Victor Veitch, Daniel M. Roy.

Source: The Annals of Statistics, Volume 47, Number 6, 3274--3299.

Abstract:
Sparse exchangeable graphs on $mathbb{R}_{+}$, and the associated graphex framework for sparse graphs, generalize exchangeable graphs on $mathbb{N}$, and the associated graphon framework for dense graphs. We develop the graphex framework as a tool for statistical network analysis by identifying the sampling scheme that is naturally associated with the models of the framework, formalizing two natural notions of consistent estimation of the parameter (the graphex) underlying these models, and identifying general consistent estimators in each case. The sampling scheme is a modification of independent vertex sampling that throws away vertices that are isolated in the sampled subgraph. The estimators are variants of the empirical graphon estimator, which is known to be a consistent estimator for the distribution of dense exchangeable graphs; both can be understood as graph analogues to the empirical distribution in the i.i.d. sequence setting. Our results may be viewed as a generalization of consistent estimation via the empirical graphon from the dense graph regime to also include sparse graphs.

Zhenguo Gao, Pang Du, Ran Jin, John L. Robertson.

Source: The Annals of Applied Statistics, Volume 14, Number 1, 143--159.

Abstract:
Liver procurement experiments with surface-temperature monitoring motivated Gao et al. ( J. Amer. Statist. Assoc. 114 (2019) 773–781) to develop a variance change-point detection method under a smoothly-changing mean trend. However, the spotwise change points yielded from their method do not offer immediate information to surgeons since an organ is often transplanted as a whole or in part. We develop a new practical method that can analyze a defined portion of the organ surface at a time. It also provides a novel addition to the developing field of functional data monitoring. Furthermore, numerical challenge emerges for simultaneously modeling the variance functions of 2D locations and the mean function of location and time. The respective sample sizes in the scales of 10,000 and 1,000,000 for modeling these functions make standard spline estimation too costly to be useful. We introduce a multistage subsampling strategy with steps educated by quickly-computable preliminary statistical measures. Extensive simulations show that the new method can efficiently reduce the computational cost and provide reasonable parameter estimates. Application of the new method to our liver surface temperature monitoring data shows its effectiveness in providing accurate status change information for a selected portion of the organ in the experiment.

Hongbin Zhang, Lang Wu.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2140--2157.

Abstract:
For a time-to-event outcome with censored time-varying covariates, a joint Cox model with a linear mixed effects model is the standard modeling approach. In some applications such as AIDS studies, mechanistic nonlinear models are available for some covariate process such as viral load during anti-HIV treatments, derived from the underlying data-generation mechanisms and disease progression. Such a mechanistic nonlinear covariate model may provide better-predicted values when the covariates are left censored or mismeasured. When the focus is on the impact of the time-varying covariate process on the survival outcome, an accelerated failure time (AFT) model provides an excellent alternative to the Cox proportional hazard model since an AFT model is formulated to allow the influence of the outcome by the entire covariate process. In this article, we consider a nonlinear mixed effects model for the censored covariates in an AFT model, implemented using a Monte Carlo EM algorithm, under the framework of a joint model for simultaneous inference. We apply the joint model to an HIV/AIDS data to gain insights for assessing the association between viral load and immunological restoration during antiretroviral therapy. Simulation is conducted to compare model performance when the covariate model and the survival model are misspecified.

Jeng-Min Chiou, Yu-Ting Chen, Tailen Hsing.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1430--1463.

Abstract:
Motivated by the study of road segmentation partitioned by shifts in traffic conditions along a freeway, we introduce a two-stage procedure, Dynamic Segmentation and Backward Elimination (DSBE), for identifying multiple changes in the mean functions for a sequence of functional data. The Dynamic Segmentation procedure searches for all possible changepoints using the derived global optimality criterion coupled with the local strategy of at-most-one-changepoint by dividing the entire sequence into individual subsequences that are recursively adjusted until convergence. Then, the Backward Elimination procedure verifies these changepoints by iteratively testing the unlikely changes to ensure their significance until no more changepoints can be removed. By combining the local strategy with the global optimal changepoint criterion, the DSBE algorithm is conceptually simple and easy to implement and performs better than the binary segmentation-based approach at detecting small multiple changes. The consistency property of the changepoint estimators and the convergence of the algorithm are proved. We apply DSBE to detect changes in traffic streams through real freeway traffic data. The practical performance of DSBE is also investigated through intensive simulation studies for various scenarios.

Jorge A. León.

Source: Bernoulli, Volume 26, Number 3, 2436--2462.

Abstract:
Let $B^{H}$ be a fractional Brownian motion with Hurst parameter $Hin (0,1/2)$ and $p:mathbb{R} ightarrow mathbb{R}$ a polynomial function. The main purpose of this paper is to introduce a Stratonovich type stochastic integral with respect to $B^{H}$, whose domain includes the process $p(B^{H})$. That is, an integral that allows us to integrate $p(B^{H})$ with respect to $B^{H}$, which does not happen with the symmetric integral given by Russo and Vallois ( Probab. Theory Related Fields 97 (1993) 403–421) in general. Towards this end, we combine the approaches utilized by León and Nualart ( Stochastic Process. Appl. 115 (2005) 481–492), and Russo and Vallois ( Probab. Theory Related Fields 97 (1993) 403–421), whose aims are to extend the domain of the divergence operator for Gaussian processes and to define some stochastic integrals, respectively. Then, we study the relation between this Stratonovich integral and the extension of the divergence operator (see León and Nualart ( Stochastic Process. Appl. 115 (2005) 481–492)), an Itô formula and the existence of a unique solution of some Stratonovich stochastic differential equations. These last results have been analyzed by Alòs, León and Nualart ( Taiwanese J. Math. 5 (2001) 609–632), where the Hurst paramert $H$ belongs to the interval $(1/4,1/2)$.

Grant (Family)

Klemm (Family)

King's Orphan Schools (New Town, Tas.)

Traeger, Ernst Wilhelm, 1805-1874.

Huppatz (Family).

Boeing CEO Dave Calhoun said the company was aiming to resume production this month, despite the ongoing grounding and coronavirus pandemic.

Barack Obama said the “rule of law is at risk” following the justice department’s decision to drop charges against former Trump advisor Mike Flynn, as he issued a stark warning about the long-term impact on the American way of life by his successor.

Jong Hee Park, Yunkyu Sohn.

Source: Bayesian Analysis, Volume 15, Number 1, 133--157.

Abstract:
Dynamic modeling of longitudinal networks has been an increasingly important topic in applied research. While longitudinal network data commonly exhibit dramatic changes in its structures, existing methods have largely focused on modeling smooth topological changes over time. In this paper, we develop a hidden Markov network change-point model (HNC) that combines the multilinear tensor regression model (Hoff, 2011) with a hidden Markov model using Bayesian inference. We model changes in network structure as shifts in discrete states yielding particular sets of network generating parameters. Our simulation results demonstrate that the proposed method correctly detects the number, locations, and types of changes in latent node characteristics. We apply the proposed method to international military alliance networks to find structural changes in the coalition structure among nations.

Stefano Peluso, Siddhartha Chib, Antonietta Mira.

Source: Bayesian Analysis, Volume 14, Number 3, 727--751.

Abstract:
We develop a general Bayesian semiparametric change-point model in which separate groups of structural parameters (for example, location and dispersion parameters) can each follow a separate multiple change-point process, driven by time-dependent transition matrices among the latent regimes. The distribution of the observations within regimes is unknown and given by a Dirichlet process mixture prior. The properties of the proposed model are studied theoretically through the analysis of inter-arrival times and of the number of change-points in a given time interval. The prior-posterior analysis by Markov chain Monte Carlo techniques is developed on a forward-backward algorithm for sampling the various regime indicators. Analysis with simulated data under various scenarios and an application to short-term interest rates are used to show the generality and usefulness of the proposed model.

Roderick J. Little.

Source: Statistical Science, Volume 34, Number 4, 580--583.

Eitan Greenshtein, Ya’acov Ritov.

Source: Statistical Science, Volume 34, Number 2, 224--228.

Abstract:
We present some personal reflections on empirical Bayes/ compound decision (EB/CD) theory following Efron (2019). In particular, we consider the role of exchangeability in the EB/CD theory and how it can be achieved when there are covariates. We also discuss the interpretation of EB/CD confidence interval, the theoretical efficiency of the CD procedure, and the impact of sparsity assumptions.

London (33 Stillness Rd, London, SE23 1NG) : Cleanair, Campaign for a Smoke-free Environment, [198-?]

London (33 Stillness Rd, London, SE23 1NG) : Cleanair, Campaign for a Smoke-free Environment, [198-?]

London : Cleanair, [1988?]

London (33 Stillness Rd, London, SE23 1NG) : Cleanair, Campaign for a Smoke-free Environment, [198-?]

Elisa Filevich
Jan 21, 2015; 35:1082-1088
BehavioralSystemsCognitive

Timothy J. Schoenfeld
May 1, 2013; 33:7770-7777
BehavioralSystemsCognitive

Vinod Venkatraman
Mar 9, 2011; 31:3712-3718
BehavioralSystemsCognitive

Peter M. Zygmunt
Jun 1, 2002; 22:4720-4727
Behavioral

Stefan Klöppel
Mar 3, 2010; 30:3271-3275
BRIEF COMMUNICATION

Fabrizio Benedetti
Nov 9, 2005; 25:10390-10402
Symposia and Mini-Symposia

Stephanie McMains
Jan 12, 2011; 31:587-597
BehavioralSystemsCognitive

Earl K. Miller
Aug 15, 1996; 16:5154-5167
Articles

RU Muller
Jul 1, 1987; 7:1951-1968
Articles

P Seguela
Feb 1, 1993; 13:596-604
Articles

Zhengui Xia
Sep 1, 1996; 16:5425-5436
Articles

Merchants soon will be able to sell products on Google Shopping at no charge. Previously, they had to pay per click, but the cost was not fixed. There was no minimum, but they had to set a maximum for ad spend and Google would stop displaying their ads once the maximum was reached. Starting next week, search results on the Google Shopping tab will consist primarily of free product listings.

Op-ed by Mr Agustín Carstens, General Manager of the BIS, published in The Business Times Singapore, 13 November 2019.

During differentiation, oligodendrocyte precursor cells (OPCs) extend a network of processes that make contact with axons and initiate myelination. Recent studies revealed that actin polymerization is required for initiation of myelination whereas actin depolymerization promotes myelin wrapping. Here, we used primary OPCs in culture isolated from neonatal rat cortices of both sexes and young male and female mice with oligodendrocyte-specific deletion of mechanistic target of rapamycin (mTOR) to demonstrate that mTOR regulates expression of specific cytoskeletal targets and actin reorganization in oligodendrocytes during developmental myelination. Loss or inhibition of mTOR reduced expression of profilin2 and ARPC3, actin polymerizing factors, and elevated levels of active cofilin, which mediates actin depolymerization. The deficits in actin polymerization were revealed in reduced phalloidin and deficits in oligodendrocyte cellular branching complexity at the peak of morphologic differentiation and a delay in initiation of myelination. We further show a critical role for mTOR in expression and localization of myelin basic protein (Mbp) mRNA and MBP protein to the cellular processes where it is necessary at the myelin membrane for axon wrapping. Mbp mRNA transport deficits were confirmed by single molecule RNA FISH. Moreover, expression of the kinesin family member 1B, an Mbp mRNA transport protein, was reduced in CC1+ cells in the mTOR cKO and in mTOR inhibited oligodendrocytes undergoing differentiation in vitro. These data support the conclusion that mTOR regulates both initiation of myelination and axon wrapping by targeting cytoskeletal reorganization and MBP localization to oligodendrocyte processes.

SIGNIFICANCE STATEMENT Myelination is essential for normal CNS development and adult axon preservation and function. The mechanistic target of rapamycin (mTOR) signaling pathway has been implicated in promoting CNS myelination; however, there is a gap in our understanding of the mechanisms by which mTOR promotes developmental myelination through regulating specific downstream targets. Here, we present evidence that mTOR promotes the initiation of myelination through regulating specific cytoskeletal targets and cellular process expansion by oligodendrocyte precursor cells as well as expression and cellular localization of myelin basic protein.

The detection and segmentation of meaningful figures from their background is one of the primary functions of vision. While work in nonhuman primates has implicated early visual mechanisms in this figure–ground modulation, neuroimaging in humans has instead largely ascribed the processing of figures and objects to higher stages of the visual hierarchy. Here, we used high-field fMRI at 7 Tesla to measure BOLD responses to task-irrelevant orientation-defined figures in human early visual cortex (N = 6, four females). We used a novel population receptive field mapping-based approach to resolve the spatial profiles of two constituent mechanisms of figure–ground modulation: a local boundary response, and a further enhancement spanning the full extent of the figure region that is driven by global differences in features. Reconstructing the distinct spatial profiles of these effects reveals that figure enhancement modulates responses in human early visual cortex in a manner consistent with a mechanism of automatic, contextually driven feedback from higher visual areas.

SIGNIFICANCE STATEMENT A core function of the visual system is to parse complex 2D input into meaningful figures. We do so constantly and seamlessly, both by processing information about visible edges and by analyzing large-scale differences between figure and background. While influential neurophysiology work has characterized an intriguing mechanism that enhances V1 responses to perceptual figures, we have a poor understanding of how the early visual system contributes to figure–ground processing in humans. Here, we use advanced computational analysis methods and high-field human fMRI data to resolve the distinct spatial profiles of local edge and global figure enhancement in the early visual system (V1 and LGN); the latter is distinct and consistent with a mechanism of automatic, stimulus-driven feedback from higher-level visual areas.

Neural plasticity due to hearing loss results in tonotopic map changes. Several studies have suggested a relation between hearing loss-induced tonotopic reorganization and tinnitus. This large fMRI study on humans was intended to clarify the relations between hearing loss, tinnitus, and tonotopic reorganization. To determine the differential effect of hearing loss and tinnitus, both male and female participants with bilateral high-frequency hearing loss, with and without tinnitus, and a control group were included. In a total of 90 participants, bilateral cortical responses to sound stimulation were measured with loudness-matched pure-tone stimuli (0.25-8 kHz). In the bilateral auditory cortices, the high-frequency sound-evoked activation level was higher in both hearing-impaired participant groups, compared with the control group. This was most prominent in the hearing loss group without tinnitus. Similarly, the tonotopic maps for the hearing loss without tinnitus group were significantly different from the controls, whereas the maps of those with tinnitus were not. These results show that higher response amplitudes and map reorganization are a characteristic of hearing loss, not of tinnitus. Both tonotopic maps and response amplitudes of tinnitus participants appear intermediate to the controls and hearing loss without tinnitus group. This observation suggests a connection between tinnitus and an incomplete form of central compensation to hearing loss, rather than excessive adaptation. One implication of this may be that treatments for tinnitus shift their focus toward enhancing the cortical plasticity, instead of reversing it.

SIGNIFICANCE STATEMENT Tinnitus, a common and potentially devastating condition, is the presence of a "phantom" sound that often accompanies hearing loss. Hearing loss is known to induce plastic changes in cortical and subcortical areas. Although plasticity is a valuable trait that allows the human brain to rewire and recover from injury and sensory deprivation, it can lead to tinnitus as an unwanted side effect. In this large fMRI study, we provide evidence that tinnitus is related to a more conservative form of reorganization than in hearing loss without tinnitus. This result contrasts with the previous notion that tinnitus is related to excessive reorganization. As a consequence, treatments for tinnitus may need to enhance the cortical plasticity, rather than reverse it.

Phototransduction in Drosophila is mediated by phospholipase C (PLC) and Ca²⁺-permeable TRP channels, but the function of endoplasmic reticulum (ER) Ca²⁺ stores in this important model for Ca²⁺ signaling remains obscure. We therefore expressed a low affinity Ca²⁺ indicator (ER-GCaMP6-150) in the ER, and measured its fluorescence both in dissociated ommatidia and in vivo from intact flies of both sexes. Blue excitation light induced a rapid (tau ~0.8 s), PLC-dependent decrease in fluorescence, representing depletion of ER Ca²⁺ stores, followed by a slower decay, typically reaching ~50% of initial dark-adapted levels, with significant depletion occurring under natural levels of illumination. The ER stores refilled in the dark within 100–200 s. Both rapid and slow store depletion were largely unaffected in InsP₃ receptor mutants, but were much reduced in trp mutants. Strikingly, rapid (but not slow) depletion of ER stores was blocked by removing external Na⁺ and in mutants of the Na⁺/Ca²⁺ exchanger, CalX, which we immuno-localized to ER membranes in addition to its established localization in the plasma membrane. Conversely, overexpression of calx greatly enhanced rapid depletion. These results indicate that rapid store depletion is mediated by Na⁺/Ca²⁺ exchange across the ER membrane induced by Na⁺ influx via the light-sensitive channels. Although too slow to be involved in channel activation, this Na⁺/Ca²⁺ exchange-dependent release explains the decades-old observation of a light-induced rise in cytosolic Ca²⁺ in photoreceptors exposed to Ca²⁺-free solutions.

SIGNIFICANCE STATEMENT Phototransduction in Drosophila is mediated by phospholipase C, which activates TRP cation channels by an unknown mechanism. Despite much speculation, it is unknown whether endoplasmic reticulum (ER) Ca²⁺ stores play any role. We therefore engineered flies expressing a genetically encoded Ca²⁺ indicator in the photoreceptor ER. Although NCX Na⁺/Ca²⁺ exchangers are classically believed to operate only at the plasma membrane, we demonstrate a rapid light-induced depletion of ER Ca²⁺ stores mediated by Na⁺/Ca²⁺ exchange across the ER membrane. This NCX-dependent release was too slow to be involved in channel activation, but explains the decades-old observation of a light-induced rise in cytosolic Ca²⁺ in photoreceptors bathed in Ca²⁺-free solutions.

Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABA_A receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca²⁺ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABA_ARs synapses through a GABA receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.

SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca²⁺-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABA_A receptor synapses via Ca²⁺/calmodulin-dependent protein kinase II. Although Ca²⁺ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.

To determine whether Cav1.2 voltage-gated Ca²⁺ channels contribute to astrocyte activation, we generated an inducible conditional knock-out mouse in which the Cav1.2 α subunit was deleted in GFAP-positive astrocytes. This astrocytic Cav1.2 knock-out mouse was tested in the cuprizone model of myelin injury and repair which causes astrocyte and microglia activation in the absence of a lymphocytic response. Deletion of Cav1.2 channels in GFAP-positive astrocytes during cuprizone-induced demyelination leads to a significant reduction in the degree of astrocyte and microglia activation and proliferation in mice of either sex. Concomitantly, the production of proinflammatory factors such as TNFα, IL1β and TGFβ1 was significantly decreased in the corpus callosum and cortex of Cav1.2 knock-out mice through demyelination. Furthermore, this mild inflammatory environment promotes oligodendrocyte progenitor cells maturation and myelin regeneration across the remyelination phase of the cuprizone model. Similar results were found in animals treated with nimodipine, a Cav1.2 Ca²⁺ channel inhibitor with high affinity to the CNS. Mice of either sex injected with nimodipine during the demyelination stage of the cuprizone treatment displayed a reduced number of reactive astrocytes and showed a faster and more efficient brain remyelination. Together, these results indicate that Cav1.2 Ca²⁺ channels play a crucial role in the induction and proliferation of reactive astrocytes during demyelination; and that attenuation of astrocytic voltage-gated Ca²⁺ influx may be an effective therapy to reduce brain inflammation and promote myelin recovery in demyelinating diseases.

SIGNIFICANCE STATEMENT Reducing voltage-gated Ca²⁺ influx in astrocytes during brain demyelination significantly attenuates brain inflammation and astrocyte reactivity. Furthermore, these changes promote myelin restoration and oligodendrocyte maturation throughout remyelination.

As an important cognitive bias, the framing effect shows that our decision preferences are sensitive to the verbal description (i.e., frame) of options. This study focuses on the neural underpinnings of the social framing effect, which is based on decision-making regarding other people. A novel paradigm was used in which participants made a trade-off between economic benefits and the feelings of others. This decision was described as either a "harm" to, or "not helping," other persons in two conditions (Harm frame vs Help frame). Both human males and females were recruited. Participants behaved more prosocially for Harm frame compared with Help frame, resulting in a significant social framing effect. Using functional magnetic resonance imaging, Experiment 1 showed that the social framing effect was associated with stronger activation in the temporoparietal junction (TPJ), especially its right part. The functional connectivity between the right TPJ (rTPJ) and medial prefrontal cortex predicted the social framing effect on the group level. In Experiment 2, we used transcranial direct current stimulation to modulate the activity of the rTPJ and found that the social framing effect became more prominent under anodal (excitatory) stimulation, while the nonsocial framing effect elicited by the economic gain/loss gambling frame remained unaffected. The rTPJ results might be associated with moral conflicts modulated by the social consequences of an action or different levels of mentalizing with others under different frame conditions, but alternative interpretations are also worth noting. These findings could help elucidate the psychological mechanisms of the social framing effect.

SIGNIFICANCE STATEMENT Previous studies have suggested that the framing effect is generated from an interaction between the amygdala and anterior cingulate cortex. This opinion, however, is based on findings from nonsocial framing tasks. Recent research has highlighted the importance of distinguishing between the social and nonsocial framing effects. The current study focuses on the social framing effect and finds out that the temporoparietal junction and its functional connectivity with the medial prefrontal cortex play a significant role. Additionally, modulating the activity of this region leads to changes in social (but not nonsocial) framing effect. Broadly speaking, these findings help understand the difference in neural mechanisms between social and nonsocial decision-making. Meanwhile, they might be illuminating to promote helping behavior in society.

Reward has a remarkable ability to invigorate motor behavior, enabling individuals to select and execute actions with greater precision and speed. However, if reward is to be exploited in applied settings, such as rehabilitation, a thorough understanding of its underlying mechanisms is required. In a series of experiments, we first demonstrate that reward simultaneously improves the selection and execution components of a reaching movement. Specifically, reward promoted the selection of the correct action in the presence of distractors, while also improving execution through increased speed and maintenance of accuracy. These results led to a shift in the speed-accuracy functions for both selection and execution. In addition, punishment had a similar impact on action selection and execution, although it enhanced execution performance across all trials within a block, that is, its impact was noncontingent to trial value. Although the reward-driven enhancement of movement execution has been proposed to occur through enhanced feedback control, an untested possibility is that it is also driven by increased arm stiffness, an energy-consuming process that enhances limb stability. Computational analysis revealed that reward led to both an increase in feedback correction in the middle of the movement and a reduction in motor noise near the target. In line with our hypothesis, we provide novel evidence that this noise reduction is driven by a reward-dependent increase in arm stiffness. Therefore, reward drives multiple error-reduction mechanisms which enable individuals to invigorate motor performance without compromising accuracy.

SIGNIFICANCE STATEMENT While reward is well-known for enhancing motor performance, how the nervous system generates these improvements is unclear. Despite recent work indicating that reward leads to enhanced feedback control, an untested possibility is that it also increases arm stiffness. We demonstrate that reward simultaneously improves the selection and execution components of a reaching movement. Furthermore, we show that punishment has a similar positive impact on performance. Importantly, by combining computational and biomechanical approaches, we show that reward leads to both improved feedback correction and an increase in stiffness. Therefore, reward drives multiple error-reduction mechanisms which enable individuals to invigorate performance without compromising accuracy. This work suggests that stiffness control plays a vital, and underappreciated, role in the reward-based imporvemenets in motor control.

Structural plasticity of dendritic spines is a key component of the refinement of synaptic connections during learning. Recent studies highlight a novel role for the NMDA receptor (NMDAR), independent of ion flow, in driving spine shrinkage and LTD. Yet little is known about the molecular mechanisms that link conformational changes in the NMDAR to changes in spine size and synaptic strength. Here, using two-photon glutamate uncaging to induce plasticity at individual dendritic spines on hippocampal CA1 neurons from mice and rats of both sexes, we demonstrate that p38 MAPK is generally required downstream of non-ionotropic NMDAR signaling to drive both spine shrinkage and LTD. In a series of pharmacological and molecular genetic experiments, we identify key components of the non-ionotropic NMDAR signaling pathway driving dendritic spine shrinkage, including the interaction between NOS1AP (nitric oxide synthase 1 adaptor protein) and neuronal nitric oxide synthase (nNOS), nNOS enzymatic activity, activation of MK2 (MAPK-activated protein kinase 2) and cofilin, and signaling through CaMKII. Our results represent a large step forward in delineating the molecular mechanisms of non-ionotropic NMDAR signaling that can drive shrinkage and elimination of dendritic spines during synaptic plasticity.

SIGNIFICANCE STATEMENT Signaling through the NMDA receptor (NMDAR) is vitally important for the synaptic plasticity that underlies learning. Recent studies highlight a novel role for the NMDAR, independent of ion flow, in driving synaptic weakening and dendritic spine shrinkage during synaptic plasticity. Here, we delineate several key components of the molecular pathway that links conformational signaling through the NMDAR to dendritic spine shrinkage during synaptic plasticity.

International Kungfu superstar and renowned Hollywood film actor Jackie Chan has joined FAO in the fight against hunger. In a recent visit to Ethiopia, Chan met with beneficiaries of the ‘Purchase from Africans for Africa’ (PAA) project as well as a South-South Cooperation Programme where he discussed with Chinese experts how they exchange technical knowledge with Ethiopian farmers to help them [...]

Today leading international experts on climate change, the IPCC, presented their latest report on the impacts of climate change on humanity, and what we can do about it. It’s a lengthy report, so we’ve shrunk it down to Oxfam's five key takeaways on climate change and hunger. 1. Climate change: the impacts on crops are worse than we thought Climate change has [...]

‘‘—the first 1000 days are a critical window in a child’s development, but let’s not forget this child on day 1,001.’’ School nutrition programmes help to address the +1,001 day gap. Today, perceptions of school gardens are changing in response to increasingly urgent needs for greater food security, environmental protection, more secure livelihoods and better nutrition. School gardens have new multiple [...]