The mammalian hippocampus is crucial for episodic memory formation and transiently retains information for about 3-4 weeks in adult mice and longer in humans. Although neuroscientists widely believe ...that neural synapses are elemental sites of information storage, there has been no direct evidence that hippocampal synapses persist for time intervals commensurate with the duration of hippocampal-dependent memory. Here we tested the prediction that the lifetimes of hippocampal synapses match the longevity of hippocampal memory. By using time-lapse two-photon microendoscopy in the CA1 hippocampal area of live mice, we monitored the turnover dynamics of the pyramidal neurons' basal dendritic spines, postsynaptic structures whose turnover dynamics are thought to reflect those of excitatory synaptic connections. Strikingly, CA1 spine turnover dynamics differed sharply from those seen previously in the neocortex. Mathematical modelling revealed that the data best matched kinetic models with a single population of spines with a mean lifetime of approximately 1-2 weeks. This implies ∼100% turnover in ∼2-3 times this interval, a near full erasure of the synaptic connectivity pattern. Although N-methyl-d-aspartate (NMDA) receptor blockade stabilizes spines in the neocortex, in CA1 it transiently increased the rate of spine loss and thus lowered spine density. These results reveal that adult neocortical and hippocampal pyramidal neurons have divergent patterns of spine regulation and quantitatively support the idea that the transience of hippocampal-dependent memory directly reflects the turnover dynamics of hippocampal synapses.
Detailed descriptions of brain-scale sensorimotor circuits underlying vertebrate behavior remain elusive. Recent advances in zebrafish neuroscience offer new opportunities to dissect such circuits ...via whole-brain imaging, behavioral analysis, functional perturbations, and network modeling. Here, we harness these tools to generate a brain-scale circuit model of the optomotor response, an orienting behavior evoked by visual motion. We show that such motion is processed by diverse neural response types distributed across multiple brain regions. To transform sensory input into action, these regions sequentially integrate eye- and direction-specific sensory streams, refine representations via interhemispheric inhibition, and demix locomotor instructions to independently drive turning and forward swimming. While experiments revealed many neural response types throughout the brain, modeling identified the dimensions of functional connectivity most critical for the behavior. We thus reveal how distributed neurons collaborate to generate behavior and illustrate a paradigm for distilling functional circuit models from whole-brain data.
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•Optomotor response is driven asymmetrically by visual motion to each eye•Dedicated circuits differentially process eye- and direction-specific motion•Neural representations are distributed over select overrepresented response types•Behavior and neural activity are captured by realistic whole-brain circuit model
Whole-brain imaging and behavioral analysis combined with network modeling reveal key circuit elements contributing to a complex sensorimotor behavior in zebrafish larvae and provide a framework for building brain-level circuit models.
Two recent emerging trends are that of Web 2.0, where users actively create content and publish it on the Web, and also location awareness, where a digital device utilizes a person's physical ...location as the context to provide specific services and/or information. This paper examines how these two phenomena can be brought together so that user‐generated content on mobile devices is used to provide informal learning opportunities relevant to a person's location. However, the generative process of such media does not always have much guidance on how or what to create, so the quality of such information can be highly variable. To overcome this, a framework has been designed to guide the authoring of user‐generated content so that it can be used for informal learning about one's immediate surroundings (particularly in an outdoor setting), combining pedagogical aspects with those from human–computer interaction and environmental aesthetics. The framework consists of six dimensions that include aspects such as curriculum area (e.g. science, art), type of communication, use of language/media related to the landscape, knowledge level of content, contextual aspects, and types of interaction. In order to test the framework before it could be used to scaffold new content, it was first used to analyse and evaluate over 200 items of existing user‐generated content, to investigate the appropriateness of the proposed dimensions and the items contained therein or if any were missing. This paper presents the findings of this initial testing phase, together with a discussion of how the framework can be improved, in order to help scaffold the creation of new user‐generated content in the future.
In order to localize the neural circuits involved in generating behaviors, it is necessary to assign activity onto anatomical maps of the nervous system. Using brain registration across hundreds of ...larval zebrafish, we have built an expandable open-source atlas containing molecular labels and definitions of anatomical regions, the Z-Brain. Using this platform and immunohistochemical detection of phosphorylated extracellular signal–regulated kinase (ERK) as a readout of neural activity, we have developed a system to create and contextualize whole-brain maps of stimulus- and behavior-dependent neural activity. This mitogen-activated protein kinase (MAP)-mapping assay is technically simple, and data analysis is completely automated. Because MAP-mapping is performed on freely swimming fish, it is applicable to studies of nearly any stimulus or behavior. Here we demonstrate our high-throughput approach using pharmacological, visual and noxious stimuli, as well as hunting and feeding. The resultant maps outline hundreds of areas associated with behaviors.
Abstract Consumption beyond homeostatic needs, referred to here as reward-based feeding behavior, is a central contributor to the current obesity epidemic worldwide. Importantly, reward-based feeding ...can be driven by palatability, the taste and texture of the food, as well as cues associated with the consumption of palatable foods. The hypothalamic orexin system regulates both diet preference and anticipation of food rewards making it a likely target to modulate reward-based feeding behavior. In the current manuscript we hypothesized that orexin signaling mediates food-motivated behaviors and reward-based feeding behavior. We further hypothesized that orexin neurons and targets of the orexin system become activated in response to cues associated with the consumption of palatable food. Data from these studies suggest that orexin signaling promotes progressive ratio responding for palatable foods while blockade of orexin signaling attenuates reward-based feeding of a high fat diet. In addition, cues linked to the consumption of chocolate, or the receipt of a daily meal, activate the orexin system and its target regions differentially. Collectively, these data suggest that orexin signaling mediates reward-based feeding behavior and, within specific target regions, may regulate cue-induced overconsumption of palatable foods.
Optical approaches for tracking neural dynamics are of widespread interest, but a theoretical framework quantifying the physical limits of these techniques has been lacking. We formulate such a ...framework by using signal detection and estimation theory to obtain physical bounds on the detection of neural spikes and the estimation of their occurrence times as set by photon counting statistics (shot noise). These bounds are succinctly expressed via a discriminability index that depends on the kinetics of the optical indicator and the relative fluxes of signal and background photons. This approach facilitates quantitative evaluations of different indicators, detector technologies, and data analyses. Our treatment also provides optimal filtering techniques for optical detection of spikes. We compare various types of Ca2+ indicators and show that background photons are a chief impediment to voltage sensing. Thus, voltage indicators that change color in response to membrane depolarization may offer a key advantage over those that change intensity. We also examine fluorescence resonance energy transfer indicators and identify the regimes in which the widely used ratiometric analysis of signals is substantially suboptimal. Overall, by showing how different optical factors interact to affect signal quality, our treatment offers a valuable guide to experimental design and provides measures of confidence to assess optically extracted traces of neural activity.
Most isolates of human rhinovirus, the common cold virus, replicate more robustly at the cool temperatures found in the nasal cavity (33–35 °C) than at core body temperature (37 °C). To gain insight ...into the mechanism of temperature-dependent growth, we compared the transcriptional response of primary mouse airway epithelial cells infected with rhinovirus at 33 °C vs. 37 °C. Mouse airway cells infected with mouse-adapted rhinovirus 1B exhibited a striking enrichment in expression of antiviral defense response genes at 37 °C relative to 33 °C, which correlated with significantly higher expression levels of type I and type III IFN genes and IFN-stimulated genes (ISGs) at 37 °C. Temperature-dependent IFN induction in response to rhinovirus was dependent on the MAVS protein, a key signaling adaptor of the RIG-I–like receptors (RLRs). Stimulation of primary airway cells with the synthetic RLR ligand poly I:C led to greater IFN induction at 37 °C relative to 33 °C at early time points poststimulation and to a sustained increase in the induction of ISGs at 37 °C relative to 33 °C. Recombinant type I IFN also stimulated more robust induction of ISGs at 37 °C than at 33 °C. Genetic deficiency of MAVS or the type I IFN receptor in infected airway cells permitted higher levels of viral replication, particularly at 37 °C, and partially rescued the temperature-dependent growth phenotype. These findings demonstrate that in mouse airway cells, rhinovirus replicates preferentially at nasal cavity temperature due, in part, to a less efficient antiviral defense response of infected cells at cool temperature.
Significance Rhinovirus is the most frequent cause of the common cold, as well as one of the most important causes of asthma exacerbations. Most rhinovirus strains replicate better at the cooler temperatures found in the nasal cavity than at lung temperature, but the underlying mechanisms are not known. Using a mouse-adapted virus, we found that airway epithelial cells supporting rhinovirus replication initiate a more robust antiviral defense response through RIG-I–like receptor (RLR)–dependent interferon secretion and enhanced interferon responsiveness at lung temperature vs. nasal cavity temperature. Airway cells with genetic deficiencies in RLR or type I interferon receptor signaling supported much higher levels of viral replication at 37 °C. Thus, cooler temperatures can enable replication of the common cold virus, at least in part, by diminishing antiviral immune responses.
Abstract Data from our laboratory indicate that the orexin system is involved in the regulation of both conditioned and unconditioned responding for palatable foods. Anticipation of food rewards ...activates orexin receptor containing neurons within the paraventricular nucleus of the thalamus (PVT). The PVT regulates mesolimbic dopamine neurochemistry through direct connections with the nucleus accumbens and modulates the processing of cognitive-emotional information, suggesting that the PVT may represent a unique brain region with the capacity to mediate orexinergic effects on brain dopamine and behavior. Here, we tested the hypothesis that PVT orexin signaling mediates mesolimbic dopamine and reward-based feeding. To do this we used a behavioral pharmacological approach in tandem with central genetic manipulation of the orexin-1 receptor in the PVT. Data from these studies indicate that orexin-A action in the PVT increases dopamine levels in the nucleus accumbens. In addition, endogenous orexin signaling in the PVT mediates locomotor activity and hedonic feeding responses. Together these data highlight the PVT as a critical site capable of mediating orexin action on brain dopamine and reward-based feeding.
All animals must transform ambiguous sensory data into successful behavior. This requires sensory representations that accurately reflect the statistics of natural stimuli and behavior. Multiple ...studies show that visual motion processing is tuned for accuracy under naturalistic conditions, but the sensorimotor circuits extracting these cues and implementing motion-guided behavior remain unclear. Here we show that the larval zebrafish retina extracts a diversity of naturalistic motion cues, and the retinorecipient pretectum organizes these cues around the elements of behavior. We find that higher-order motion stimuli, gliders, induce optomotor behavior matching expectations from natural scene analyses. We then image activity of retinal ganglion cell terminals and pretectal neurons. The retina exhibits direction-selective responses across glider stimuli, and anatomically clustered pretectal neurons respond with magnitudes matching behavior. Peripheral computations thus reflect natural input statistics, whereas central brain activity precisely codes information needed for behavior. This general principle could organize sensorimotor transformations across animal species.
•Higher-order glider motion stimuli elicit optomotor responses in larval zebrafish•Gliders recruit brain-wide activity lateralized by the induced turning direction•Direction-selective retinal ganglion cells respond directionally to glider stimuli•Behavioral patterns precisely predict neuronal response magnitudes in pretectum
Glider stimuli connect motion estimation algorithms to higher-order statistics of natural visual environments. Yildizoglu et al. use behavior and brain-wide imaging to show that gliders induce optomotor responses in larval zebrafish, with multiple visual processing stages extracting motion cues and organizing them by their behavioral relevance.
‘Global surgery’ is the term adopted to describe a rapidly developing multidisciplinary field aiming to provide improved and equitable surgical care across international health systems. Sitting at ...the interface between numerous clinical and non-clinical specialisms, it encompasses multiple aspects that surround the treatment of surgical disease and its equitable provision across health systems globally. From defining the role of, and need for, optimal surgical care through to identifying barriers and implementing improvement, global surgery has an expansive remit. Advocacy, education, research and clinical components can all involve surgeons, anaesthetists, nurses and allied healthcare professionals working together with non-clinicians, including policy makers, epidemiologists and economists. Long neglected as a topic within the global and public health arenas, an increasing awareness of the extreme disparities internationally has driven greater engagement. Not necessarily restricted to specific diseases, populations or geographical regions, these disparities have led to a particular focus on surgical care in low-income and middle-income countries with the greatest burden and needs. This review considers the major factors defining the interface between surgery, anaesthesia and public health in these settings.
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