Reward Behavior Research Articles

Magnetoelectric nanodiscs enable wireless transgene-free neuromodulation.

Deep brain stimulation with implanted electrodes has transformed neuroscience studies and treatment of neurological and psychiatric conditions. Discovering less invasive alternatives to deep brain stimulation could expand its clinical and research applications. Nanomaterial-mediated transduction of magnetic fields into electric potentials has been explored as a means for remote neuromodulation. Here we synthesize magnetoelectric nanodiscs (MENDs) with a core-double-shell Fe3O4-CoFe2O4-BaTiO3 architecture (250 nm diameter and 50 nm thickness) with efficient magnetoelectric coupling. We find robust responses to magnetic field stimulation in neurons decorated with MENDs at a density of 1 µg mm-2 despite individual-particle potentials below the neuronal excitation threshold. We propose a model for repetitive subthreshold depolarization that, combined with cable theory, supports our observations in vitro and informs magnetoelectric stimulation in vivo. Injected into the ventral tegmental area or the subthalamic nucleus of genetically intact mice at concentrations of 1 mg ml-1, MENDs enable remote control of reward or motor behaviours, respectively. These findings set the stage for mechanistic optimization of magnetoelectric neuromodulation towards applications in neuroscience research.

Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice

The dopamine D3 receptor (D3R), principally confined to the nucleus accumbens (NAc), is involved in regulating natural and drug rewards; however, the molecular mechanisms underlying the associated process remain unclear. Earlier research has reported the concurrent influence of D3R and miR-29c expressed in the NAc on methamphetamine (METH)-induced reward behaviors and microglial activation, hinting at regulatory roles in reward processing. Herein, we performed viral manipulation-mediating D3R/miR-29c overexpression and inhibition in the whole NAc in male D3R knockout and wild-type mice to investigate this potential relationship. Behavioral responses to the rewarding stimuli were assessed using sucrose preference score, METH-induced locomotor sensitization, and METH-induced conditioned place preference tests. Overall, we observed a notable decrease in the behavioral response to sucrose and METH in D3R-deficient mice, accompanied by the downregulation of miR-29c expression in the NAc. Diminished responses to those rewarding stimuli in D3R-deficient mice primarily stemmed from the reduction of GSK3β activity and subsequent down-regulation of miR-29c in the NAc. Microglial activation in the NAc mediates the effect of D3R-miR-29c deficiency on the reward effects of sucrose and METH. Pharmacological suppression of microglial activity rescued the reduced response in mice lacking D3R-miR-29c in the NAc. Overall, this study revealed the mechanism by which D3R regulates both natural and drug rewards via miR-29c in the murine NAc, highlighting the role of the NAc D3R-miR-29c pathway as a critical regulator of rewards, and providing new insights into the role of NAc D3R-miR-29c in encoding rewarding experiences.

Blunted food conditioned place preference-like behavior in adolescent-stressed male hamsters

Social stress during adolescence results in long lasting weight gain, obesity, and enhanced food hoarding behavior in hamsters. We wanted to determine whether stress also enhanced conditioned place preference-like behavior (CPP-like) for food reward, as would be expected from studies with substances like cocaine. Our experimental animals were exposed daily to aggressive adults for two weeks in early puberty, while also trained to explore a V-shaped maze containing a food reward at one end. They were tested for CPP-like behavior on the last day of social stress. Our results showed that while stress enhanced weight gain, food intake, food efficiency, and body fat, it caused a reduction of Place Preference as compared to controls. In fact, the correlated relationship between Place Preference and body fat was inverted by stress exposure: while it was positively correlated in controls, it was mildly negatively correlated in stressed hamsters. These unexpected data illustrate the extent of adaptive behavior in foraging animals once a resource has become untrustworthy.

Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive-like behavior and attenuates motivation for reward.

Astrocytes are multi-functional glial cells in the central nervous system that play critical roles in modulation of metabolism, extracellular ion and neurotransmitter levels, and synaptic plasticity. Astrocyte-derived signaling molecules mediate many of these modulatory functions of astrocytes, including vesicular release of ATP. In the present study, we used a unique genetic mouse model to investigate the functional significance of astrocytic exocytosis of ATP. Using primary cultured astrocytes, we show that loss of vesicular nucleotide transporter (Vnut), a primary transporter responsible for loading cytosolic ATP into the secretory vesicles, dramatically reduces ATP loading into secretory lysosomes and ATP release, without any change in the molecular machinery of exocytosis or total intracellular ATP content. Deletion of astrocytic Vnut in adult mice leads to increased anxiety, depressive-like behaviors, and decreased motivation for reward, especially in females, without significant impact on food intake, systemic glucose metabolism, cognition, or sociability. These behavioral alterations are associated with significant decreases in the basal extracellular dopamine levels in the nucleus accumbens. Likewise, ex vivo brain slices from these mice show a strong trend toward a reduction in evoked dopamine release in the nucleus accumbens. Mechanistically, the reduced dopamine signaling we observed is likely due to an increased expression of monoamine oxidases. Together, these data demonstrate a key modulatory role of astrocytic exocytosis of ATP in anxiety, depressive-like behavior, and motivation for reward, by regulating the mesolimbic dopamine circuitry.

Chronic stress deficits in reward behaviour co-occur with low nucleus accumbens dopamine activity during reward anticipation specifically

Whilst reward pathologies are major and common in stress-related neuropsychiatric disorders, their neurobiology and treatment are poorly understood. Imaging studies in human reward pathology indicate attenuated BOLD activity in nucleus accumbens (NAc) coincident with reward anticipation but not reinforcement; potentially, this is dopamine (DA) related. In mice, chronic social stress (CSS) leads to reduced reward learning and motivation. Here, DA-sensor fibre photometry is used to investigate whether these behavioural deficits co-occur with altered NAc DA activity during reward anticipation and/or reinforcement. In CSS mice relative to controls: (1) Reduced discriminative learning of the sequence, tone-on + appetitive behaviour = tone-on + sucrose reinforcement, co-occurs with attenuated NAc DA activity throughout tone-on and sucrose reinforcement. (2) Reduced motivation during the sequence, operant behaviour = tone-on + sucrose delivery + sucrose reinforcement, co-occurs with attenuated NAc DA activity at tone-on and typical activity at sucrose reinforcement. (3) Reduced motivation during the sequence, operant behaviour = appetitive behaviour + sociosexual reinforcement, co-occurs with typical NAc DA activity at female reinforcement. Therefore, in CSS mice, low NAc DA activity co-occurs with low reward anticipation and could account for deficits in learning and motivation, with important implications for understanding human reward pathology.

Don't Give-Up: Why some intervention schemes encourage suboptimal behavior.

Many social challenges stem from individuals' tendency to prefer immediately rewarding but suboptimal behaviors ("Give-Up" options) over more costly endeavors that yield much better outcomes in the long run ("Try" options). For example, many people forgo the long-term benefits of formal education, healthy diets, learning new technologies, and even finding true love. This paper examines various incentivization programs that combine external rewards and punishments to discourage such counterproductive behaviors, which often result in only temporary behavioral change. Our findings suggest that some interventions' limited impact may be due to their focus on only shifting behaviors from "Give-Up" (e.g., dropping out of college, avoiding the gym) to "Try" (e.g., attending college, exercising regularly), without promoting sufficient exploration of these "Try" options. Yet exploration of the long-term benefits of "Trying" may be crucial to increase the chances of long-term learning and commitment. Using a simplified abstraction of this dilemma, our results show a high tendency to choose "Give-Up" options prior to intervention. Examination of four different incentivization strategies suggests that onlyrewarding exploration of new "Try" options is a straightforward strategy to increase exploration and optimal choice. Punishing both the selection of "Give-Up" options and the choice to exploit suboptimal "Try" options produced similar results. Other common guidance strategies were less effective, as these strategies simply tended to replace one suboptimal behavior with another. Surprisingly, punishments seemed to bea relatively more successful incentive than rewards. We discuss how these insights can help guide policy aiming to improve long-term outcomes through incentivization.

Opioid Use and Gut Dysbiosis in Cancer Pain Patients.

Opioids are commonly used for the management of severe chronic cancer pain. Their well-known pharmacological effects on the gastrointestinal system, particularly opioid-induced constipation (OIC), are the most common limiting factors in the optimization of analgesia, and have led to the wide use of laxatives and/or peripherally acting mu-opioid receptor antagonists (PAMORAs). A growing interest has been recently recorded in the possible effects of opioid treatment on the gut microbiota. Preclinical and clinical data, as presented in this review, showed that alterations of the gut microbiota play a role in modulating opioid-mediated analgesia and tolerability, including constipation. Moreover, due to the bidirectional crosstalk between gut bacteria and the central nervous system, gut dysbiosis may be crucial in modulating opioid reward and addictive behavior. The microbiota may also modulate pain regulation and tolerance, by activating microglial cells and inducing the release of inflammatory cytokines and chemokines, which sustain neuroinflammation. In the subset of cancer patients, the clinical meaning of opioid-induced gut dysbiosis, particularly its possible interference with the efficacy of chemotherapy and immunotherapy, is still unclear. Gut dysbiosis could be a new target for treatment in cancer patients. Restoring the physiological amount of specific gut bacteria may represent a promising therapeutic option for managing gastrointestinal symptoms and optimizing analgesia for cancer patients using opioids.

Cellular and circuit architecture of the lateral septum for reward processing

The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LSEsr1) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LSEsr1 neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization.

Regulator of G Protein Signaling 14 protein expression profile in the adult mouse brain.

Regulator of G protein signaling 14 (RGS14) is a multifunctional signaling protein that serves as a natural suppressor of synaptic plasticity in the mouse brain. Our previous studies showed that RGS14 is highly expressed in postsynaptic dendrites and spines of pyramidal neurons in hippocampal area CA2 of the developing mouse brain. However, our more recent work with adult rhesus macaque brain shows that RGS14 is found in multiple neuron populations throughout hippocampal area CA1 and CA2, caudate nucleus, putamen, globus pallidus, substantia nigra, and amygdala in the adult rhesus monkey brain. In the mouse brain, we also have observed RGS14 protein in discrete limbic regions linked to reward behavior and addiction, including the central amygdala and the nucleus accumbens, but a comprehensive mapping of RGS14 protein expression in the adult mouse brain is lacking. Here, we report that RGS14 is more broadly expressed in mouse brain than previously known. Intense RGS14 staining is observed in specific neuron populations of the hippocampal formation, amygdala, septum, bed nucleus of stria terminalis and ventral striatum/nucleus accumbens. RGS14 is also observed in axon fiber tracts including the dorsal fornix, fimbria, stria terminalis, and the ventrohippocampal commissure. Moderate RGS14 staining is observed in various other adjacent regions not previously reported. These findings show that RGS14 is expressed in brain regions that govern aspects of core cognitive functions such as sensory perception, emotion, memory, motivation, and execution of actions, and suggests that RGS14 may serve to suppress plasticity and filter inputs in these brain regions to set the overall tone on experience-to-action processes.

VTA glutamatergic projections to the nucleus accumbens suppress psychostimulant-seeking behavior

Converging evidence indicates that both dopamine and glutamate neurotransmission within the nucleus accumbens (NAc) play a role in psychostimulant self-administration and relapse in rodent models. Increased NAc dopamine release from ventral tegmental area (VTA) inputs is critical to psychostimulant self-administration and NAc glutamate release from prelimbic prefrontal cortex (PFC) inputs synapsing on medium spiny neurons (MSNs) is critical to reinstatement of psychostimulant-seeking after extinction. The regulation of the activity of MSNs by VTA dopamine inputs has been extensively studied, and recent findings have demonstrated that VTA glutamate neurons target the NAc medial shell. Here, we determined whether the mesoaccumbal glutamatergic pathway plays a role in psychostimulant conditioned place preference and self-administration in mice. We used optogenetics to induce NAc release of glutamate from VTA inputs during the acquisition, expression, and reinstatement phases of cocaine- or methamphetamine-induced conditioned place preference (CPP), and during priming-induced reinstatement of cocaine-seeking behavior. We found that NAc medial shell release of glutamate resulting from the activation of VTA glutamatergic fibers did not affect the acquisition of cocaine-induced CPP, but it blocked the expression, stress- and priming-induced reinstatement of cocaine- and methamphetamine CPP, as well as it blocked the priming-induced reinstatement of cocaine-seeking behavior after extinction. These findings indicate that in contrast to the well-recognized mesoaccumbal dopamine system that is critical to psychostimulant reward and relapse, there is a parallel mesoaccumbal glutamatergic system that suppresses reward and psychostimulant-seeking behavior.

Synchronous Measurements of Extracellular Action Potentials and Neurochemical Activity with Carbon Fiber Electrodes in Nonhuman Primates.

Measuring the dynamic relationship between neuromodulators, such as dopamine, and neuronal action potentials is imperative to understand how these fundamental modes of neural signaling interact to mediate behavior. We developed methods to measure concurrently dopamine and extracellular action potentials (i.e., spikes) in monkeys. Standard fast-scan cyclic voltammetric (FSCV) electrochemical (EChem) and electrophysiological (EPhys) recording systems are combined and used to collect spike and dopamine signals, respectively, from an array of carbon fiber (CF) sensors implanted in the monkey striatum. FSCV requires the application of small voltages at the implanted sensors to measure redox currents generated from target molecules, such as dopamine. These applied voltages create artifacts at neighboring EPhys measurement sensors which may lead to misclassification of these signals as physiological spikes. Therefore, simple automated temporal interpolation algorithms were designed to remove these artifacts and enable accurate spike extraction. We validated these methods using simulated artifacts and demonstrated an average spike recovery rate of 84.5%. We identified and discriminated cell type-specific units in the monkey striatum that were shown to correlate to specific behavioral task parameters related to reward size and eye movement direction. Synchronously recorded spike and dopamine signals displayed contrasting relations to the task variables, suggesting a complex relationship between these two modes of neural signaling. Future application of our methods will help advance our understanding of the interactions between neuromodulator signaling and neuronal activity, to elucidate more detailed mechanisms of neural circuitry and plasticity mediating behaviors in health and in disease.

A Learnheuristic Algorithm Based on Thompson Sampling for the Heterogeneous and Dynamic Team Orienteering Problem

The team orienteering problem (TOP) is a well-studied optimization challenge in the field of Operations Research, where multiple vehicles aim to maximize the total collected rewards within a given time limit by visiting a subset of nodes in a network. With the goal of including dynamic and uncertain conditions inherent in real-world transportation scenarios, we introduce a novel dynamic variant of the TOP that considers real-time changes in environmental conditions affecting reward acquisition at each node. Specifically, we model the dynamic nature of environmental factors—such as traffic congestion, weather conditions, and battery level of each vehicle—to reflect their impact on the probability of obtaining the reward when visiting each type of node in a heterogeneous network. To address this problem, a learnheuristic optimization framework is proposed. It combines a metaheuristic algorithm with Thompson sampling to make informed decisions in dynamic environments. Furthermore, we conduct empirical experiments to assess the impact of varying reward probabilities on resource allocation and route planning within the context of this dynamic TOP, where nodes might offer a different reward behavior depending upon the environmental conditions. Our numerical results indicate that the proposed learnheuristic algorithm outperforms static approaches, achieving up to 25% better performance in highly dynamic scenarios. Our findings highlight the effectiveness of our approach in adapting to dynamic conditions and optimizing decision-making processes in transportation systems.

Unlocking Innovation from Within: The Power of Tacit Knowledge and Change Adaptability in Indonesian Internal Organisational Innovation Processes

Abstract Research purpose. The study examines how tacit knowledge sharing affects internal organisational innovation by exploring change adaptability as a mediator. Hence, it tries to fill this gap and further explain the role played by tacit knowledge sharing in the entire knowledge management process. Given the mediating effect of change adaptability, this study aims to provide new insight into effective management and sharing tacit knowledge among organisations to improve their innovation processes. Design / Methodology / Approach. This study adopted a quantitative cross-sectional survey design, with Partial Least Squares Structural Equation Modeling (PLS-SEM) as the main statistical technique. Such a method is best applied in this research, where one confirms hypotheses and the relationship between observed and latent variables. The samples were selected based on judgmental non-probability and purposive sampling approaches. The SEM was used in data analysis. It contributed to understanding the relationship of the variables, such as sharing tacit knowledge, change adaptability, and internal organisational innovation. Findings. The study proved that tacit knowledge sharing is highly significant in internal organisational innovation, mediated by change adaptability. Direct effect: Tacit knowledge sharing directly affects the organisational ability to adapt to change and internal innovativeness, thus underpinning its basis. Change adaptability mediates the effect of tacit knowledge sharing on internal organisational innovation, which influences innovation outcomes. Path coefficient analysis confirms the positive influence of tacit knowledge sharing on adaptability to change and innovation. Indirect Effects: Empirical examination has proved the significant mediating effect of change adaptability in leveraging tacit knowledge for innovation. These results suggest that the strategic value of tacit knowledge and adaptability, which will drive sustainable innovation within organisations and support their integration within strategic frameworks, is fully justified. Originality / Value / Practical implications. This is a new model used for the first time to suggest novel contributions and usefulness in understanding the relationship among sharing of tacit knowledge, change adaptability, and innovation at the internal level of the organisation. Tacit knowledge sharing, combined with change adaptability, is a model for internal organisational innovation. Therefore, it fills an important gap in the existing literature: the quantification of adaptability in mediating the effect of tacit knowledge on innovation. The results of this study will provide empirical validation of these relationships and further contribute to the knowledge in practice, particularly by emphasising the mediating role of change adaptability, which has been relatively underexplored. Practically, tacit knowledge sharing within adaptive organisational environments is thus an important call towards effective adaptation to change. The level of enhancement of these dimensions as core competencies through strategies could make a difference in the success of businesses. The importance of adaptability has to be emphasised by training programs and management practices that would provide the same skills. Other important avenues include those that work towards cultivating supportive organisational cultures that would facilitate tacit knowledge exchange, support employee interaction and informal knowledge exchange, and measures to reward innovation efforts. Investment in human resources practices that encourage learning and adaptability will continue to encourage knowledge sharing and innovation, including improving training programs, offering mentorship opportunities, and developing performance management systems that support and reward behaviours around innovation. This study contributes to the literature with a developed framework and empirical examination of the interrelations between tacit knowledge sharing, change adaptability, and innovation. It provides practical strategies that can be of value to the organisation in enhancing innovation capabilities through knowledge management.

Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity.

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPe PV ) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPe PV cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNr GABA ), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTA DA ) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPe PV cells is the indirect pathway of the dorsomedial striatum (DMS D 2 ), which receives DAergic innervation from collaterals of VTA DA →NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMS D 2 cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPe PV cells, closing the loop. Interestingly, the level of GPe PV cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPe PV cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPe PV cells following a single cocaine exposure, contributing to the elevation in GPe PV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPe PV cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.

Sex differences in the structure and function of the vasopressin system in the ventral pallidum are associated with the sex-specific regulation of social play behavior in juvenile rats

Vasopressin (AVP) regulates various social behaviors, often in sex-specific ways, including social play behavior, a rewarding behavior displayed primarily by juveniles. Here, we examined whether and how AVP acting in the brain's reward system regulates social play behavior in juvenile rats. Specifically, we focused on AVP signaling in the ventral pallidum (VP), a brain region that is a part of the reward system. First, we examined the organization of the VP-AVP system in juvenile rats and found sex differences, with higher density of both AVP-immunoreactive fibers and AVP V1a receptor (V1aR) binding in males compared to females while females show a greater number of V1aR-expressing cells compared to males. We further found that, in both sexes, V1aR-expressing cells co-express a GABA marker to a much greater extent (approx. 10 times) than a marker for glutamate. Next, we examined the functional involvement of V1aR-expressing VP cells in social play behavior. We found that exposure to social play enhanced the proportion of activated V1aR-expressing VP cells in males only. Finally, we showed that infusion of a specific V1aR antagonist into the VP increased social play behaviors in juvenile male rats while decreasing these behaviors in juvenile female rats. Overall, these findings reveal structural and functional sex differences in the AVP-V1aR system in the VP that are associated with the sex-specific regulation of social play behavior.

The feasibility of acupuncture on post-spinal cord injury treatment

Spinal cord injury (SCI) simultaneously causes multiple and interrelated pathophysiological disorders throughout the nervous system, hindering the development of effective treatment strategies. Mechanistically, SCI triggers excitatory signaling activation, downregulation of the inhibitory system, neuronal death, followed by the development of new synaptic circuits and reorganization, leading to chronic neurological dysfunctions and mental disorders. Therefore, a simultaneous treatment strategy, known as overlapping treatment, is needed. Over decades, both preclinical and clinical studies have established that acupuncture treatment offers neuroprotection, pain attenuation, improvement of functional recovery, and promotes reward behaviors, suggesting potential roles of acupuncture in post-SCI treatment. Recently, the importance of overlapping treatment has been recognized in developing effective treatments for post-SCI pathophysiology. However, there has been no systematic study investigating the role of acupuncture in various SCI pathophysiology. In this review, we briefly address the mechanisms of post-SCI pathophysiology and discuss the potential therapeutic effects of acupuncture, suggesting its feasibility as a treatment for post-SCI pathophysiology.

The mutated cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)-interacting protein 2 (CYFIP2 S968F) regulates cocaine-induced reward behaviour and plasticity in the nucleus accumbens.

Cytoplasmic fragile X messenger ribonucleoprotein 1 (FMR1)-interacting protein 2 (CYFIP2), as a component of the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) regulatory complex, is involved in actin polymerization, contributing to neuronal development and structural plasticity. Mutating serine-968 to phenylalanine (S968F) in CYFIP2 causes an altered cocaine response in mice. The neuronal mechanisms underlying this response remain unknown. We performed cocaine reward-related behavioural tests and examined changes in synaptic protein phenotypes and neuronal morphology in the nucleus accumbens (NAc), using CYFIP2 S968F knock-in mice to investigate the role of CYFIP2 in regulating cocaine reward. CYFIP2 S968F mutation attenuated cocaine-induced behavioural sensitization and conditioned place preference. Cocaine-induced c-Fos was not observed in the NAc of CYFIP2 S968F knock-in mice. However, c-Fos induction was still evident in the medial prefrontal cortex (mPFC). CYFIP2 S968F mutation altered cocaine-associated CYFIP2 signalling, glutamatergic protein expression and synaptic density in the NAc following cocaine exposure. To further determine the role of CYFIP2 in NAc neuronal activity and the mPFC projecting to the NAc activity-mediating reward response, we used optogenetic tools to stimulate the NAc or mPFC-NAc pathway and observed that optogenetic activation of the NAc or mPFC-NAc pathway induced reward-related behaviours. This effect was not observed in the S968F mutation in CYFIP2. These results suggest that CYFIP2 plays a role in controlling cocaine-mediated neuronal function and structural plasticity in the NAc, and that CYFIP2 could serve as a target for regulating cocaine reward.

Dopamine Pharmacodynamics: New Insights.

Dopamine is a key neurotransmitter involved in physiological processes such as motor control, motivation, reward, cognitive function, and maternal and reproductive behaviors. Therefore, dysfunctions of the dopaminergic system are related to a plethora of human diseases. Dopamine, via different circuitries implicated in compulsive behavior, reward, and habit formation, also represents a key player in substance use disorder and the formation and perpetuation of mechanisms leading to addiction. Here, we propose dopamine as a model not only of neurotransmission but also of neuromodulation capable of modifying neuronal architecture. Abuse of substances like methamphetamine, cocaine, and alcohol and their consumption over time can induce changes in neuronal activities. These modifications lead to synaptic plasticity and finally to morphological and functional changes, starting from maladaptive neuro-modulation and ending in neurodegeneration.

Predicting suicidality with small sets of interpretable reward behavior and survey variables

The prediction of suicidal thought and behavior has met with mixed results. This study of 3,476 de-identified participants (4,019 before data exclusion) quantified the prediction of four suicidal thought and behavior (STB) variables using a short reward/aversion judgment task and a limited set of demographic and mental health surveys. The focus was to produce a simple, quick and objective framework for assessing STB that might be automatable, without the use of big data. A balanced random forest classifier performed better than a Gaussian mixture model and four standard machine learning classifiers for predicting passive suicide ideation, active suicide ideation, suicide planning and planning for safety. Accuracies ranged from 78% to 92% (optimal area under the curve between 0.80 and 0.95) without overfitting, and peak performance was observed for predicting suicide planning. The relative importance of features for prediction showed distinct weighting across judgment variables, contributing between 40% and 64% to prediction per Gini scores. Mediation/moderation analyses showed that depression, anxiety, loneliness and age variables moderated the judgment variables, indicating that the interaction of judgment with mental health and demographic indices is fundamental for the high-accuracy prediction of STB. These findings suggest the feasibility of an efficient and highly scalable system for suicide assessment, without requiring psychiatric records or neural measures. The findings suggest that STB might be understood within a cognitive framework for judgment with quantitative variables whose unique constellation separates passive and active suicidal thought (ideation) from suicide planning and planning for safety.

WEBSITES IN VASCULAR HEALTH: A TOOL FOR WHOM? USER CHARACTERISTICS AND MOTIVATIONS

Objective: Limited data is available to describe the characteristics and motivations of users of health websites. Self-determination theory (Deci & Ryan, 2000) proposed three categories of motivation: 1) autonomous motivation: engaging in a behavior because it is perceived to be consistent with intrinsic and meaningful goals, 2) controlled motivation: engaging in a behavior for reward, or trying to avoid feelings of guilt, and 3) amotivation: lack of autonomous and controlled motivation. The aim of this study is to profile users and described the motivations behind using a health website. Design and method: In this multicenter study, participants had to be 18 years and older, concerned by a vascular health condition, and skilled to use digital tools. They were approached by collaborating physicians (n=30) during routine consultations or through social networks. An anonymous, validated electronic questionnaire assessed socio-demographic variables, digital competence, and motivations for using a health website. Results: 137 participants, mean age of 65.25 (± 11.78 years, 52.5% female) were recruited. The most prevalent diagnoses among participants were hypertension (48.70%) and diabetes (31.40%). The group aged 64 and below self-evaluated with better digital competence (8.97 ± 2.76) compared to the 65-74 age group (7.5 ± 2.70) and the 75 years and older group (6.41 ± 3.25) (p < 0.01). The difference between the women's and men's group did not reach statistical significance. Regarding motivation to consult a health website, the group aged 64 and below shows higher autonomous motivation (5.53± 0.16) than the 65-74 age group (5.33 ± 0.11) and the 75 years and older group (5.40 ± 0.38) (p < 0.01). Autonomous motivation was higher in the women's group (5.48 ± 0.13) than in the men's group (5.39 ± 0.32) (p < 0.05). Inversely, controlled motivation (2.94 ± 0.58) and amotivation (3.61 ± 0.33), was higher in men's group than in women's group (2.54 ± 0.55 and 3.30 ± 0.40) (p < 0.001). Conclusions: Motivations to use a health website vary according to gender and age. This study may contribute to a more tailored to users and guide the development and dissemination of health websites.