Australian fiction.

Dementia.

Rentzenbrink, Cathy -- Family.

Autism spectrum disorders in children.

Paris : E. Leroux, 1874.

London : Walton & Maberly, 1866.

Berlin : G. Reimer, 1899.

London : J. Murray, 1877.

Manchester : J. Heywood, 1888.

London : Adlard, 1904.

London : Philadelphia, 1889.

The Minneapolis district—with large achievement gaps between white and black students—is enlisting parents from communities of color to help it gather broader and better feedback on how to improve.

Nearly 45 percent of children in rural McDowell County, West Virginia do not live with their parents and many are being raised by grandparents.

Yichong Wu, Tiejun Li, Xiaoping Liu, Luonan Chen.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1269--1301.

Abstract:
Detecting the change of biological interaction networks is of great importance in biological and medical research. We proposed a simple loss function, named as CrossFDTL, to identify the network change or differential network by estimating the difference between two precision matrices under Gaussian assumption. The CrossFDTL is a natural fusion of the D-trace loss for the considered two networks by imposing the $ell _{1}$ penalty to the differential matrix to ensure sparsity. The key point of our method is to utilize the cross variables, which correspond to the sum and difference of two precision matrices instead of using their original forms. Moreover, we developed an efficient minimization algorithm for the proposed loss function and further rigorously proved its convergence. Numerical results showed that our method outperforms the existing methods in both accuracy and convergence speed for the simulated and real data.

Fabien Panloup, Samy Tindel, Maylis Varvenne.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1075--1136.

Abstract:
In this paper we consider the drift estimation problem for a general differential equation driven by an additive multidimensional fractional Brownian motion, under ergodic assumptions on the drift coefficient. Our estimation procedure is based on the identification of the invariant measure, and we provide consistency results as well as some information about the convergence rate. We also give some examples of coefficients for which the identifiability assumption for the invariant measure is satisfied.

Recurrent Neural Networks have been widely used to process sequence data, but have long been criticized for their biological implausibility and training difficulties related to vanishing and exploding gradients. This paper presents a novel algorithm for training recurrent networks, target propagation through time (TPTT), that outperforms standard backpropagation through time (BPTT) on four out of the five problems used for testing. The proposed algorithm is initially tested and compared to BPTT on four synthetic time lag tasks, and its performance is also measured using the sequential MNIST data set. In addition, as TPTT uses target propagation, it allows for discrete nonlinearities and could potentially mitigate the credit assignment problem in more complex recurrent architectures.

Abbas Pak, M. E. Ghitany, Mohammad Reza Mahmoudi.

Source: Brazilian Journal of Probability and Statistics, Volume 33, Number 4, 894--914.

Abstract:
This paper focuses on Bayesian estimation of the parameters and reliability function of the power Lindley distribution by using various symmetric and asymmetric loss functions. Assuming suitable priors on the parameters, Bayes estimates are derived by using squared error, linear exponential (linex) and general entropy loss functions. Since, under these loss functions, Bayes estimates of the parameters do not have closed forms we use lindley’s approximation technique to calculate the Bayes estimates. Moreover, we obtain the Bayes estimates of the parameters using a Markov Chain Monte Carlo (MCMC) method. Simulation studies are conducted in order to evaluate the performances of the proposed estimators under the considered loss functions. Finally, analysis of a real data set is presented for illustrative purposes.

Christian Olivera, Ciprian Tudor.

Source: Brazilian Journal of Probability and Statistics, Volume 33, Number 3, 520--531.

Abstract:
Via a special transform and by using the techniques of the Malliavin calculus, we analyze the density of the solution to a stochastic differential equation with unbounded drift.

Rodrigo Citton P. dos Reis, Enrico A. Colosimo, Gustavo L. Gilardoni.

Source: Brazilian Journal of Probability and Statistics, Volume 33, Number 2, 374--396.

Abstract:
In the data analysis from multiple repairable systems, it is usual to observe both different truncation times and heterogeneity among the systems. Among other reasons, the latter is caused by different manufacturing lines and maintenance teams of the systems. In this paper, a hierarchical model is proposed for the statistical analysis of multiple repairable systems under different truncation times. A reparameterization of the power law process is proposed in order to obtain a quasi-conjugate bayesian analysis. An empirical Bayes approach is used to estimate model hyperparameters. The uncertainty in the estimate of these quantities are corrected by using a parametric bootstrap approach. The results are illustrated in a real data set of failure times of power transformers from an electric company in Brazil.

Data-space inversion (DSI) and related procedures represent a family of methods applicable for data assimilation in subsurface flow settings. These methods differ from model-based techniques in that they provide only posterior predictions for quantities (time series) of interest, not posterior models with calibrated parameters. DSI methods require a large number of flow simulations to first be performed on prior geological realizations. Given observed data, posterior predictions can then be generated directly. DSI operates in a Bayesian setting and provides posterior samples of the data vector. In this work we develop and evaluate a new approach for data parameterization in DSI. Parameterization reduces the number of variables to determine in the inversion, and it maintains the physical character of the data variables. The new parameterization uses a recurrent autoencoder (RAE) for dimension reduction, and a long-short-term memory (LSTM) network to represent flow-rate time series. The RAE-based parameterization is combined with an ensemble smoother with multiple data assimilation (ESMDA) for posterior generation. Results are presented for two- and three-phase flow in a 2D channelized system and a 3D multi-Gaussian model. The RAE procedure, along with existing DSI treatments, are assessed through comparison to reference rejection sampling (RS) results. The new DSI methodology is shown to consistently outperform existing approaches, in terms of statistical agreement with RS results. The method is also shown to accurately capture derived quantities, which are computed from variables considered directly in DSI. This requires correlation and covariance between variables to be properly captured, and accuracy in these relationships is demonstrated. The RAE-based parameterization developed here is clearly useful in DSI, and it may also find application in other subsurface flow problems.

A deep neural network has relieved the burden of feature engineering by human experts, but comparable efforts are instead required to determine an effective architecture. On the other hands, as the size of a network has over-grown, a lot of resources are also invested to reduce its size. These problems can be addressed by sparsification of an over-complete model, which removes redundant parameters or connections by pruning them away after training or encouraging them to become zero during training. In general, however, these approaches are not fully differentiable and interrupt an end-to-end training process with the stochastic gradient descent in that they require either a parameter selection or a soft-thresholding step. In this paper, we propose a fully differentiable sparsification method for deep neural networks, which allows parameters to be exactly zero during training, and thus can learn the sparsified structure and the weights of networks simultaneously using the stochastic gradient descent. We apply the proposed method to various popular models in order to show its effectiveness.

A major difficulty of solving continuous POMDPs is to infer the multi-modal distribution of the unobserved true states and to make the planning algorithm dependent on the perceived uncertainty. We cast POMDP filtering and planning problems as two closely related Sequential Monte Carlo (SMC) processes, one over the real states and the other over the future optimal trajectories, and combine the merits of these two parts in a new model named the DualSMC network. In particular, we first introduce an adversarial particle filter that leverages the adversarial relationship between its internal components. Based on the filtering results, we then propose a planning algorithm that extends the previous SMC planning approach [Piche et al., 2018] to continuous POMDPs with an uncertainty-dependent policy. Crucially, not only can DualSMC handle complex observations such as image input but also it remains highly interpretable. It is shown to be effective in three continuous POMDP domains: the floor positioning domain, the 3D light-dark navigation domain, and a modified Reacher domain.

Simplicity is the ultimate sophistication. Differentiable Architecture Search (DARTS) has now become one of the mainstream paradigms of neural architecture search. However, it largely suffers from several disturbing factors of optimization process whose results are unstable to reproduce. FairDARTS points out that skip connections natively have an unfair advantage in exclusive competition which primarily leads to dramatic performance collapse. While FairDARTS turns the unfair competition into a collaborative one, we instead impede such unfair advantage by injecting unbiased random noise into skip operations' output. In effect, the optimizer should perceive this difficulty at each training step and refrain from overshooting on skip connections, but in a long run it still converges to the right solution area since no bias is added to the gradient. We name this novel approach as NoisyDARTS. Our experiments on CIFAR-10 and ImageNet attest that it can effectively break the skip connection's unfair advantage and yield better performance. It generates a series of models that achieve state-of-the-art results on both datasets.

Joe Watson, James V. Zidek, Gavin Shaddick.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2662--2700.

Abstract:
This paper presents a general model framework for detecting the preferential sampling of environmental monitors recording an environmental process across space and/or time. This is achieved by considering the joint distribution of an environmental process with a site-selection process that considers where and when sites are placed to measure the process. The environmental process may be spatial, temporal or spatio-temporal in nature. By sharing random effects between the two processes, the joint model is able to establish whether site placement was stochastically dependent of the environmental process under study. Furthermore, if stochastic dependence is identified between the two processes, then inferences about the probability distribution of the spatio-temporal process will change, as will predictions made of the process across space and time. The embedding into a spatio-temporal framework also allows for the modelling of the dynamic site-selection process itself. Real-world factors affecting both the size and location of the network can be easily modelled and quantified. Depending upon the choice of the population of locations considered for selection across space and time under the site-selection process, different insights about the precise nature of preferential sampling can be obtained. The general framework developed in the paper is designed to be easily and quickly fit using the R-INLA package. We apply this framework to a case study involving particulate air pollution over the UK where a major reduction in the size of a monitoring network through time occurred. It is demonstrated that a significant response-biased reduction in the air quality monitoring network occurred, namely the relocation of monitoring sites to locations with the highest pollution levels, and the routine removal of sites at locations with the lowest. We also show that the network was consistently unrepresenting levels of particulate matter seen across much of GB throughout the operating life of the network. Finally we show that this may have led to a severe overreporting of the population-average exposure levels experienced across GB. This could have great impacts on estimates of the health effects of black smoke levels.

Javier Cárcamo, Antonio Cuevas, Luis-Alberto Rodríguez.

Source: Bernoulli, Volume 26, Number 3, 2143--2175.

Abstract:
We show that various functionals related to the supremum of a real function defined on an arbitrary set or a measure space are Hadamard directionally differentiable. We specifically consider the supremum norm, the supremum, the infimum, and the amplitude of a function. The (usually non-linear) derivatives of these maps adopt simple expressions under suitable assumptions on the underlying space. As an application, we improve and extend to the multidimensional case the results in Raghavachari ( Ann. Statist. 1 (1973) 67–73) regarding the limiting distributions of Kolmogorov–Smirnov type statistics under the alternative hypothesis. Similar results are obtained for analogous statistics associated with copulas. We additionally solve an open problem about the Berk–Jones statistic proposed by Jager and Wellner (In A Festschrift for Herman Rubin (2004) 319–331 IMS). Finally, the asymptotic distribution of maximum mean discrepancies over Donsker classes of functions is derived.

Cristina Butucea, Amandine Dubois, Martin Kroll, Adrien Saumard.

Source: Bernoulli, Volume 26, Number 3, 1727--1764.

Abstract:
We address the problem of non-parametric density estimation under the additional constraint that only privatised data are allowed to be published and available for inference. For this purpose, we adopt a recent generalisation of classical minimax theory to the framework of local $alpha$-differential privacy and provide a lower bound on the rate of convergence over Besov spaces $mathcal{B}^{s}_{pq}$ under mean integrated $mathbb{L}^{r}$-risk. This lower bound is deteriorated compared to the standard setup without privacy, and reveals a twofold elbow effect. In order to fulfill the privacy requirement, we suggest adding suitably scaled Laplace noise to empirical wavelet coefficients. Upper bounds within (at most) a logarithmic factor are derived under the assumption that $alpha$ stays bounded as $n$ increases: A linear but non-adaptive wavelet estimator is shown to attain the lower bound whenever $pgeq r$ but provides a slower rate of convergence otherwise. An adaptive non-linear wavelet estimator with appropriately chosen smoothing parameters and thresholding is shown to attain the lower bound within a logarithmic factor for all cases.

David Corlin Marchand, Ioan Manolescu.

Source: Bernoulli, Volume 26, Number 3, 1665--1705.

Abstract:
We study randomly growing trees governed by the affine preferential attachment rule. Starting with a seed tree $S$, vertices are attached one by one, each linked by an edge to a random vertex of the current tree, chosen with a probability proportional to an affine function of its degree. This yields a one-parameter family of preferential attachment trees $(T_{n}^{S})_{ngeq |S|}$, of which the linear model is a particular case. Depending on the choice of the parameter, the power-laws governing the degrees in $T_{n}^{S}$ have different exponents. We study the problem of the asymptotic influence of the seed $S$ on the law of $T_{n}^{S}$. We show that, for any two distinct seeds $S$ and $S'$, the laws of $T_{n}^{S}$ and $T_{n}^{S'}$ remain at uniformly positive total-variation distance as $n$ increases. This is a continuation of Curien et al. ( J. Éc. Polytech. Math. 2 (2015) 1–34), which in turn was inspired by a conjecture of Bubeck et al. ( IEEE Trans. Netw. Sci. Eng. 2 (2015) 30–39). The technique developed here is more robust than previous ones and is likely to help in the study of more general attachment mechanisms.

Wensheng Wang, Zhonggen Su, Yimin Xiao.

Source: Bernoulli, Volume 26, Number 2, 1410--1430.

Abstract:
We establish the exact moduli of non-differentiability of Gaussian random fields with stationary increments. As an application of the result, we prove that the uniform Hölder condition for the maximum local times of Gaussian random fields with stationary increments obtained in Xiao (1997) is optimal. These results are applicable to fractional Riesz–Bessel processes and stationary Gaussian random fields in the Matérn and Cauchy classes.

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.

Pasha Tkachov.

Source: Bernoulli, Volume 26, Number 2, 1354--1380.

Abstract:
The aim of this paper is to prove stability of traveling waves for integro-differential equations connected with branching Markov processes. In other words, the limiting law of the left-most particle of a (time-continuous) branching Markov process with a Lévy non-branching part is demonstrated. The key idea is to approximate the branching Markov process by a branching random walk and apply the result of Aïdékon [ Ann. Probab. 41 (2013) 1362–1426] on the limiting law of the latter one.

Christian Hirsch, Christian Mönch.

Source: Bernoulli, Volume 26, Number 2, 927--947.

Abstract:
This paper considers two asymptotic properties of a spatial preferential-attachment model introduced by E. Jacob and P. Mörters (In Algorithms and Models for the Web Graph (2013) 14–25 Springer). First, in a regime of strong linear reinforcement, we show that typical distances are at most of doubly-logarithmic order. Second, we derive a large deviation principle for the empirical neighbourhood structure and express the rate function as solution to an entropy minimisation problem in the space of stationary marked point processes.

Richard A. Davis, Mikkel Slot Nielsen, Victor Rohde.

Source: Bernoulli, Volume 26, Number 2, 799--827.

Abstract:
In this paper, we introduce a model, the stochastic fractional delay differential equation (SFDDE), which is based on the linear stochastic delay differential equation and produces stationary processes with hyperbolically decaying autocovariance functions. The model departs from the usual way of incorporating this type of long-range dependence into a short-memory model as it is obtained by applying a fractional filter to the drift term rather than to the noise term. The advantages of this approach are that the corresponding long-range dependent solutions are semimartingales and the local behavior of the sample paths is unaffected by the degree of long memory. We prove existence and uniqueness of solutions to the SFDDEs and study their spectral densities and autocovariance functions. Moreover, we define a subclass of SFDDEs which we study in detail and relate to the well-known fractionally integrated CARMA processes. Finally, we consider the task of simulating from the defining SFDDEs.

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.

Benjamin E. Reese
Mar 2, 2005; 25:2167-2175
BehavioralSystemsCognitive

Benjamin Meyer
Jul 3, 2019; 39:5326-5335
Systems/Circuits

Human ventral temporal cortex (VTC) is critical for visual recognition. It is thought that this ability is supported by large-scale patterns of activity across VTC that contain information about visual categories. However, it is unknown how category representations in VTC are organized at the submillimeter scale and across cortical depths. To fill this gap in knowledge, we measured BOLD responses in medial and lateral VTC to images spanning 10 categories from five domains (written characters, bodies, faces, places, and objects) at an ultra-high spatial resolution of 0.8 mm using 7 Tesla fMRI in both male and female participants. Representations in lateral VTC were organized most strongly at the general level of domains (e.g., places), whereas medial VTC was also organized at the level of specific categories (e.g., corridors and houses within the domain of places). In both lateral and medial VTC, domain-level and category-level structure decreased with cortical depth, and downsampling our data to standard resolution (2.4 mm) did not reverse differences in representations between lateral and medial VTC. The functional diversity of representations across VTC partitions may allow downstream regions to read out information in a flexible manner according to task demands. These results bridge an important gap between electrophysiological recordings in single neurons at the micron scale in nonhuman primates and standard-resolution fMRI in humans by elucidating distributed responses at the submillimeter scale with ultra-high-resolution fMRI in humans.

SIGNIFICANCE STATEMENT Visual recognition is a fundamental ability supported by human ventral temporal cortex (VTC). However, the nature of fine-scale, submillimeter distributed representations in VTC is unknown. Using ultra-high-resolution fMRI of human VTC, we found differential distributed visual representations across lateral and medial VTC. Domain representations (e.g., faces, bodies, places, characters) were most salient in lateral VTC, whereas category representations (e.g., corridors/houses within the domain of places) were equally salient in medial VTC. These results bridge an important gap between electrophysiological recordings in single neurons at a micron scale and fMRI measurements at a millimeter scale.

The action potential (AP) waveform controls the opening of voltage-gated calcium channels and contributes to the driving force for calcium ion flux that triggers neurotransmission at presynaptic nerve terminals. Although the frog neuromuscular junction (NMJ) has long been a model synapse for the study of neurotransmission, its presynaptic AP waveform has never been directly studied, and thus the AP waveform shape and propagation through this long presynaptic nerve terminal are unknown. Using a fast voltage-sensitive dye, we have imaged the AP waveform from the presynaptic terminal of male and female frog NMJs and shown that the AP is very brief in duration and actively propagated along the entire length of the terminal. Furthermore, based on measured AP waveforms at different regions along the length of the nerve terminal, we show that the terminal is divided into three distinct electrical regions: A beginning region immediately after the last node of Ranvier where the AP is broadest, a middle region with a relatively consistent AP duration, and an end region near the tip of nerve terminal branches where the AP is briefer. We hypothesize that these measured changes in the AP waveform along the length of the motor nerve terminal may explain the proximal-distal gradient in transmitter release previously reported at the frog NMJ.

SIGNIFICANCE STATEMENT The AP waveform plays an essential role in determining the behavior of neurotransmission at the presynaptic terminal. Although the frog NMJ is a model synapse for the study of synaptic transmission, there are many unknowns centered around the shape and propagation of its presynaptic AP waveform. Here, we demonstrate that the presynaptic terminal of the frog NMJ has a very brief AP waveform and that the motor nerve terminal contains three distinct electrical regions. We propose that the changes in the AP waveform as it propagates along the terminal can explain the proximal-distal gradient in transmitter release seen in electrophysiological studies.

Hydrocephalus is a pathologic condition associated with various brain diseases, including Alzheimer's disease (AD). Dysfunctional ependymal cells (EpCs) are believed to contribute to the development of hydrocephalus. It is thus of interest to investigate EpCs' development and function. Here, we report that vacuolar protein sorting-associated protein 35 (VPS35) is critical for EpC differentiation, ciliogenesis, and survival, and thus preventing neonatal hydrocephalus. VPS35 is abundantly expressed in EpCs. Mice with conditional knock-out (cKO) of Vps35 in embryonic (Vps35^GFAP-Cre and Vps35^Emx1-Cre) or postnatal (Vps35^Foxj1-CreER) EpC progenitors exhibit enlarged lateral ventricles (LVs) and hydrocephalus-like pathology. Further studies reveal marked reductions in EpCs and their cilia in both Vps35^GFAP-Cre and Vps35^Foxj1-CreER mutant mice. The reduced EpCs appear to be due to impairments in EpC differentiation and survival. Additionally, both Vps35^GFAP-Cre and Vps35^Foxj1-CreER neonatal pups exhibit increased cell proliferation and death largely in a region close to LV-EpCs. Many microglia close to the mutant LV-EpC region become activated. Depletion of the microglia by PLX3397, an antagonist of colony-stimulating factor 1 receptor (CSF1R), restores LV-EpCs and diminishes the pathology of neonatal hydrocephalus in Vps35^Foxj1-CreER mice. Taken together, these observations suggest unrecognized functions of Vps35 in EpC differentiation, ciliogenesis, and survival in neonatal LV, and reveal pathologic roles of locally activated microglia in EpC homeostasis and hydrocephalus development.

SIGNIFICANCE STATEMENT This study reports critical functions of vacuolar protein sorting-associated protein 35 (VPS35) not only in promoting ependymal cell (EpC) differentiation, ciliogenesis, and survival, but also in preventing local microglial activation. The dysfunctional EpCs and activated microglia are likely to induce hydrocephalus.

Behavior can be guided by neuronal activity in visual, auditory, or somatosensory cerebral cortex, depending on task requirements. In contrast to this flexible access of cortical signals, several observations suggest that behaviors depend more on neurons in later areas of visual cortex than those in earlier areas, although neurons in earlier areas would provide more reliable signals for many tasks. We recorded from neurons in different levels of visual cortex of 2 male rhesus monkeys while the animals did a visual discrimination task and examined trial-to-trial correlations between neuronal and behavioral responses. These correlations became stronger in primary visual cortex as neuronal signals in that area became more reliable relative to the other areas. The results suggest that the mechanisms that read signals from cortex might access any cortical area depending on the relative value of those signals for the task at hand.

SIGNIFICANCE STATEMENT Information is encoded by the action potentials of neurons in various cortical areas in a hierarchical manner such that increasingly complex stimulus features are encoded in successive stages. The brain must extract information from the response of appropriate neurons to drive optimal behavior. A widely held view of this decoding process is that the brain relies on the output of later cortical areas to make decisions, although neurons in earlier areas can provide more reliable signals. We examined correlations between perceptual decisions and the responses of neurons in different levels of monkey visual cortex. The results suggest that the brain may access signals in any cortical area depending on the relative value of those signals for the task at hand.

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.