODS: In November 2007, the International Hip Protector Research Group met in Copenhagen to address barriers to the clinical effectiveness of hip protectors. This paper represents an evidence-based consensus statement from the group on recommended methods for evaluating the biomechanical performance of hip protectors. RESULTS AND CONCLUSIONS: The primary outcome of testing should be the percent reduction (compared with the unpadded condition) in peak value of the axial compressive force applied to the femoral neck during a simulated fall on the greater trochanter. To provide reasonable results, the test system should accurately simulate the pelvic anatomy, and the impact velocity (3.4 m/s), pelvic stiffness (acceptable range: 39-55 kN/m), and effective mass of the body (acceptable range: 22-33 kg) during impact. Given the current lack of clear evidence regarding the clinical efficacy of specific hip protectors, the primary value of biomechanical testing at present is to compare the protective value of different products, as opposed to rejecting or accepting specific devices for market use.

Smoking and alcohol intervention before surgery: evidence for best practice.

Smoking and hazardous drinking are common and important risk factors for an increased rate of complications after surgery. The underlying pathophysiological mechanisms include organic dysfunctions that can recover with abstinence. Abstinence starting 3-8 weeks before surgery will significantly reduce the incidence of several serious postoperative complications, such as wound and cardiopulmonary complications and infections. However, this intervention must be intensive to obtain sufficient effect on surgical complications. All patients presenting for surgery should be questioned regarding smoking and hazardous drinking, and interventions appropriate for the surgical setting applied.

Rod-cone crossover connectome of mammalian bipolar cells.

The basis of cross-suppression between rod and cone channels has long been an enigma. Using rabbit retinal connectome RC1, we show that all cone bipolar cell (BC) classes inhibit rod BCs via amacrine cell (AC) motifs (C1-6); that all cone BC classes are themselves inhibited by AC motifs (R1-5, R25) driven by rod BCs. A sparse symmetric AC motif (CR) is presynaptic and postsynaptic to both rod and cone BCs. ON cone BCs of all classes drive inhibition of rod BCs via motif C1 wide-field GABAergic ACs (γACs) and motif C2 narrow field glycinergic ON ACs (GACs). Each rod BC receives ≈10 crossover AC synapses and each ON cone BC can target ≈10 or more rod BCs via separate AC processes. OFF cone BCs mediate monosynaptic inhibition of rod BCs via motif C3 driven by OFF γACs and GACs and disynaptic inhibition via motifs C4 and C5 driven by OFF wide-field γACs and narrow-field GACs, respectively. Motifs C4 and C5 form halos of 60-100 inhibitory synapses on proximal dendrites of AI γACs. Rod BCs inhibit surrounding arrays of cone BCs through AII GAC networks that access ON and OFF cone BC patches via motifs R1, R2, R4, R5 and a unique ON AC motif R3 that collects rod BC inputs and targets ON cone BCs. Crossover synapses for motifs C1, C4, C5, and R3 are 3-4× larger than typical feedback synapses, which may be a signature for synaptic winner-take-all switches. J. Comp. Neurol. 527:87-116, 2019. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Local synaptic inputs support opposing, network-specific odor representations in a widely projecting modulatory neuron.

Serotonin plays different roles across networks within the same sensory modality. Previously, we used whole-cell electrophysiology in Drosophila to show that serotonergic neurons innervating the first olfactory relay are inhibited by odorants (Zhang and Gaudry, 2016). Here we show that network-spanning serotonergic neurons segregate information about stimulus features, odor intensity and identity, by using opposing coding schemes in different olfactory neuropil. A pair of serotonergic neurons (the CSDns) innervate the antennal lobe and lateral horn, which are first and second order neuropils. CSDn processes in the antennal lobe are inhibited by odors in an identity independent manner. In the lateral horn, CSDn processes are excited in an odor identity dependent manner. Using functional imaging, modeling, and EM reconstruction, we demonstrate that antennal lobe derived inhibition arises from local GABAergic inputs and acts as a means of gain control on branch-specific inputs that the CSDns receive within the lateral horn.

A Neural Circuit Arbitrates between Persistence and Withdrawal in Hungry Drosophila.

In pursuit of food, hungry animals mobilize significant energy resources and overcome exhaustion and fear. How need and motivation control the decision to continue or change behavior is not understood. Using a single fly treadmill, we show that hungry flies persistently track a food odor and increase their effort over repeated trials in the absence of reward suggesting that need dominates negative experience. We further show that odor tracking is regulated by two mushroom body output neurons (MBONs) connecting the MB to the lateral horn. These MBONs, together with dopaminergic neurons and Dop1R2 signaling, control behavioral persistence. Conversely, an octopaminergic neuron, VPM4, which directly innervates one of the MBONs, acts as a brake on odor tracking by connecting feeding and olfaction. Together, our data suggest a function for the MB in internal state-dependent expression of behavior that can be suppressed by external inputs conveying a competing behavioral drive.

Within-category discontinuity interacts with verbal rule complexity in perceptual category learning.

A test of the predicted interaction between within-category discontinuity and verbal rule complexity on information-integration and rule-based category learning was conducted. Within-category discontinuity adversely affected information-integration category learning but not rule-based category learning. Model-based analyses suggested that some information-integration participants improved performance by recruiting more "units" in the discontinuous condition. Verbal rule complexity adversely affected rule-based category learning but not information-integration category learning. Model-based analyses suggested that the rule based effect was on both decision criterion learning and variability in decision criterion placement. These results suggest that within-category discontinuity and decision rule complexity differentially impact information-integration and rule-based category learning and provide information regarding the detailed processing characteristics of these two proposed category learning systems.

Discontinuous categories affect information-integration but not rule-based category learning.

Three experiments were conducted that provide a direct examination of within-category discontinuity manipulations on the implicit, procedural-based learning and the explicit, hypothesis-testing systems proposed in F. G. Ashby, L. A. Alfonso-Reese, A. U. Turken, and E. M. Waldron's (1998) competition between verbal and implicit systems model. Discontinuous categories adversely affected information-integration but not rule-based category learning. Increasing the magnitude of the discontinuity did not lead to a significant decline in performance. The distance to the bound provides a reasonable description of the generalization profile associated with the hypothesis-testing system, whereas the distance to the bound plus the distance to the trained response region provides a reasonable description of the generalization profile associated with the procedural-based learning system. These results suggest that within-category discontinuity differentially impacts information-integration but not rule-based category learning and provides information regarding the detailed processing characteristics of each category learning system.

Hip fractures: incidence, risk factors, energy absorption, and prevention.

The present review summarizes the pathogenic mechanisms leading to hip fracture based on epidemiological, experimental, and controlled clinical studies. The estimated lifetime risk of hip fracture is about 14% in postmenopausal women and 6% in men. The incidence of hip fractures increases exponentially with aging, but the time trend in increasing age-specific incidence may finally reach a plateau. Postmenopausal women suffering earlier non-hip fractures have an increased risk of later hip fracture. The relative risk is highest within the first years following the fracture. Nursing home residents have a high risk of hip fracture (annual rate of 5-6%), and their incidence of falls is about 1.5 falls/person per year. Most hip fractures are a result of a direct trauma against the hip. The incidence of falls on the hip among nursing home residents is about 0.29 falls/person per year and about 20% of these traumas lead to hip fracture. Women with hip fractures have a lower body weight compared with controls, and they may also have less soft tissue covering the hip, even when adjusted for body mass index, indicating a more android body habitus. Experimental studies show that the passive energy absorption in soft tissue covering the hip may influence the risk of hip fracture and be an important determinant for the development of hip fracture, perhaps even more important than bone strength. External hip protectors were developed and tested in an open randomized nursing home study. The rate of hip fracture was reduced by 50%, corresponding to 9 of 247 residents saved from sustaining a hip fracture. This review points to the essentials in the development of hip fracture: risk of fall; type of fall; type of impact; energy absorption; and last, bone strength, which is the final permissive factor leading to hip fracture. Risk estimation and prevention of hip fracture may prove realistic when these issues are taken into consideration.

Tobacco smoking and risk of hip fracture in men and women.

BACKGROUND: Previous findings suggest that tobacco smoking increases the risk of hip fracture in women. A similar adverse effect of smoking is suspected to be present in men, but bone mineral density studies have raised the concern that men may be more sensitive to the deleterious effect of smoking on bone than women. In this study we prospectively determined the influence of current, previous, and cumulative smoking history on risk of hip fracture in men and women and addressed the issue of possible gender difference in the susceptibility to tobacco smoking. METHODS: Pooled data from three population studies conducted in Copenhagen with detailed information on smoking habit. A total of 13,393 women and 17,379 men, initially examined between 1964 and 1992, were followed until 1997 for first admission due to hip fracture. The relative risks (RR) of hip fracture associated with smoking were estimated by means of multiplicative Poisson regression models. RESULTS: During follow-up, 722 hip fractures were identified in women, and 447 in men. After adjustment for potential confounders, including body mass index, female current smokers had an RR of hip fracture of 1.36 (95% CI: 1.12-1.65) and male smokers 1.59 (95% CI: 1.04-2.43) relative to never smokers. In both sexes, the RR of hip fracture gradually increased by current and accumulated tobacco consumption. The RR were consistently higher in men than in women, but the test for interaction between sex and tobacco smoking was insignificant. After 5 years, male ex-smokers had an adjusted RR of 0.73 (95% CI: 0.55-0.98) relative to current smokers, while no significant decrease in risk was observed in female ex-smokers (RR = 0.91; 95% CI: 0.72-1.17)). Approximately 19% of all hip fractures in the present study population were attributable to tobacco smoking. CONCLUSION: Tobacco smoking is an independent risk factor for hip fracture in men and women, and there appears to be no gender differences in smoking related risk. Smoking cessation reduces the risk of hip fracture in men after 5 years, while the deleterious effect of smoking seems to be more long-lasting in female ex-smokers.