Stephen M. S. Lee, Puyudi Yang.

Source: The Annals of Statistics, Volume 48, Number 1, 274--299.

Abstract:
Suppose that a confidence region is desired for a subvector $ heta $ of a multidimensional parameter $xi =( heta ,psi )$, based on an M-estimator $hat{xi }_{n}=(hat{ heta }_{n},hat{psi }_{n})$ calculated from a random sample of size $n$. Under nonstandard conditions $hat{xi }_{n}$ often converges at a nonregular rate $r_{n}$, in which case consistent estimation of the distribution of $r_{n}(hat{ heta }_{n}- heta )$, a pivot commonly chosen for confidence region construction, is most conveniently effected by the $m$ out of $n$ bootstrap. The above choice of pivot has three drawbacks: (i) the shape of the region is either subjectively prescribed or controlled by a computationally intensive depth function; (ii) the region is not transformation equivariant; (iii) $hat{xi }_{n}$ may not be uniquely defined. To resolve the above difficulties, we propose a one-dimensional pivot derived from the criterion function, and prove that its distribution can be consistently estimated by the $m$ out of $n$ bootstrap, or by a modified version of the perturbation bootstrap. This leads to a new method for constructing confidence regions which are transformation equivariant and have shapes driven solely by the criterion function. A subsampling procedure is proposed for selecting $m$ in practice. Empirical performance of the new method is illustrated with examples drawn from different nonstandard M-estimation settings. Extension of our theory to row-wise independent triangular arrays is also explored.

John Goes, Gilad Lerman, Boaz Nadler.

Source: The Annals of Statistics, Volume 48, Number 1, 86--110.

Abstract:
Estimating a high-dimensional sparse covariance matrix from a limited number of samples is a fundamental task in contemporary data analysis. Most proposals to date, however, are not robust to outliers or heavy tails. Toward bridging this gap, in this work we consider estimating a sparse shape matrix from $n$ samples following a possibly heavy-tailed elliptical distribution. We propose estimators based on thresholding either Tyler’s M-estimator or its regularized variant. We prove that in the joint limit as the dimension $p$ and the sample size $n$ tend to infinity with $p/n ogamma>0$, our estimators are minimax rate optimal. Results on simulated data support our theoretical analysis.

Zhou Fan, Iain M. Johnstone.

Source: The Annals of Statistics, Volume 47, Number 5, 2855--2886.

Abstract:
We study the spectra of MANOVA estimators for variance component covariance matrices in multivariate random effects models. When the dimensionality of the observations is large and comparable to the number of realizations of each random effect, we show that the empirical spectra of such estimators are well approximated by deterministic laws. The Stieltjes transforms of these laws are characterized by systems of fixed-point equations, which are numerically solvable by a simple iterative procedure. Our proof uses operator-valued free probability theory, and we establish a general asymptotic freeness result for families of rectangular orthogonally invariant random matrices, which is of independent interest. Our work is motivated in part by the estimation of components of covariance between multiple phenotypic traits in quantitative genetics, and we specialize our results to common experimental designs that arise in this application.

Robert A. Vandermeulen, Clayton D. Scott.

Source: The Annals of Statistics, Volume 47, Number 5, 2704--2733.

Abstract:
When estimating finite mixture models, it is common to make assumptions on the mixture components, such as parametric assumptions. In this work, we make no distributional assumptions on the mixture components and instead assume that observations from the mixture model are grouped, such that observations in the same group are known to be drawn from the same mixture component. We precisely characterize the number of observations $n$ per group needed for the mixture model to be identifiable, as a function of the number $m$ of mixture components. In addition to our assumption-free analysis, we also study the settings where the mixture components are either linearly independent or jointly irreducible. Furthermore, our analysis considers two kinds of identifiability, where the mixture model is the simplest one explaining the data, and where it is the only one. As an application of these results, we precisely characterize identifiability of multinomial mixture models. Our analysis relies on an operator-theoretic framework that associates mixture models in the grouped-sample setting with certain infinite-dimensional tensors. Based on this framework, we introduce a general spectral algorithm for recovering the mixture components.

Qiyang Han, Jon A. Wellner.

Source: The Annals of Statistics, Volume 47, Number 4, 2286--2319.

Abstract:
We study the performance of the least squares estimator (LSE) in a general nonparametric regression model, when the errors are independent of the covariates but may only have a $p$th moment ($pgeq1$). In such a heavy-tailed regression setting, we show that if the model satisfies a standard “entropy condition” with exponent $alphain(0,2)$, then the $L_{2}$ loss of the LSE converges at a rate [mathcal{O}_{mathbf{P}}igl(n^{-frac{1}{2+alpha}}vee n^{-frac{1}{2}+frac{1}{2p}}igr).] Such a rate cannot be improved under the entropy condition alone. This rate quantifies both some positive and negative aspects of the LSE in a heavy-tailed regression setting. On the positive side, as long as the errors have $pgeq1+2/alpha$ moments, the $L_{2}$ loss of the LSE converges at the same rate as if the errors are Gaussian. On the negative side, if $p<1+2/alpha$, there are (many) hard models at any entropy level $alpha$ for which the $L_{2}$ loss of the LSE converges at a strictly slower rate than other robust estimators. The validity of the above rate relies crucially on the independence of the covariates and the errors. In fact, the $L_{2}$ loss of the LSE can converge arbitrarily slowly when the independence fails. The key technical ingredient is a new multiplier inequality that gives sharp bounds for the “multiplier empirical process” associated with the LSE. We further give an application to the sparse linear regression model with heavy-tailed covariates and errors to demonstrate the scope of this new inequality.

Trang Quynh Nguyen, Elizabeth A. Stuart.

Source: The Annals of Applied Statistics, Volume 14, Number 1, 518--520.

Li Zhu, Zhiguang Huo, Tianzhou Ma, Steffi Oesterreich, George C. Tseng.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2611--2636.

Abstract:
Variable selection is a pervasive problem in modern high-dimensional data analysis where the number of features often exceeds the sample size (a.k.a. small-n-large-p problem). Incorporation of group structure knowledge to improve variable selection has been widely studied. Here, we consider prior knowledge of a hierarchical overlapping group structure to improve variable selection in regression setting. In genomics applications, for instance, a biological pathway contains tens to hundreds of genes and a gene can be mapped to multiple experimentally measured features (such as its mRNA expression, copy number variation and methylation levels of possibly multiple sites). In addition to the hierarchical structure, the groups at the same level may overlap (e.g., two pathways can share common genes). Incorporating such hierarchical overlapping groups in traditional penalized regression setting remains a difficult optimization problem. Alternatively, we propose a Bayesian indicator model that can elegantly serve the purpose. We evaluate the model in simulations and two breast cancer examples, and demonstrate its superior performance over existing models. The result not only enhances prediction accuracy but also improves variable selection and model interpretation that lead to deeper biological insight of the disease.

Armin Schwartzman, Andrew J. Schork, Rong Zablocki, Wesley K. Thompson.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2509--2538.

Abstract:
Analysis of genome-wide association studies (GWAS) is characterized by a large number of univariate regressions where a quantitative trait is regressed on hundreds of thousands to millions of single-nucleotide polymorphism (SNP) allele counts, one at a time. This article proposes an estimator of the SNP heritability of the trait, defined here as the fraction of the variance of the trait explained by the SNPs in the study. The proposed GWAS heritability (GWASH) estimator is easy to compute, highly interpretable and is consistent as the number of SNPs and the sample size increase. More importantly, it can be computed from summary statistics typically reported in GWAS, not requiring access to the original data. The estimator takes full account of the linkage disequilibrium (LD) or correlation between the SNPs in the study through moments of the LD matrix, estimable from auxiliary datasets. Unlike other proposed estimators in the literature, we establish the theoretical properties of the GWASH estimator and obtain analytical estimates of the precision, allowing for power and sample size calculations for SNP heritability estimates and forming a firm foundation for future methodological development.

Ningshan Zhang, Kyle Schmaus, Patrick O. Perry.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2260--2288.

Abstract:
We consider a particular instance of a common problem in recommender systems, using a database of book reviews to inform user-targeted recommendations. In our dataset, books are categorized into genres and subgenres. To exploit this nested taxonomy, we use a hierarchical model that enables information pooling across across similar items at many levels within the genre hierarchy. The main challenge in deploying this model is computational. The data sizes are large and fitting the model at scale using off-the-shelf maximum likelihood procedures is prohibitive. To get around this computational bottleneck, we extend a moment-based fitting procedure proposed for fitting single-level hierarchical models to the general case of arbitrarily deep hierarchies. This extension is an order of magnitude faster than standard maximum likelihood procedures. The fitting method can be deployed beyond recommender systems to general contexts with deeply nested hierarchical generalized linear mixed models.

Jason Xu, Samson Koelle, Peter Guttorp, Chuanfeng Wu, Cynthia Dunbar, Janis L. Abkowitz, Vladimir N. Minin.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2091--2119.

Abstract:
Single-cell lineage tracking strategies enabled by recent experimental technologies have produced significant insights into cell fate decisions, but lack the quantitative framework necessary for rigorous statistical analysis of mechanistic models describing cell division and differentiation. In this paper, we develop such a framework with corresponding moment-based parameter estimation techniques for continuous-time, multi-type branching processes. Such processes provide a probabilistic model of how cells divide and differentiate, and we apply our method to study hematopoiesis , the mechanism of blood cell production. We derive closed-form expressions for higher moments in a general class of such models. These analytical results allow us to efficiently estimate parameters of much richer statistical models of hematopoiesis than those used in previous statistical studies. To our knowledge, the method provides the first rate inference procedure for fitting such models to time series data generated from cellular barcoding experiments. After validating the methodology in simulation studies, we apply our estimator to hematopoietic lineage tracking data from rhesus macaques. Our analysis provides a more complete understanding of cell fate decisions during hematopoiesis in nonhuman primates, which may be more relevant to human biology and clinical strategies than previous findings from murine studies. For example, in addition to previously estimated hematopoietic stem cell self-renewal rate, we are able to estimate fate decision probabilities and to compare structurally distinct models of hematopoiesis using cross validation. These estimates of fate decision probabilities and our model selection results should help biologists compare competing hypotheses about how progenitor cells differentiate. The methodology is transferrable to a large class of stochastic compartmental and multi-type branching models, commonly used in studies of cancer progression, epidemiology and many other fields.

Gabriela V. Cohen Freue, David Kepplinger, Matías Salibián-Barrera, Ezequiel Smucler.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2065--2090.

Abstract:
In large-scale quantitative proteomic studies, scientists measure the abundance of thousands of proteins from the human proteome in search of novel biomarkers for a given disease. Penalized regression estimators can be used to identify potential biomarkers among a large set of molecular features measured. Yet, the performance and statistical properties of these estimators depend on the loss and penalty functions used to define them. Motivated by a real plasma proteomic biomarkers study, we propose a new class of penalized robust estimators based on the elastic net penalty, which can be tuned to keep groups of correlated variables together in the selected model and maintain robustness against possible outliers. We also propose an efficient algorithm to compute our robust penalized estimators and derive a data-driven method to select the penalty term. Our robust penalized estimators have very good robustness properties and are also consistent under certain regularity conditions. Numerical results show that our robust estimators compare favorably to other robust penalized estimators. Using our proposed methodology for the analysis of the proteomics data, we identify new potentially relevant biomarkers of cardiac allograft vasculopathy that are not found with nonrobust alternatives. The selected model is validated in a new set of 52 test samples and achieves an area under the receiver operating characteristic (AUC) of 0.85.

Chanmin Kim, Michael J. Daniels, Joseph W. Hogan, Christine Choirat, Corwin M. Zigler.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1927--1956.

Abstract:
Emission control technologies installed on power plants are a key feature of many air pollution regulations in the US. While such regulations are predicated on the presumed relationships between emissions, ambient air pollution and human health, many of these relationships have never been empirically verified. The goal of this paper is to develop new statistical methods to quantify these relationships. We frame this problem as one of mediation analysis to evaluate the extent to which the effect of a particular control technology on ambient pollution is mediated through causal effects on power plant emissions. Since power plants emit various compounds that contribute to ambient pollution, we develop new methods for multiple intermediate variables that are measured contemporaneously, may interact with one another, and may exhibit joint mediating effects. Specifically, we propose new methods leveraging two related frameworks for causal inference in the presence of mediating variables: principal stratification and causal mediation analysis. We define principal effects based on multiple mediators, and also introduce a new decomposition of the total effect of an intervention on ambient pollution into the natural direct effect and natural indirect effects for all combinations of mediators. Both approaches are anchored to the same observed-data models, which we specify with Bayesian nonparametric techniques. We provide assumptions for estimating principal causal effects, then augment these with an additional assumption required for causal mediation analysis. The two analyses, interpreted in tandem, provide the first empirical investigation of the presumed causal pathways that motivate important air quality regulatory policies.

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 $(1/4,1/2)$.

Galatia Cleanthous, Athanasios G. Georgiadis, Gerard Kerkyacharian, Pencho Petrushev, Dominique Picard.

Source: Bernoulli, Volume 26, Number 3, 1832--1862.

Abstract:
We consider the problem of estimating the density of observations taking values in classical or nonclassical spaces such as manifolds and more general metric spaces. Our setting is quite general but also sufficiently rich in allowing the development of smooth functional calculus with well localized spectral kernels, Besov regularity spaces, and wavelet type systems. Kernel and both linear and nonlinear wavelet density estimators are introduced and studied. Convergence rates for these estimators are established and discussed.

Kamran Kalbasi, Thomas Mountford.

Source: Bernoulli, Volume 26, Number 2, 1504--1534.

Abstract:
In this paper, we study the local times of vector-valued Gaussian fields that are ‘diagonally operator-self-similar’ and whose increments are stationary. Denoting the local time of such a Gaussian field around the spatial origin and over the temporal unit hypercube by $Z$, we show that there exists $lambdain(0,1)$ such that under some quite weak conditions, $lim_{n ightarrow+infty}frac{sqrt[n]{mathbb{E}(Z^{n})}}{n^{lambda}}$ and $lim_{x ightarrow+infty}frac{-logmathbb{P}(Z>x)}{x^{frac{1}{lambda}}}$ both exist and are strictly positive (possibly $+infty$). Moreover, we show that if the underlying Gaussian field is ‘strongly locally nondeterministic’, the above limits will be finite as well. These results are then applied to establish similar statements for the intersection local times of diagonally operator-self-similar Gaussian fields with stationary increments.

Ilya Pavlyukevich, Georgiy Shevchenko.

Source: Bernoulli, Volume 26, Number 2, 1381--1409.

Abstract:
In this paper, we study the Stratonovich stochastic differential equation $mathrm{d}X=|X|^{alpha }circ mathrm{d}B$, $alpha in (-1,1)$, which has been introduced by Cherstvy et al. ( New J. Phys. 15 (2013) 083039) in the context of analysis of anomalous diffusions in heterogeneous media. We determine its weak and strong solutions, which are homogeneous strong Markov processes spending zero time at $0$: for $alpha in (0,1)$, these solutions have the form egin{equation*}X_{t}^{ heta }=((1-alpha)B_{t}^{ heta })^{1/(1-alpha )},end{equation*} where $B^{ heta }$ is the $ heta $-skew Brownian motion driven by $B$ and starting at $frac{1}{1-alpha }(X_{0})^{1-alpha }$, $ heta in [-1,1]$, and $(x)^{gamma }=|x|^{gamma }operatorname{sign}x$; for $alpha in (-1,0]$, only the case $ heta =0$ is possible. The central part of the paper consists in the proof of the existence of a quadratic covariation $[f(B^{ heta }),B]$ for a locally square integrable function $f$ and is based on the time-reversion technique for Markovian diffusions.

Eric Beutner, Laurent Bordes, Laurent Doyen.

Source: Bernoulli, Volume 26, Number 1, 557--586.

Abstract:
Virtual age models are very useful to analyse recurrent events. Among the strengths of these models is their ability to account for treatment (or intervention) effects after an event occurrence. Despite their flexibility for modeling recurrent events, the number of applications is limited. This seems to be a result of the fact that in the semiparametric setting all the existing results assume the virtual age function that describes the treatment (or intervention) effects to be known. This shortcoming can be overcome by considering semiparametric virtual age models with parametrically specified virtual age functions. Yet, fitting such a model is a difficult task. Indeed, it has recently been shown that for these models the standard profile likelihood method fails to lead to consistent estimators. Here we show that consistent estimators can be constructed by smoothing the profile log-likelihood function appropriately. We show that our general result can be applied to most of the relevant virtual age models of the literature. Our approach shows that empirical process techniques may be a worthwhile alternative to martingale methods for studying asymptotic properties of these inference methods. A simulation study is provided to illustrate our consistency results together with an application to real data.

Yi Shen, Yizao Wang.

Source: Bernoulli, Volume 26, Number 1, 500--530.

Abstract:
We propose an aggregated random-field model, and investigate the scaling limits of the aggregated partial-sum random fields. In this model, each copy in the aggregation is a $pm 1$-valued random field built from two correlated one-dimensional random walks, the law of each determined by a random persistence parameter. A flexible joint distribution of the two parameters is introduced, and given the parameters the two correlated random walks are conditionally independent. For the aggregated random field, when the persistence parameters are independent, the scaling limit is a fractional Brownian sheet. When the persistence parameters are tail-dependent, characterized in the framework of multivariate regular variation, the scaling limit is more delicate, and in particular depends on the growth rates of the underlying rectangular region along two directions: at different rates different operator-scaling Gaussian random fields appear as the region area tends to infinity. In particular, at the so-called critical speed, a large family of Gaussian random fields with long-range dependence arise in the limit. We also identify four different regimes at non-critical speed where fractional Brownian sheets arise in the limit.

[London], 2019.

Jasper Akerboom
Oct 3, 2012; 32:13819-13840
Cellular

Erin E. Hecht
Sep 25, 2019; 39:7748-7758
BehavioralSystemsCognitive

Jozsef Csicsvari
Jan 1, 1999; 19:274-287
Articles

Jasper Akerboom
Oct 3, 2012; 32:13819-13840
Cellular

Thomas Schikorski
Aug 1, 1997; 17:5858-5867
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Jessica A. Gorski
Aug 1, 2002; 22:6309-6314
BRIEF COMMUNICATION

Italian translation of the BIS press release about the BIS Quarterly Review, December 2017

Spanish translation of press release - the Basel Committee on Banking Supervision is finalising stress-testing principles, reviews ways to stop regulatory arbitrage behaviour, agrees on annual G-SIB list, discusses leverage ratio, crypto-assets, market risk framework and implementation, 20 September 2018.

Mitochondrial fission catalyzed by dynamin-related protein 1 (Drp1) is necessary for mitochondrial biogenesis and maintenance of healthy mitochondria. However, excessive fission has been associated with multiple neurodegenerative disorders, and we recently reported that mice with smaller mitochondria are sensitized to ischemic stroke injury. Although pharmacological Drp1 inhibition has been put forward as neuroprotective, the specificity and mechanism of the inhibitor used is controversial. Here, we provide genetic evidence that Drp1 inhibition is neuroprotective. Drp1 is activated by dephosphorylation of an inhibitory phosphorylation site, Ser637. We identify Bβ2, a mitochondria-localized protein phosphatase 2A (PP2A) regulatory subunit, as a neuron-specific Drp1 activator in vivo. Bβ2 KO mice of both sexes display elongated mitochondria in neurons and are protected from cerebral ischemic injury. Functionally, deletion of Bβ2 and maintained Drp1 Ser637 phosphorylation improved mitochondrial respiratory capacity, Ca²⁺ homeostasis, and attenuated superoxide production in response to ischemia and excitotoxicity in vitro and ex vivo. Last, deletion of Bβ2 rescued excessive stroke damage associated with dephosphorylation of Drp1 S637 and mitochondrial fission. These results indicate that the state of mitochondrial connectivity and PP2A/Bβ2-mediated dephosphorylation of Drp1 play a critical role in determining the severity of cerebral ischemic injury. Therefore, Bβ2 may represent a target for prophylactic neuroprotective therapy in populations at high risk of stroke.

SIGNIFICANCE STATEMENT With recent advances in clinical practice including mechanical thrombectomy up to 24 h after the ischemic event, there is resurgent interest in neuroprotective stroke therapies. In this study, we demonstrate reduced stroke damage in the brain of mice lacking the Bβ2 regulatory subunit of protein phosphatase 2A, which we have shown previously acts as a positive regulator of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). Importantly, we provide evidence that deletion of Bβ2 can rescue excessive ischemic damage in mice lacking the mitochondrial PKA scaffold AKAP1, apparently via opposing effects on Drp1 S637 phosphorylation. These results highlight reversible phosphorylation in bidirectional regulation of Drp1 activity and identify Bβ2 as a potential pharmacological target to protect the brain from stroke injury.

Despite their opposing actions on food intake, POMC and NPY/AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) are derived from the same progenitors that give rise to ARH neurons. However, the mechanism whereby common neuronal precursors subsequently adopt either the anorexigenic (POMC) or the orexigenic (NPY/AgRP) identity remains elusive. We hypothesize that POMC and NPY/AgRP cell fates are specified and maintained by distinct intrinsic factors. In search of them, we profiled the transcriptomes of developing POMC and NPY/AgRP neurons in mice. Moreover, cell-type-specific transcriptomic analyses revealed transcription regulators that are selectively enriched in either population, but whose developmental functions are unknown in these neurons. Among them, we found the expression of the PR domain-containing factor 12 (Prdm12) was enriched in POMC neurons but absent in NPY/AgRP neurons. To study the role of Prdm12 in vivo, we developed and characterized a floxed Prdm12 allele. Selective ablation of Prdm12 in embryonic POMC neurons led to significantly reduced Pomc expression as well as early-onset obesity in mice of either sex that recapitulates symptoms of human POMC deficiency. Interestingly, however, specific deletion of Prdm12 in adult POMC neurons showed that it is no longer required for Pomc expression or energy balance. Collectively, these findings establish a critical role for Prdm12 in the anorexigenic neuron identity and suggest that it acts developmentally to program body weight homeostasis. Finally, the combination of cell-type-specific genomic and genetic analyses provides a means to dissect cellular and functional diversity in the hypothalamus whose neurodevelopment remains poorly studied.

SIGNIFICANCE STATEMENT POMC and NPY/AgRP neurons are derived from the same hypothalamic progenitors but have opposing effects on food intake. We profiled the transcriptomes of genetically labeled POMC and NPY/AgRP neurons in the developing mouse hypothalamus to decipher the transcriptional codes behind the versus orexigenic neuron identity. Our analyses revealed 29 transcription regulators that are selectively enriched in one of the two populations. We generated new mouse genetic models to selective ablate one of POMC-neuron enriched transcription factors Prdm12 in developing and adult POMC neurons. Our studies establish a previously unrecognized role for Prdm12 in the anorexigenic neuron identity and suggest that it acts developmentally to program body weight homeostasis.

Sensory systems integrate multiple stimulus features to generate coherent percepts. Spectral surround suppression, the phenomenon by which sound-evoked responses of auditory neurons are suppressed by stimuli outside their receptive field, is an example of this integration taking place in the auditory system. While this form of global integration is commonly observed in auditory cortical neurons, and potentially used by the nervous system to separate signals from noise, the mechanisms that underlie this suppression of activity are not well understood. We evaluated the contributions to spectral surround suppression of the two most common inhibitory cell types in the cortex, parvalbumin-expressing (PV+) and somatostatin-expressing (SOM⁺) interneurons, in mice of both sexes. We found that inactivating SOM⁺ cells, but not PV+ cells, significantly reduces sustained spectral surround suppression in excitatory cells, indicating a dominant causal role for SOM⁺ cells in the integration of information across multiple frequencies. The similarity of these results to those from other sensory cortices provides evidence of common mechanisms across the cerebral cortex for generating global percepts from separate features.

SIGNIFICANCE STATEMENT To generate coherent percepts, sensory systems integrate simultaneously occurring features of a stimulus, yet the mechanisms by which this integration occurs are not fully understood. Our results show that neurochemically distinct neuronal subtypes in the primary auditory cortex have different contributions to the integration of different frequency components of an acoustic stimulus. Together with findings from other sensory cortices, our results provide evidence of a common mechanism for cortical computations used for global integration of stimulus features.

Persistent alterations in neuronal activity elicit homeostatic plastic changes in synaptic transmission and/or intrinsic excitability. However, it is unknown whether these homeostatic processes operate in concert or at different temporal scales to maintain network activity around a set-point value. Here we show that chronic neuronal hyperactivity, induced by M-channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in cultured hippocampal pyramidal neurons from mice of either sex. Homeostatic changes of intrinsic excitability occurred at a fast timescale (1–4 h) and depended on ongoing spiking activity. This fast intrinsic adaptation included plastic changes in the threshold current and a distal relocation of FGF14, a protein physically bridging Na_v1.6 and K_v7.2 channels along the axon initial segment. In contrast, synaptic adaptations occurred at a slower timescale (~2 d) and involved decreases in miniature EPSC amplitude. To examine how these temporally distinct homeostatic responses influenced hippocampal network activity, we quantified the rate of spontaneous spiking measured by multielectrode arrays at extended timescales. M-Channel blockade triggered slow homeostatic renormalization of the mean firing rate (MFR), concomitantly accompanied by a slow synaptic adaptation. Thus, the fast intrinsic adaptation of excitatory neurons is not sufficient to account for the homeostatic normalization of the MFR. In striking contrast, homeostatic adaptations of intrinsic excitability and spontaneous MFR failed in hippocampal GABAergic inhibitory neurons, which remained hyperexcitable following chronic M-channel blockage. Our results indicate that a single perturbation such as M-channel inhibition triggers multiple homeostatic mechanisms that operate at different timescales to maintain network mean firing rate.

SIGNIFICANCE STATEMENT Persistent alterations in synaptic input elicit homeostatic plastic changes in neuronal activity. Here we show that chronic neuronal hyperexcitability, induced by M-type potassium channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in hippocampal excitatory neurons. The data indicate that the fast adaptation of intrinsic excitability depends on ongoing spiking activity but is not sufficient to provide homeostasis of the mean firing rate. Our results show that a single perturbation such as M-channel inhibition can trigger multiple homeostatic processes that operate at different timescales to maintain network mean firing rate.

What do cucumbers, mustard, almonds and alfalfa have in common? On the surface it appears to be very little. However, there is one thing they do share: They all owe their existence to the service of bees. There is more to the tiny striped helper than sweet honey and a painful sting. For millennia, it has carried out its service [...]

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