scholarly journals Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction

2019 ◽  
Author(s):  
Opeyemi Alabi ◽  
Mara Robinson ◽  
Michael Fortunato ◽  
Joe W. Kable ◽  
Marc V. Fuccillo
Keyword(s):  
Decision Making ◽  
Normal Function ◽  
Reward Processing ◽  
Projection Neurons ◽  
Choice Data ◽  
Behavioral Alterations ◽  
Gene Ablation ◽  
Reinforcement Learning Models ◽  
Knockout Animals

SUMMARYGoal-directed behaviors, complex action sequences that maximize reward, are essential for normal function and are significantly impaired across neuropsychiatric disorders. Despite extensive associations between genetic mutations and these brain disorders, the mechanisms by which candidate genes contribute to goal-directed dysfunction remains unclear, owing to challenges in (1) describing aspects of reward processing that drive goal-directed dysfunction, (2) localizing these deficits to specific brain circuits and (3) relating changes in physiology to behavioral alterations. Here we examined mice with mutations in Neurexin1α, a presynaptically-localized adhesion molecule with widespread neuropsychiatric dis ease association, in value-based decision-making paradigms. We found that Neurexin1α knockout animals exhibited blunted choice bias towards outcomes associated with greater benefits. Mutant mice were similarly impaired in avoiding costlier, benefit-neutral actions. Analysis of trial-by-trial choice data via reinforcement learning models suggested these behavioral patterns were driven largely by deficits in the updating and representation of choice values. Employing conditional gene ablation and region-specific Cre-recombinase strains, we revealed that Neurexin1α disruption within forebrain excitatory projection neurons, but not thalamic population s, recapitulated most aspects of the whole-brain knockout phenotype. Finally, utilizing in vivo recordings of direct pathway spiny neuron population calcium activity, we demonstrated that selective knockout of Neurexin1α within forebrain excitatory neurons disrupts reward-associated neural signals within striatum, a major site of feedback-based learning. By relating deficits in value-based decision-making to region-specific Nrxn1α disruption and changes in reward-associated neural activity, we reveal potential neural substrates for the pathophysiology of neuropsychiatric disease-associated cognitive dysfunction.

scholarly journals Generation and Characterization of Rac3 Knockout Mice

2005 ◽  
Vol 25 (13) ◽  
pp. 5763-5776 ◽  
Author(s):  
Sara Corbetta ◽  
Sara Gualdoni ◽  
Chiara Albertinazzi ◽  
Simona Paris ◽  
Laura Croci ◽  
...  
Keyword(s):  
Nervous System ◽  
Motor Coordination ◽  
Actin Dynamics ◽  
Projection Neurons ◽  
Behavioral Differences ◽  
Developmental Defects ◽  
Rho Family ◽  
Knockout Animals

ABSTRACT Rac proteins are members of the Rho family of GTPases involved in the regulation of actin dynamics. The three highly homologous Rac proteins in mammals are the ubiquitous Rac1, the hematopoiesis-specific Rac2, and the least-characterized Rac3. We show here that Rac3 mRNA is widely and specifically expressed in the developing nervous system, with highest concentration at embryonic day 13 in the dorsal root ganglia and ventral spinal cord. At postnatal day 7 Rac3 appears particularly abundant in populations of projection neurons in several regions of the brain, including the fifth layer of the cortex and the CA1-CA3 region of the hippocampus. We generated mice deleted for the Rac3 gene with the aim of analyzing the function of this GTPase in vivo. Rac3 knockout animals survive embryogenesis and show no obvious developmental defects. Interestingly, specific behavioral differences were detected in the Rac3-deficient animals, since motor coordination and motor learning on the rotarod was superior to that of their wild-type littermates. No obvious histological or immunohistological differences were observed at major sites of Rac3 expression. Our results indicate that, in vivo, Rac3 activity is not strictly required for normal development in utero but may be relevant to later events in the development of a functional nervous system.

scholarly journals Mechanism for differential recruitment of orbitostriatal transmission during outcomes and actions in alcohol dependence

2020 ◽  
Author(s):  
Rafael Renteria ◽  
Christian Cazares ◽  
Emily T. Baltz ◽  
Drew C. Schreiner ◽  
Ege A. Yalcinbas ◽  
...  
Keyword(s):  
Decision Making ◽  
Alcohol Dependence ◽  
Dorsal Striatum ◽  
Psychiatric Disease ◽  
Projection Neurons ◽  
Orbital Frontal Cortex ◽  
Underlying Mechanisms ◽  
Reduced Activity

AbstractPsychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyper-activity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively, however, the underlying mechanisms are unknown. Here we show that alcohol dependence enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid (eCB) signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activity in vivo and rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation specific mechanism gating OFC activity following the induction of alcohol dependence.

scholarly journals Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Rafael Renteria ◽  
Christian Cazares ◽  
Emily T Baltz ◽  
Drew C Schreiner ◽  
Ege A Yalcinbas ◽  
...  
Keyword(s):  
Decision Making ◽  
Dorsal Striatum ◽  
Alcohol Exposure ◽  
Psychiatric Disease ◽  
Projection Neurons ◽  
Orbital Frontal Cortex ◽  
Underlying Mechanisms ◽  
Reduced Activity

Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyper-activity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively, however, the underlying mechanisms are unknown. Here we show that alcohol exposed mice have enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid (eCB) signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activity in vivo and rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation specific mechanism gating OFC activity in alcohol exposed mice.

The face value of feedback: Facial behavior is shaped by goals and punishments during interaction with dynamic faces

2020 ◽  
Author(s):  
Jonathan Yi ◽  
Philip Pärnamets ◽  
Andreas Olsson
Keyword(s):  
Decision Making ◽  
Facial Expression ◽  
Facial Expressions ◽  
Large Body ◽  
Mechanistic Explanation ◽  
Experimental Manipulation ◽  
Corrugator Supercilii ◽  
Dynamic Faces ◽  
Facial Behavior ◽  
Reinforcement Learning Models

Responding appropriately to others’ facial expressions is key to successful social functioning. Despite the large body of work on face perception and spontaneous responses to static faces, little is known about responses to faces in dynamic, naturalistic situations, and no study has investigated how goal directed responses to faces are influenced by learning during dyadic interactions. To experimentally model such situations, we developed a novel method based on online integration of electromyography (EMG) signals from the participants’ face (corrugator supercilii and zygomaticus major) during facial expression exchange with dynamic faces displaying happy and angry facial expressions. Fifty-eight participants learned by trial-and-error to avoid receiving aversive stimulation by either reciprocate (congruently) or respond opposite (incongruently) to the expression of the target face. Our results validated our method, showing that participants learned to optimize their facial behavior, and replicated earlier findings of faster and more accurate responses in congruent vs. incongruent conditions. Moreover, participants performed better on trials when confronted with smiling, as compared to frowning, faces, suggesting it might be easier to adapt facial responses to positively associated expressions. Finally, we applied drift diffusion and reinforcement learning models to provide a mechanistic explanation for our findings which helped clarifying the underlying decision-making processes of our experimental manipulation. Our results introduce a new method to study learning and decision-making in facial expression exchange, in which there is a need to gradually adapt facial expression selection to both social and non-social reinforcements.

Evaluation of the In Vivo Acute Toxicity and In Vitro Hemolytic and Immunomodulatory Activities of the Moringa oleifera Flower Trypsin Inhibitor (MoFTI)

2020 ◽  
Vol 27 ◽  
Author(s):  
Leydianne Leite de Siqueira Patriota ◽  
Dayane Kelly Dias do Nascimento Santos ◽  
Bárbara Rafaela da Silva Barros ◽  
Lethícia Maria de Souza Aguiar ◽  
Yasmym Araújo Silva ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Trypsin Inhibitor ◽  
Hemolytic Activity ◽  
Moringa Oleifera ◽  
Biological Activities ◽  
Hematological Parameters ◽  
Behavioral Alterations ◽  
Female Mice

Background: Protease inhibitors have been isolated from plants and present several biological activities, including immunomod-ulatory action. Objective: This work aimed to evaluate a Moringa oleifera flower trypsin inhibitor (MoFTI) for acute toxicity in mice, hemolytic activity on mice erythrocytes and immunomodulatory effects on mice splenocytes. Methods: The acute toxicity was evaluated using Swiss female mice that received a single dose of the vehicle control or MoFTI (300 mg/kg, i.p.). Behavioral alterations were observed 15–240 min after administration, and survival, weight gain, and water and food consumption were analyzed daily. Organ weights and hematological parameters were analyzed after 14 days. Hemolytic activity of MoFTI was tested using Swiss female mice erythrocytes. Splenocytes obtained from BALB/c mice were cultured in the absence or presence of MoFTI for the evaluation of cell viability and proliferation. Mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) levels were also determined. Furthermore, the culture supernatants were analyzed for the presence of cytokines and nitric oxide (NO). Results: MoFTI did not cause death or any adverse effects on the mice except for abdominal contortions at 15–30 min after administration. MoFTI did not exhibit a significant hemolytic effect. In addition, MoFTI did not induce apoptosis or necrosis in splenocytes and had no effect on cell proliferation. Increases in cytosolic and mitochondrial ROS release, as well as ΔΨm reduction, were observed in MoFTI-treated cells. MoFTI was observed to induce TNF-α, IFN-γ, IL-6, IL-10, and NO release. Conclusion: These results contribute to the ongoing evaluation of the antitumor potential of MoFTI and its effects on other immunological targets.

iTSP-PseAAC: Identify Tumor Suppressor Proteins by Using Fully Connected Neural Network and PseAAC

2021 ◽  
Vol 15 ◽  
Author(s):  
Muhammad Awais ◽  
Waqar Hussain ◽  
Nouman Rasool ◽  
Yaser Daanial Khan
Keyword(s):  
Tumor Suppressor ◽  
Cross Validation ◽  
Control Cell ◽  
Normal Function ◽  
In Vivo Studies ◽  
Tumor Suppressor Proteins ◽  
Proposed Model ◽  
Self Consistency

Background: The uncontrolled growth due to accumulation of genetic and epigenetic changes as a result of loss or reduction in the normal function of Tumor Suppressor Genes (TSGs) and Pro-oncogenes is known as cancer. TSGs control cell division and growth by repairing of DNA mistakes during replication and restrict the unwanted proliferation of a cell or activities, those are the part of tumor production. Objectives: This study aims to propose a novel, accurate, user-friendly model to predict tumor suppressor proteins, which would be freely available to experimental molecular biologists to assist them using in vitro and in vivo studies. Methods: The predictor model has used the input feature vector (IFV) calculated from the physicochemical properties of proteins based on FCNN to compute the accuracy, sensitivity, specificity, and MCC. The proposed model was validated against different exhaustive validation techniques i.e. self-consistency and cross-validation. Results: Using self-consistency, the accuracy is 99%, for cross-validation and independent testing has 99.80% and 100% accuracy respectively. The overall accuracy of the proposed model is 99%, sensitivity value 98% and specificity 99% and F1-score was 0.99. Conclusion: It concludes, the proposed model for prediction of the tumor suppressor proteins can predict the tumor suppressor proteins efficiently, but it still has space for improvements in computational ways as the protein sequences may rapidly increase, day by day.

Neurobiological Reward-Related Abnormalities Across Mood Disorders

2019 ◽  
pp. 222-238
Author(s):  
Alexis E. Whitton ◽  
Michael T. Treadway ◽  
Manon L. Ironside ◽  
Diego A. Pizzagalli
Keyword(s):  
Decision Making ◽  
Mood Disorders ◽  
Treatment Strategies ◽  
Reward Processing ◽  
Reward Learning ◽  
Symptom Presentation ◽  
Psychiatric Symptomatology ◽  
Symptom Dimensions ◽  
Psychotherapeutic Interventions ◽  
Primary Focus

This chapter provides a critical review of recent behavioral and neuroimaging evidence of reward processing abnormalities in mood disorders. The primary focus is on the neural mechanisms underlying disruption in approach motivation, reward learning, and reward-based decision-making in major depression and bipolar disorder. Efforts focused on understanding how reward-related impairments contribute to psychiatric symptomatology have grown substantially in recent years. This has been driven by significant advances in the understanding of the neurobiology of reward processing and a growing recognition that disturbances in motivation and hedonic capacity are poorly targeted by current pharmacological and psychotherapeutic interventions. As a result, numerous studies have sought to test the presence of reward circuit dysfunction in psychiatric disorders that are marked by anhedonia, amotivation, mania, and impulsivity. Moreover, as the field has increasingly eschewed categorical diagnostic boundaries in favor of symptom dimensions, there has been a parallel rise in studies seeking to identify transdiagnostic neural markers of reward processing dysfunction that may transcend disorders. The thesis of this chapter is twofold: First, evidence indicates that specific subcomponents of reward processing map onto partially distinct neurobiological pathways. Second, specific subcomponents of reward processing, including reward learning and effort-based decision-making, are impaired across different mood disorder diagnoses and may point to dimensions in symptom presentation that possess more reliable behavioral and neural correlates. The potential for these findings to inform the development of prevention and treatment strategies is discussed.

scholarly journals All-Trans Retinoic Acid Increases DRP1 Levels and Promotes Mitochondrial Fission

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1202
Author(s):  
Bojjibabu Chidipi ◽  
Syed Islamuddin Shah ◽  
Michelle Reiser ◽  
Manasa Kanithi ◽  
Amanda Garces ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Mitochondrial Fission ◽  
Normal Function ◽  
Mitochondrial Network ◽  
Protein Levels ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Area And Perimeter

In the heart, mitochondrial homeostasis is critical for sustaining normal function and optimal responses to metabolic and environmental stressors. Mitochondrial fusion and fission are thought to be necessary for maintaining a robust population of mitochondria, and disruptions in mitochondrial fission and/or fusion can lead to cellular dysfunction. The dynamin-related protein (DRP1) is an important mediator of mitochondrial fission. In this study, we investigated the direct effects of the micronutrient retinoid all-trans retinoic acid (ATRA) on the mitochondrial structure in vivo and in vitro using Western blot, confocal, and transmission electron microscopy, as well as mitochondrial network quantification using stochastic modeling. Our results showed that ATRA increases DRP1 protein levels, increases the localization of DRP1 to mitochondria in isolated mitochondrial preparations. Our results also suggested that ATRA remodels the mitochondrial ultrastructure where the mitochondrial area and perimeter were decreased and the circularity was increased. Microscopically, mitochondrial network remodeling is driven by an increased rate of fission over fusion events in ATRA, as suggested by our numerical modeling. In conclusion, ATRA results in a pharmacologically mediated increase in the DRP1 protein. It also results in the modulation of cardiac mitochondria by promoting fission events, altering the mitochondrial network, and modifying the ultrastructure of mitochondria in the heart.

scholarly journals Individual differences in experienced and observational decision-making illuminate interactions between reinforcement learning and declarative memory

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Batel Yifrah ◽  
Ayelet Ramaty ◽  
Genela Morris ◽  
Avi Mendelsohn
Keyword(s):  
Decision Making ◽  
Reinforcement Learning ◽  
Declarative Memory ◽  
Contextual Information ◽  
Memory Performance ◽  
Relevant Information ◽  
Subjective Memory ◽  
Types Of Information ◽  
Reinforcement Learning Models ◽  
Implicit And Explicit

AbstractDecision making can be shaped both by trial-and-error experiences and by memory of unique contextual information. Moreover, these types of information can be acquired either by means of active experience or by observing others behave in similar situations. The interactions between reinforcement learning parameters that inform decision updating and memory formation of declarative information in experienced and observational learning settings are, however, unknown. In the current study, participants took part in a probabilistic decision-making task involving situations that either yielded similar outcomes to those of an observed player or opposed them. By fitting alternative reinforcement learning models to each subject, we discerned participants who learned similarly from experience and observation from those who assigned different weights to learning signals from these two sources. Participants who assigned different weights to their own experience versus those of others displayed enhanced memory performance as well as subjective memory strength for episodes involving significant reward prospects. Conversely, memory performance of participants who did not prioritize their own experience over others did not seem to be influenced by reinforcement learning parameters. These findings demonstrate that interactions between implicit and explicit learning systems depend on the means by which individuals weigh relevant information conveyed via experience and observation.

Sign in / Sign up

Export Citation Format

Share Document