scholarly journals Inhibition and Excitation Shape Activity Selection: Effect of Oscillations in a Decision-Making Circuit

2019 ◽  
Vol 31 (5) ◽  
pp. 870-896 ◽  
Author(s):  
Thomas Bose ◽  
Andreagiovanni Reina ◽  
James A. R. Marshall
Keyword(s):  
Decision Making ◽  
Neural Circuit ◽  
Selection Effect ◽  
Mechanistic Study ◽  
Nonlinear Feedback ◽  
Oscillatory Phase ◽  
Neural Computations ◽  
Underlying Mechanisms ◽  
Decision Circuit ◽  
And Function

Decision making is a complex task, and its underlying mechanisms that regulate behavior, such as the implementation of the coupling between physiological states and neural networks, are hard to decipher. To gain more insight into neural computations underlying ongoing binary decision-making tasks, we consider a neural circuit that guides the feeding behavior of a hypothetical animal making dietary choices. We adopt an inhibition motif from neural network theory and propose a dynamical system characterized by nonlinear feedback, which links mechanism (the implementation of the neural circuit and its coupling to the animal's nutritional state) and function (improving behavioral performance). A central inhibitory unit influences evidence-integrating excitatory units, which in our terms correspond to motivations competing for selection. We determine the parameter regime where the animal exhibits improved decision-making behavior and explain different behavioral outcomes by making the link between accessible states of the nonlinear neural circuit model and decision-making performance. We find that for given deficits in nutritional items, the variation of inhibition strength and ratio of excitation and inhibition strengths in the decision circuit allows the animal to enter an oscillatory phase that describes its internal motivational state. Our findings indicate that this oscillatory phase may improve the overall performance of the animal in an ongoing foraging task and underpin the importance of an integrated functional and mechanistic study of animal activity selection.

scholarly journals Inhibition and excitation shape activity selection: effect of oscillations in a decision-making circuit

2018 ◽  
Author(s):  
Thomas Bose ◽  
Andreagiovanni Reina ◽  
James A.R. Marshall
Keyword(s):  
Decision Making ◽  
Neural Circuit ◽  
Reproductive Value ◽  
Mechanistic Study ◽  
Perceptual Decision Making ◽  
Substantial Impact ◽  
Oscillatory Phase ◽  
Model Animal ◽  
Foraging Decisions ◽  
Overall Performance

AbstractDecision-making is a complex task and requires adaptive mechanisms that facilitate efficient behaviour. Here, we consider a neural circuit that guides the behaviour of an animal in ongoing binary choice tasks. We adopt an inhibition motif from neural network theory and propose a dynamical system characterized by nonlinear feedback, which links mechanism (the implementation of the neural circuit) and function (increasing reproductive value). A central inhibitory unit influences evidence-integrating excitatory units, which in our terms correspond to motivations competing for selection. We determine the parameter regime where the animal exhibits improved decision-making behaviour, and explain different behavioural outcomes by making the link between bifurcation analysis of the nonlinear neural circuit model and decision-making performance. We find that the animal performs best if it tunes internal parameters of the neural circuit in accordance with the underlying bifurcation structure. In particular, variation of inhibition strength and excitation-over-inhibition ratio have a crucial effect on the decision outcome, by allowing the animal to break decision deadlock and to enter an oscillatory phase that describes its internal motivational state. Our findings indicate that this oscillatory phase may improve the overall performance of the animal in an ongoing foraging task. Our results underpin the importance of an integrated functional and mechanistic study of animal activity selection.Author summaryOrganisms frequently select activities, which relate to economic, social and perceptual decision-making problems. The choices made may have substantial impact on their lives. In foraging decisions, for example, animals aim at reaching a target intake of nutrients; it is generally believed that a balanced diet improves reproductive success, yet little is known about the underlying mechanisms that integrate nutritional needs within the brain. In our study, we address this coupling between physiological states and a decision-making circuit in the context of foraging decisions. We consider a model animal that has the drive to eat or drink. The motivation to select and perform one of these activities (i.e. eating or drinking), is processed in artificial neuronal units that have access to information on how hungry and thirsty the animal is at the point it makes the decision. We show that inhibitory and excitatory mechanisms in the neural circuit shape ongoing binary decisions, and we reveal under which conditions oscillating motivations may improve the overall performance of the animal. Our results indicate that inefficient or pathological decision-making may originate from suboptimal modulation of excitation and inhibition in the neurobiological network.

scholarly journals Residual dynamics resolves recurrent contributions to neural computation

2021 ◽  
Author(s):  
Aniruddh R Galgali ◽  
Maneesh Sahani ◽  
Valerio Mante
Keyword(s):  
Decision Making ◽  
Large Scale ◽  
Neural Circuit ◽  
Neural Population ◽  
Perceptual Decision Making ◽  
Neural Recordings ◽  
Fine Grained ◽  
Neural Computations ◽  
Population Trajectory ◽  
The Mean

Relating neural activity to behavior requires an understanding of how neural computations arise from the coordinated dynamics of distributed, recurrently connected neural populations. However, inferring the nature of recurrent dynamics from partial recordings of a neural circuit presents significant challenges. Here, we show that some of these challenges can be overcome by a fine-grained analysis of the dynamics of neural residuals, i.e. trial-by-trial variability around the mean neural population trajectory for a given task condition. Residual dynamics in macaque pre-frontal cortex (PFC) in a saccade-based perceptual decision-making task reveals recurrent dynamics that is time-dependent, but consistently stable, and implies that pronounced rotational structure in PFC trajectories during saccades are driven by inputs from upstream areas. The properties of residual dynamics restrict the possible contributions of PFC to decision-making and saccade generation, and suggest a path towards fully characterizing distributed neural computations with large-scale neural recordings and targeted causal perturbations.

scholarly journals Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 359
Author(s):  
Hsiang-Hao Chuang ◽  
Yen-Yi Zhen ◽  
Yu-Chen Tsai ◽  
Cheng-Hao Chuang ◽  
Ming-Shyan Huang ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tumor Suppressors ◽  
Protein Conformation ◽  
Genome Stability ◽  
Recent Progress ◽  
Multiple Roles ◽  
Cancer Development ◽  
Cancer Hallmarks ◽  
Underlying Mechanisms ◽  
And Function

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.

Comparative study on e-bikes’ decision-making behaviors under flashing green and green countdown

2021 ◽  
pp. 1-8
Author(s):  
Haoyang Meng ◽  
Sheng Dong ◽  
Jibiao Zhou ◽  
Shuichao Zhang ◽  
Zhenjiang Li
Keyword(s):  
Decision Making ◽  
Critical Issue ◽  
Trajectory Data ◽  
Decision Points ◽  
Binary Logit ◽  
The One ◽  
Common Signal ◽  
And Function ◽  
Decision Behaviors ◽  
Stop Line

Green flash light (FG) and green countdown (GC) are the two most common signal formats applied in green-red transition that provides drivers additional alert before termination of green phase. Due to their importance and function in stop-pass decision-making process, proper use of them has become a critical issue to greatly improve the safety and efficiency of signalized intersections. Gradually e-bike riders have become more important commuters in China, however, the influence of FG or GC on them is not clear yet and need pay more attention to it. This study chooses two almost identical intersections to obtain highly accurate trajectory data of e-bike riders to study their decision-making behaviors under FG or GC. The e-bike riders’ behavior is classified into four categories and is to identify their stop-pass decision points using the acceleration trend. Two binary-logit models were built to predict the stop–pass decision behaviors for the different e-bike rider groups, explaining that the potential time to the stop-line is the dominant independent factor of the different behaviors of GC and FG. Furthermore empirical analysis of decision points indicated that GC provides the earlier stop-pass decision point and longer decision making duration on the one side while results in more complexity of decision making and greater risk of stop-line crossing than FG on the other side.

scholarly journals Decision Making for Treatment After ACL Injury From an Orthopaedic Surgeon and Patient Perspective: Results From the NACOX Study

2021 ◽  
Vol 9 (4) ◽  
pp. 232596712110050
Author(s):  
Hanna Tigerstrand Grevnerts ◽  
Sofi Sonesson ◽  
Håkan Gauffin ◽  
Clare L. Ardern ◽  
Anders Stålman ◽  
...  
Keyword(s):  
Decision Making ◽  
High Activity ◽  
Treatment Decision ◽  
Acl Injury ◽  
Treatment Decisions ◽  
Activity Level ◽  
Knee Instability ◽  
Acl Injuries ◽  
Patient Reported ◽  
And Function

Background: In the treatment of anterior cruciate ligament (ACL) injuries, there is little evidence of when and why a decision for ACL reconstruction (ACLR) or nonoperative treatment (non-ACLR) is made. Purpose: To (1) describe the key characteristics of ACL injury treatment decisions and (2) compare patient-reported knee instability, function, and preinjury activity level between patients with non-ACLR and ACLR treatment decisions. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 216 patients with acute ACL injury were evaluated during the first year after injury. The treatment decision was non-ACLR in 73 patients and ACLR in 143. Reasons guiding treatment decision were obtained from medical charts and questionnaires to patients and orthopaedic surgeons. Patient-reported instability and function were obtained via questionnaires and compared between patients with non-ACLR and ACLR treatment decisions. The ACLR treatment group was classified retrospectively by decision phase: acute phase (decision made between injury day and 31 days after injury), subacute phase (decision made between 32 days and up to 5 months after injury), and late phase (decision made 5-12 months after injury). Data were evaluated using descriptive statistics, and group comparisons were made using parametric or nonparametric tests as appropriate. Results: The main reasons for a non-ACLR treatment decision were no knee instability and no problems with knee function. The main reasons for an ACLR treatment decision were high activity demands and knee instability. Patients in the non-ACLR group were significantly older ( P = .031) and had a lower preinjury activity level than did those in the acute-phase ( P < .01) and subacute-phase ( P = .006) ACLR decision groups. There were no differences in patient-reported instability and function between treatment decision groups at baseline, 4 weeks after injury, or 3 months after injury. Conclusion: Activity demands, not patient-reported knee instability, may be the most important factor in the decision-making process for treatment after ACL injury. We suggest a decision-making algorithm for patients with ACL injuries and no high activity demands; waiting for >3 months can help distinguish those who need surgical intervention from those who can undergo nonoperative management. Registration: NCT02931084 ( ClinicalTrials.gov identifier).

scholarly journals The Demethoxy Derivatives of Curcumin Exhibit Greater Differentiation Suppression in 3T3-L1 Adipocytes Than Curcumin: A Mechanistic Study of Adipogenesis and Molecular Docking

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1025
Author(s):  
Ahmed Alalaiwe ◽  
Jia-You Fang ◽  
Hsien-Ju Lee ◽  
Chun-Hui Chiu ◽  
Ching-Yun Hsu
Keyword(s):  
Molecular Docking ◽  
Fatty Acid Synthase ◽  
Structural Similarity ◽  
Mechanistic Study ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Enhancer Binding Protein ◽  
Underlying Mechanisms ◽  
Amp Activated Protein Kinase

Curcumin is a known anti-adipogenic agent for alleviating obesity and related disorders. Comprehensive comparisons of the anti-adipogenic activity of curcumin with other curcuminoids is minimal. This study compared adipogenesis inhibition with curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), and their underlying mechanisms. We differentiated 3T3-L1 cells in the presence of curcuminoids, to determine lipid accumulation and triglyceride (TG) production. The expression of adipogenic transcription factors and lipogenic proteins was analyzed by Western blot. A significant reduction in Oil red O (ORO) staining was observed in the cells treated with curcuminoids at 20 μM. Inhibition was increased in the order of curcumin < DMC < BDMC. A similar trend was observed in the detection of intracellular TG. Curcuminoids suppressed differentiation by downregulating the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), leading to the downregulation of the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). AMP-activated protein kinase α (AMPKα) phosphorylation was also activated by BDMC. Curcuminoids reduced the release of proinflammatory cytokines and leptin in 3T3-L1 cells in a dose-dependent manner, with BDMC showing the greatest potency. BDMC at 20 μM significantly decreased leptin by 72% compared with differentiated controls. Molecular docking computation indicated that curcuminoids, despite having structural similarity, had different interaction positions to PPARγ, C/EBPα, and ACC. The docking profiles suggested a possible interaction of curcuminoids with C/EBPα and ACC, to directly inhibit their expression.

scholarly journals Zebrafish Dscaml1 is Essential for Retinal Patterning and Function of Oculomotor Subcircuits

2019 ◽  
Author(s):  
Manxiu Ma ◽  
Alexandro D. Ramirez ◽  
Tong Wang ◽  
Rachel L. Roberts ◽  
Katherine E. Harmon ◽  
...  
Keyword(s):  
Animal Model ◽  
Light Adaptation ◽  
Neural Circuit ◽  
Oculomotor System ◽  
Gaze Stabilization ◽  
Ocular Disorders ◽  
Motor Apraxia ◽  
Premotor Pathways ◽  
And Function ◽  
Circuit Function

AbstractDown Syndrome Cell Adhesion Molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the role of dscaml1 in the zebrafish oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Loss of zebrafish dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses showed that mutants have abnormal gaze stabilization, impaired fixation, disconjugation, and faster fatigue. Notably, the saccade and fatigue phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, for which no animal model exists. Two-photon calcium imaging showed that loss of dscaml1 leads to impairment in the saccadic premotor pathway but not the pretectum-vestibular premotor pathway, indicating a subcircuit requirement for dscaml1. Together, we show that dscaml1 has both broad and specific roles in oculomotor circuit function, providing a new animal model to investigate the development of premotor pathways and their associated human ocular disorders.

scholarly journals FLAMs: A self-replicating ex vivo model of alveolar macrophages for functional genetic studies

2021 ◽  
Author(s):  
Sean Thomas ◽  
Kathryn Wierenga ◽  
James Pestka ◽  
Andrew Olive
Keyword(s):  
Alveolar Macrophages ◽  
Ex Vivo ◽  
Fetal Liver ◽  
Expression Profiles ◽  
Surface Expression ◽  
Specific Gene ◽  
Ex Vivo Model ◽  
A Genome ◽  
Underlying Mechanisms ◽  
And Function

Alveolar macrophages (AMs) are tissue resident cells in the lungs derived from the fetal liver that maintain lung homeostasis and respond to inhaled stimuli. While the importance of AMs is undisputed, they remain refractory to standard experimental approaches and high-throughput functional genetics as they are challenging to isolate and rapidly lose AM properties in standard culture. This limitation hinders our understanding of key regulatory mechanisms that control AM maintenance and function. Here, we describe the development of a new model, fetal liver-derived alveolar-like macrophages (FLAMs), which maintains cellular morphologies, expression profiles, and functional mechanisms similar to murine AMs. FLAMs combine treatment with two key cytokines for AM maintenance, GM-CSF and TGFβ. We leveraged the long-term stability of FLAMs to develop functional genetic tools using CRISPR-Cas9-mediated gene editing. Targeted editing confirmed the role of AM-specific gene Marco and the IL-1 receptor Il1r1 in modulating the AM response to crystalline silica. Furthermore, a genome-wide knockout library using FLAMs identified novel genes required for surface expression of the AM marker Siglec-F, most notably those related to the peroxisome. Taken together, our results suggest that FLAMs are a stable, self-replicating model of AM function that enables previously impossible global genetic approaches to define the underlying mechanisms of AM maintenance and function.

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