scholarly journals Corrective feedback control of competing neural network with entire connections

2022 ◽  
Uramogi Wang

Continuous persist activity of the competitive network is related to many functions, such as working memory, oculomotor integrator and decision making. Many competition models with mutual inhibition structures achieve activity maintenance via positive feedback, which requires meticulous fine tuning of the network parameters strictly. Negative derivative feedback, according to recent research, might represent a novel mechanism for sustaining neural activity that is more resistant to multiple neural perturbations than positive feedback. Many classic models with only mutual inhibition structure are not capable of providing negative derivative feedback because double-inhibition acts as a positive feedback loop, and lack of negative feedback loop that is indispensable for negative derivative feedback. Here in the proposal, we aim to derive a new competition network with negative derivative feedback. The network is made up of two symmetric pairs of EI populations that the four population are completely connected. We conclude that the negative derivative occurs in two circumstances, in which one the activity of the two sides is synchronous but push-pull-like in the other, as well as the switch of two conditions in mathematical analysis and numerical simulation.

2021 ◽  
Vol 22 (23) ◽  
pp. 12862
Rune Kleppe ◽  
Qaiser Waheed ◽  
Peter Ruoff

Dopamine (DA) is an important signal mediator in the brain as well as in the periphery. The term “dopamine homeostasis” occasionally found in the literature refers to the fact that abnormal DA levels can be associated with a variety of neuropsychiatric disorders. An analysis of the negative feedback inhibition of tyrosine hydroxylase (TH) by DA indicates, with support from the experimental data, that the TH-DA negative feedback loop has developed to exhibit 3,4-dihydroxyphenylalanine (DOPA) homeostasis by using DA as a derepression regulator. DA levels generally decline when DOPA is removed, for example, by increased oxidative stress. Robust DOPA regulation by DA further implies that maximum vesicular DA levels are established, which appear necessary for a reliable translation of neural activity into a corresponding chemical transmitter signal. An uncontrolled continuous rise (windup) in DA occurs when Levodopa treatment exceeds a critical dose. Increased oxidative stress leads to the successive breakdown of DOPA homeostasis and to a corresponding reduction in DA levels. To keep DOPA regulation robust, the vesicular DA loading requires close to zero-order kinetics combined with a sufficiently high compensatory flux provided by TH. The protection of DOPA and DA due to a channeling complex is discussed.

1993 ◽  
Vol 106 (4) ◽  
pp. 1153-1168 ◽  
B. Novak ◽  
J.J. Tyson

To contribute to a deeper understanding of M-phase control in eukaryotic cells, we have constructed a model based on the biochemistry of M-phase promoting factor (MPF) in Xenopus oocyte extracts, where there is evidence for two positive feedback loops (MPF stimulates its own production by activating Cdc25 and inhibiting Wee1) and a negative feedback loop (MPF stimulates its own destruction by indirectly activating the ubiquitin pathway that degrades its cyclin subunit). To uncover the full dynamical possibilities of the control system, we translate the regulatory network into a set of differential equations and study these equations by graphical techniques and computer simulation. The positive feedback loops in the model account for thresholds and time lags in cyclin-induced and MPF-induced activation of MPF, and the model can be fitted quantitatively to these experimental observations. The negative feedback loop is consistent with observed time lags in MPF-induced cyclin degradation. Furthermore, our model indicates that there are two possible mechanisms for autonomous oscillations. One is driven by the positive feedback loops, resulting in phosphorylation and abrupt dephosphorylation of the Cdc2 subunit at an inhibitory tyrosine residue. These oscillations are typical of oocyte extracts. The other type is driven by the negative feedback loop, involving rapid cyclin turnover and negligible phosphorylation of the tyrosine residue of Cdc2. The early mitotic cycles of intact embryos exhibit such characteristics. In addition, by assuming that unreplicated DNA interferes with M-phase initiation by activating the phosphatases that oppose MPF in the positive feedback loops, we can simulate the effect of addition of sperm nuclei to oocyte extracts, and the lengthening of cycle times at the mid-blastula transition of intact embryos.

2019 ◽  
Vol 60 (12) ◽  
pp. 2684-2691 ◽  
Kyoko Ohashi-Ito ◽  
Kuninori Iwamoto ◽  
Yoshinobu Nagashima ◽  
Mikiko Kojima ◽  
Hitoshi Sakakibara ◽  

Abstract The phytohormone auxin governs various developmental processes in plants including vascular formation. Auxin transport and biosynthesis are important factors in determining auxin distribution in tissues. Although the role of auxin transport in vein pattern formation is widely recognized, that of auxin biosynthesis in vascular development is poorly understood. Heterodimer complexes comprising two basic helix–loop–helix protein families, LONESOME HIGHWAY (LHW) and TARGET OF MONOPTEROS5 (TMO5)/TMO5-LIKE1 (T5L1), are master transcriptional regulators of the initial process of vascular development. The LHW–TMO5/T5L1 dimers regulate vascular initial cell production, vascular cell proliferation and xylem fate determination in the embryo and root apical meristem (RAM). In this study, we investigated the function of local auxin biosynthesis in initial vascular development in RAM. Results showed that LHW–T5L1 upregulated the expression of YUCCA4 (YUC4), a key auxin biosynthesis gene. The expression of YUC4 was essential for promoting xylem differentiation and vascular cell proliferation in RAM. Conversely, auxin biosynthesis was required for maintaining the expression levels of LHW, TMO5/T5L1 and their targets. Our results suggest that local auxin biosynthesis forms a positive feedback loop for fine-tuning the level of LHW–TMO5/T5L1, which is necessary for initiating vascular development.

2020 ◽  
Vol 10 (1) ◽  
Marianna Holczer ◽  
Bence Hajdú ◽  
Tamás Lőrincz ◽  
András Szarka ◽  
Gábor Bánhegyi ◽  

Abstract Autophagy is an intracellular digestive process, which has a crucial role in maintaining cellular homeostasis by self-eating the unnecessary and/or damaged components of the cell at various stress events. ULK1, one of the key elements of autophagy activator complex, together with the two sensors of nutrient and energy conditions, called mTORC1 and AMPK kinases, guarantee the precise function of cell response mechanism. We claim that the feedback loops of AMPK–mTORC1–ULK1 regulatory triangle determine an accurate dynamical characteristic of autophagic process upon cellular stress. By using both molecular and theoretical biological techniques, here we reveal that a delayed negative feedback loop between active AMPK and ULK1 is essential to manage a proper cellular answer after prolonged starvation or rapamycin addition. AMPK kinase quickly gets induced followed by AMPK-P-dependent ULK1 activation, whereas active ULK1 has a rapid negative effect on AMPK-P resulting in a delayed inhibition of ULK1. The AMPK-P → ULK1 ˧ AMPK-P negative feedback loop results in a periodic repeat of their activation and inactivation and an oscillatory activation of autophagy, as well. We demonstrate that the periodic induction of self-cannibalism is necessary for the proper dynamical behaviour of the control network when mTORC1 is inhibited with respect to various stress events. By computational simulations we also suggest various scenario to introduce “delay” on AMPK-P-dependent ULK1 activation (i.e. extra regulatory element in the wiring diagram or multi-phosphorylation of ULK1).

2009 ◽  
Vol 390 (10) ◽  
Marco A. Calzado ◽  
Laureano de la Vega ◽  
Eduardo Muñoz ◽  
M. Lienhard Schmitz

Abstract The different activities of the tumor suppressor p53 are tightly regulated by various negative and positive feedback loops, which allow accurate control of its function. Here we show that the p53-inducible ubiquitin E3 ligase Siah-1L can bind to the p53 phosphorylating kinase HIPK2 and thus allows its ubiquitination and proteasomal elimination. Siah-1L also eliminates the HIPK family member HIPK3, indicating that its activity is not restricted to one member of the HIPK family. The stimulating effect of HIPK2 on p53-triggered transcription is counteracted by Siah-1L, thus showing the occurrence of another negative feedback loop controlling the p53 response.

2020 ◽  
Benjamin Heidebrecht ◽  
Jing Chen ◽  
John J. Tyson

ABSTRACTA wide variety of organisms possess endogenous circadian rhythms (~24 h period), which coordinate many physiological functions with the day-night cycle. These rhythms are mediated by a molecular mechanism based on transcription-translation feedback. A number of mathematical models have been developed to study features of the circadian clock in a variety of organisms. In this paper, we use bifurcation theory to explore properties of mathematical models based on Kim & Forger’s interpretation of the circadian clock in mammals. Their models are based on a simple negative feedback (SNF) loop between a regulatory protein (PER) and its transcriptional activator (BMAL). In their model, PER binds to BMAL to form a stoichiometric complex (PER:BMAL) that is inactive as a transcription factor. However, for oscillations to occur in the SNF model, the dissociation constant of the PER:BMAL complex, Kd, must be smaller than 10−3 nM, orders of magnitude below the limit set by the biophysics of protein binding. We have relaxed this constraint by introducing two modifications to Kim & Forger’s SNF model: (1) replacing the first-order rate law for degradation of PER in the nucleus by a Michaelis-Menten rate law, and (2) introducing a multistep reaction chain for posttranslational modifications of PER. These modifications significantly increase the robustness of oscillations, and increase the maximum allowable Kd to more reasonable values, 1—100 nM. In a third modification, we considered alternative rate laws for gene transcription to resolve an unrealistically large rate of PER transcription at very low levels of BMAL transcription factor. Additionally, we studied Kim & Forger’s extensions of the SNF model to include a second negative feedback loop (involving REV-ERB) and a supplementary positive feedback loop (involving ROR). We found that the supplementary positive feedback loop—but not the supplementary negative feedback loop— provides additional robustness to the clock model.AUTHOR SUMMARYThe circadian rhythm aligns bodily functions to the day/night cycle and is important for our health. The rhythm originates from an intracellular, molecular clock mechanism that mediates rhythmic gene expression. It is long understood that transcriptional negative feedback with sufficient time delay is key to generating circadian oscillations. However, some of the most widely cited mathematical models for the circadian clock suffer from problems of parameter “fragilities”. That is, sustained oscillations are possible only for physically unrealistic parameter values. A recent model by Kim and Forger nicely incorporates the inhibitory binding of PER, a key clock protein, to its transcription activator BMAL, but oscillations in their model require a binding affinity between PER and BMAL that is orders of magnitude lower than the physical limit of protein-protein binding. To rectify this problem, we make several physiologically credible modifications to the Kim-Forger model, which allow oscillations to occur with realistic binding affinity. The modified model is further extended to explore the potential roles of supplementary feedback loops in the mammalian clock mechanism. Ultimately, accurate models of the circadian clock will provide predictive tools for chronotherapy and chrono-pharmacology studies.

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