GSK3β Activity in Reward Circuit Functioning and Addiction

Glycogen synthase kinase-3β (GSK3β), primarily described as a regulator of glycogen metabolism, is a molecular hub linking numerous signaling pathways and regulates many cellular processes like cytoskeletal rearrangement, cell migration, apoptosis, and proliferation. In neurons, the kinase is engaged in molecular events related to the strengthening and weakening of synapses, which is a subcellular manifestation of neuroplasticity. Dysregulation of GSK3β activity has been reported in many neuropsychiatric conditions, like schizophrenia, major depressive disorder, bipolar disorder, and Alzheimer’s disease. In this review, we describe the kinase action in reward circuit-related structures in health and disease. The effect of pharmaceuticals used in the treatment of addiction in the context of GSK3β activity is also discussed.

Art Is Its Own Reward

The “art infusion effect” suggests that people evaluate products more positively when they are associated with art images than non-art images. Using functional magnetic resonance imaging during viewing of art and non-art images matched for content, the authors investigated whether artistic status alone could activate the reward circuit. Relative to non-art images, art images indeed activated reward-related regions including the ventral striatum. This activity was uncorrelated with response times, ratings of familiarity, or aesthetic preference for art images, suggesting that these variables were unrelated to the art-selective activations. Effective connectivity analyses showed that the ventral striatum was driven by visual cortical regions when viewing art images but not non-art images and was not driven by regions that correlated with aesthetic preference for either art or non-art images. These findings suggest that visual art involves activation of reward circuitry based on artistic status alone and independently of its aesthetic value.

Different Features of Metabolic Connectivity Map and Granger Causality Method in Revealing Directed Dopamine Pathways: A Pilot Study Based on Integrated PET/MR

Granger causality (GC) analysis and metabolic connectivity map (MCM) are two effective connectivity (EC) methods commonly used in functional brain researches. Although they have a common basis in central neurophysiology, their differences in depicting EC are not clear because of absenting data acquired simultaneously and exactly aligned. Integrated positron emission tomography and magnetic resonance image (PET/MR) technology makes this available. Using the “Monash rs-PET/MR” dataset obtained from the OpenNeuro database, we first conducted GC and MCM analysis of the brain dopamine reward circuit, a well-known system mainly consisting of the bilateral Orbital Frontal Cortex (OFC), Caudate (CAU), Nucleus Accumbens (NAc), Thalamus (THA) and Substantia Nigra (SN). Then, we validated their ability of describing EC to priori knowledge. The significance of each directed pathways within group were tested through one-sample t-test (for MCM) or Wilcoxcon test (for GC), the significance level was set at p<0.05 after FDR correction. Three types of connections were found: the cortico-nucleus (long-range), the nucleus-nucleus (neighborhood) and the symmetrical connections. GC revealed long-range connections including OFC-CAU and OFC-NAc; MCM revealed neighborhood connections including NAc-CAU, SN-THA, and THA-CAU, the symmetrical connections including the bilateral NAc, CAU, THA, as well as OFC-CAU. Thus, different patterns in directional networks of dopamine reward circuit revealed by GC and MCM. GC predominated at aspects of cortico-nucleus bidirected connections, while MCM of directed connections among close regions and symmetrical regions. This study implicates that research involving in effective connections should choose an appropriate analysis method according to the study purpose.

Oxytocin neurons mediates the effect of social isolation via the VTA circuits

Social interaction during adolescence strongly influences brain function and behaviour, and the recent pandemic has emphasized the devastating effect of social distancing on mental health. While accumulating evidences have shown the importance of the reward system in encoding specific aspects of social interaction, the consequences of social isolation on the reward system and the development of social skills later in adulthood are still largely unknown. Here, we found that one week of social isolation during adolescence in mice increased social interaction at the expense of social habituation and social novelty preference. Behavioural changes were accompanied by the acute hyperexcitability of dopamine (DA) neurons in the ventral segmental area (VTA) and long-lasting expression of GluA2-lacking AMPARs at excitatory inputs onto DA neurons that project to the prefrontal cortex (PFC). Social isolation-dependent behavioural deficits and changes in neural activity and synaptic plasticity were reversed by chemogenetic inhibition of oxytocin neurons in the paraventricular nucleus (PVN) of the hypothalamus. These results demonstrate that social isolation has acute and long-lasting effects on social interaction and suggest that these effects are mediated by homeostatic adaptations within the reward circuit.

Early Life Adversity in Male Mice Sculpts Reward Circuits.

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In this study, we focused on the projections from the dorsal raphe (DR) to the ventral tegmental area (VTA) and on to the nucleus accumbens (NAcc), an important pathway within the reward circuit. We hypothesized that ELA alters connectivity within the DR-VTA-NAcc pathway, manifested behaviorally as anhedonia in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was acquired and processed for regional DTI metrics, including tractography to assess circuit organization. We found brain-wide changes in radial diffusivity (RD) and altered connectivity of the reward circuit in the ELA group. DR-VTA-NAcc circuit tractography and axial diffusivity (AD) along this tract exhibited dispersed organization where AD was increased in the VTA segment. Behaviorally, ELA elicited an anhedonic phenotype in adulthood with decreased direct social approach and time spent with peer but no overt differences in sucrose preference test. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may drive enduring reward deficits.

Decreased Nucleus Accumbens Connectivity at Rest in Medication-Free Patients with Obsessive-Compulsive Disorder

Background. Patients with obsessive-compulsive disorder (OCD) experience deficiencies in reward processing. The investigation of the reward circuit and its essential connectivity may further clarify the pathogenesis of OCD. Methods. The current research was designed to analyze the nucleus accumbens (NAc) functional connectivity at rest in medicine-free patients with OCD. Forty medication-free patients and 38 gender-, education-, and age-matched healthy controls (HCs) were recruited for resting-state functional magnetic resonance imaging. Seed-based functional connectivity (FC) was used to analyze the data. LIBSVM (library for support vector machines) was designed to identify whether altered FC could be applied to differentiate OCD. Results. Patients with OCD showed remarkably decreased FC values between the left NAc and the bilateral orbitofrontal cortex (OFC) and bilateral medial prefrontal cortex (MPFC) and between the right NAc and the left OFC at rest in the reward circuit. Moreover, decreased left NAc-bilateral MPFC connectivity can be deemed as a potential biomarker to differentiate OCD from HCs with a sensitivity of 80.00% and a specificity of 76.32%. Conclusion. The current results emphasize the importance of the reward circuit in the pathogenesis of OCD.