The effects of GABAergic polarity changes on episodic neural network activity in developing neural systems

This is the final version of the article. Available from the publisher via the DOI in this record.Early in development, neural systems have primarily excitatory coupling, where even GABAergic synapses are excitatory. Many of these systems exhibit spontaneous episodes of activity that have been characterized through both experimental and computational studies. As development progress the neural system goes through many changes, including synaptic remodeling, intrinsic plasticity in the ion channel expression, and a transformation of GABAergic synapses from excitatory to inhibitory. What effect each of these, and other, changes have on the network behavior is hard to know from experimental studies since they all happen in parallel. One advantage of a computational approach is that one has the ability to study developmental changes in isolation. Here, we examine the effects of GABAergic synapse polarity change on the spontaneous activity of both a mean field and a neural network model that has both glutamatergic and GABAergic coupling, representative of a developing neural network. We find some intuitive behavioral changes as the GABAergic neurons go from excitatory to inhibitory, shared by both models, such as a decrease in the duration of episodes. We also find some paradoxical changes in the activity that are only present in the neural network model. In particular, we find that during early development the inter-episode durations become longer on average, while later in development they become shorter. In addressing this unexpected finding, we uncover a priming effect that is particularly important for a small subset of neurons, called the "intermediate neurons." We characterize these neurons and demonstrate why they are crucial to episode initiation, and why the paradoxical behavioral change result from priming of these neurons. The study illustrates how even arguably the simplest of developmental changes that occurs in neural systems can present non-intuitive behaviors. It also makes predictions about neural network behavioral changes that occur during development that may be observable even in actual neural systems where these changes are convoluted with changes in synaptic connectivity and intrinsic neural plasticity.WB was supported by a scholarship (Process #202320/2015-4) from the Brazilian National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Cientifico e Tecnológico—CNPq). RB was partially supported by National Science Foundation gran

Quantifying the relative contributions of divisive and subtractive feedback to rhythm generation.

PublishedResearch Support, N.I.H., ExtramuralBiological systems are characterized by a high number of interacting components. Determining the role of each component is difficult, addressed here in the context of biological oscillations. Rhythmic behavior can result from the interplay of positive feedback that promotes bistability between high and low activity, and slow negative feedback that switches the system between the high and low activity states. Many biological oscillators include two types of negative feedback processes: divisive (decreases the gain of the positive feedback loop) and subtractive (increases the input threshold) that both contribute to slowly move the system between the high- and low-activity states. Can we determine the relative contribution of each type of negative feedback process to the rhythmic activity? Does one dominate? Do they control the active and silent phase equally? To answer these questions we use a neural network model with excitatory coupling, regulated by synaptic depression (divisive) and cellular adaptation (subtractive feedback). We first attempt to apply standard experimental methodologies: either passive observation to correlate the variations of a variable of interest to system behavior, or deletion of a component to establish whether a component is critical for the system. We find that these two strategies can lead to contradictory conclusions, and at best their interpretive power is limited. We instead develop a computational measure of the contribution of a process, by evaluating the sensitivity of the active (high activity) and silent (low activity) phase durations to the time constant of the process. The measure shows that both processes control the active phase, in proportion to their speed and relative weight. However, only the subtractive process plays a major role in setting the duration of the silent phase. This computational method can be used to analyze the role of negative feedback processes in a wide range of biological rhythms.This work is supported by National Institutes of Health (NIH) grant DK043200 (JT, RB). JR values the hospitality and resources provided by the Laboratory of Biological Modeling, NIDDK-IR, on the NIH campus. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Tracking system study

A digital computer program was generated which mathematically describes an optimal estimator-controller technique as applied to the control of antenna tracking systems used by NASA. Simulation studies utilizing this program were conducted using the IBM 360/91 computer. The basic ideas of applying optimal estimator-controller techniques to antenna tracking systems are discussed. A survey of existing tracking methods is given along with shortcomings and inherent errors. It is explained how these errors can be considerably reduced if optimal estimation and control are used. The modified programs generated in this project are described and the simulation results are summarized. The new algorithms for direct synthesis and stabilization of the systems including nonlinearities, are presented

Is Bursting More Effective than Spiking in Evoking Pituitary Hormone Secretion? A Spatiotemporal Simulation Study of Calcium and Granule Dynamics

This is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this record.Endocrine cells of the pituitary gland secrete a number of hormones, and the amount of hormone released by a cell is controlled in large part by the cell's electrical activity and subsequent Ca2+ influx. Typical electrical behaviors of pituitary cells include continuous spiking and so-called pseudo-plateau bursting. It has been shown that the amplitude of Ca2+ fluctuations is greater in bursting cells, leading to the hypothesis that bursting cells release more hormone than spiking cells. In this work, we apply computer simulations to test this hypothesis. We use experimental recordings of electrical activity as input to mathematical models of Ca2+ channel activity, buffered Ca2+ diffusion, and Ca2+-driven exocytosis. To compare the efficacy of spiking and bursting on the same cell, we pharmacologically block the large conductance potassium (BK) current from a bursting cell, or add a BK current to a spiking cell via dynamic clamp. We find that bursting is generally at least as effective as spiking at evoking hormone release, and is often considerably more effective, even when normalizing to Ca2+ influx. Our hybrid experimental/modeling approach confirms that adding a BK-type K+ current, which is typically associated with decreased cell activity and reduced secretion, can actually produce an increase in hormone secretion, as suggested earlier.JT and RB were partially supported by grant DMS1220063 from the National Science Foundation

Interpreting frequency responses to dose-conserved pulsatile input signals in simple cell signaling motifs.

This is the final version of the article. Available from PLoS via the DOI in this record.Many hormones are released in pulsatile patterns. This pattern can be modified, for instance by changing pulse frequency, to encode relevant physiological information. Often other properties of the pulse pattern will also change with frequency. How do signaling pathways of cells targeted by these hormones respond to different input patterns? In this study, we examine how a given dose of hormone can induce different outputs from the target system, depending on how this dose is distributed in time. We use simple mathematical models of feedforward signaling motifs to understand how the properties of the target system give rise to preferences in input pulse pattern. We frame these problems in terms of frequency responses to pulsatile inputs, where the amplitude or duration of the pulses is varied along with frequency to conserve input dose. We find that the form of the nonlinearity in the steady state input-output function of the system predicts the optimal input pattern. It does so by selecting an optimal input signal amplitude. Our results predict the behavior of common signaling motifs such as receptor binding with dimerization, and protein phosphorylation. The findings have implications for experiments aimed at studying the frequency response to pulsatile inputs, as well as for understanding how pulsatile patterns drive biological responses via feedforward signaling pathways.This work was partially supported by the National Science Foundation grant DMS-1220063 to R. Bertram and J. Tabak (http://www.nsf.gov) and by the large-scale action REGATE (REgulation of the GonAdoTropE axis) to F. Clement and A. Vidal (https://www.rocq.inria.fr/sisyphe/reglo/regate.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The dynamics underlying pseudo-plateau bursting in a pituitary cell model.

This is the final version of the article. Available from BioMed Central via the DOI in this record.Pituitary cells of the anterior pituitary gland secrete hormones in response to patterns of electrical activity. Several types of pituitary cells produce short bursts of electrical activity which are more effective than single spikes in evoking hormone release. These bursts, called pseudo-plateau bursts, are unlike bursts studied mathematically in neurons (plateau bursting) and the standard fast-slow analysis used for plateau bursting is of limited use. Using an alternative fast-slow analysis, with one fast and two slow variables, we show that pseudo-plateau bursting is a canard-induced mixed mode oscillation. Using this technique, it is possible to determine the region of parameter space where bursting occurs as well as salient properties of the burst such as the number of spikes in the burst. The information gained from this one-fast/two-slow decomposition complements the information obtained from a two-fast/one-slow decomposition.This work was supported by NSF grant DMS 0917664 to RB and NIH grant DK 043200 to RB and JT

Fast-activating voltage- and calcium-dependent potassium (BK) conductance promotes bursting in pituitary cells: a dynamic clamp study.

This is the final version of the article. Available from the Society for Neuroscience via the DOI in this record.The electrical activity pattern of endocrine pituitary cells regulates their basal secretion level. Rat somatotrophs and lactotrophs exhibit spontaneous bursting and have high basal levels of hormone secretion, while gonadotrophs exhibit spontaneous spiking and have low basal hormone secretion. It has been proposed that the difference in electrical activity between bursting somatotrophs and spiking gonadotrophs is due to the presence of large conductance potassium (BK) channels on somatotrophs but not on gonadotrophs. This is one example where the role of an ion channel type may be clearly established. We demonstrate here that BK channels indeed promote bursting activity in pituitary cells. Blocking BK channels in bursting lacto-somatotroph GH4C1 cells changes their firing activity to spiking, while further adding an artificial BK conductance via dynamic clamp restores bursting. Importantly, this burst-promoting effect requires a relatively fast BK activation/deactivation, as predicted by computational models. We also show that adding a fast-activating BK conductance to spiking gonadotrophs converts the activity of these cells to bursting. Together, our results suggest that differences in BK channel expression may underlie the differences in electrical activity and basal hormone secretion levels among pituitary cell types and that the rapid rate of BK channel activation is key to its role in burst promotion.This work was supported by NIH Grant DK43200 and National Science Foundation Grant DMS0917664

Large conductance Ca²⁺-activated K⁺ (BK) channels promote secretagogue-induced transition from spiking to bursting in murine anterior pituitary corticotrophs.

This is the final version of the article. Available from Wiley via the DOI in this record.Anterior pituitary corticotroph cells are a central component of the hypothalamic-pituitary-adrenal (HPA) axis essential for the neuroendocrine response to stress. Corticotrophs are excitable cells that receive input from two hypothalamic secretagogues, corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) to control the release of adrenocorticotrophic hormone (ACTH). Although corticotrophs are spontaneously active and increase in excitability in response to CRH and AVP the patterns of electrical excitability and underlying ionic conductances are poorly understood. In this study, we have used electrophysiological, pharmacological and genetic approaches coupled with mathematical modelling to investigate whether CRH and AVP promote distinct patterns of electrical excitability and to interrogate the role of large conductance calcium- and voltage-activated potassium (BK) channels in spontaneous and secretagogue-induced activity. We reveal that BK channels do not play a significant role in the generation of spontaneous activity but are critical for the transition to bursting in response to CRH. In contrast, AVP promotes an increase in single spike frequency, a mechanism independent of BK channels but dependent on background non-selective conductances. Co-stimulation with CRH and AVP results in complex patterns of excitability including increases in both single spike frequency and bursting. The ability of corticotroph excitability to be differentially regulated by hypothalamic secretagogues provides a mechanism for differential control of corticotroph excitability in response to different stressors.P.J.D. was supported by an MRC PhD studentship in the College of Medicine and Veterinary Medicine, University of Edinburgh. Work was supported by grants to M.J.S. and P.R. from the Wellcome Trust (082407), to M.J.S. from MRC (J008893), and to R.B. and J.T. from the National Institutes of Health (DK43200)