Functional connectivity based brain signatures of behavioral regulation in children with ADHD, DCD, and ADHD-DCD

Behavioral regulation problems have been associated with daily-life and mental health challenges in children with neurodevelopmental conditions such as attention-deficit/hyperactivity disorder (ADHD) and developmental coordination disorder (DCD). Here, we investigated transdiagnostic brain signatures associated with behavioral regulation. Resting-state fMRI data were collected from 115 children (31 typically developing (TD), 35 ADHD, 21 DCD, 28 ADHD-DCD) aged 7–17 years. Behavioral regulation was measured using the Behavior Rating Inventory of Executive Function and was found to differ between children with ADHD (i.e., children with ADHD and ADHD-DCD) and without ADHD (i.e., TD children and children with DCD). Functional connectivity (FC) maps were computed for 10 regions of interest and FC maps were tested for correlations with behavioral regulation scores. Across the entire sample, greater behavioral regulation problems were associated with stronger negative FC within prefrontal pathways and visual reward pathways, as well as with weaker positive FC in frontostriatal reward pathways. These findings significantly increase our knowledge on FC in children with and without ADHD and highlight the potential of FC as brain-based signatures of behavioral regulation across children with differing neurodevelopmental conditions.

Why Does Music Evoke Strong Emotions?

Although much is known about the brain mechanisms underlying music perception and cognition, there is much work to be done in understanding aesthetic responses to music: Why does music make us feel the way we do? Why does it make us feel anything? In the article under discussion, the authors suggest that the brain’s own endogenous opioids mediate musical emotion, using the hypothesis of naltrexone-induced musical anhedonia. They conclude that endogenous opioids are critical to experiencing both positive and negative emotions in music and that music uses the same reward pathways as food, drugs, and sexual pleasure. Their findings add to the growing body of evidence for the evolutionary biological substrates of music.

Systematic review of Pharmacogenomics Knowledgebase evidence for pharmacogenomic links to the dopamine reward pathway for heroin dependence

Genetics play an important role in opioid use disorder (OUD); however, few specific gene variants have been identified. Therefore, there is a need to further understand the pharmacogenomics influences on the pharmacodynamics of opioids. The Pharmacogenomics Knowledgebase (PharmGKB), a database that links genetic variation and drug interaction in the body, was queried to identify polymorphisms associated with heroin dependence in the context of opioid related disorders/OUD. Eight genes with 22 variants were identified as linked to increased risk of heroin dependence, with three genes and variants linked to decreased risk, although the level of evidence was moderate to low. Therefore, continued exploration of biomarker influences on OUD, reward pathways and other contributing circuitries is necessary to understand the true impact of genetics on OUD before integration into clinical guidelines.

Drosophila Corazonin Neurons as a Hub for Regulating Growth, Stress Responses, Ethanol-Related Behaviors, Copulation Persistence and Sexually Dimorphic Reward Pathways

The neuronal mechanisms by which complex behaviors are coordinated and timed often involve neuropeptidergic regulation of stress and reward pathways. Recent studies of the neuropeptide Corazonin (Crz), a homolog of the mammalian Gonadotrophin Releasing Hormone (GnRH), have suggested its crucial role in the regulation of growth, internal states and behavioral decision making. We focus this review on Crz neurons with the goal to (1) highlight the diverse roles of Crz neuron function, including mechanisms that may be independent of the Crz peptide, (2) emphasize current gaps in knowledge about Crz neuron functions, and (3) propose exciting ideas of novel research directions involving the use of Crz neurons. We describe the different developmental fates of distinct subsets of Crz neurons, including recent findings elucidating the molecular regulation of apoptosis. Crz regulates systemic growth, food intake, stress responses and homeostasis by interacting with the short Neuropeptide F (sNPF) and the steroid hormone ecdysone. Additionally, activation of Crz neurons is shown to be pleasurable by interacting with the Neuropeptide F (NPF) and regulates reward processes such as ejaculation and ethanol-related behaviors in a sexually dimorphic manner. Crz neurons are proposed to be a motivational switch regulating copulation duration using a CaMKII-dependent mechanism described as the first neuronal interval timer lasting longer than a few seconds. Lastly, we propose ideas to use Crz neuron-induced ejaculation to study the effects of fictive mating and sex addiction in flies, as well as to elucidate dimorphic molecular mechanisms underlying reward behaviors and feeding disorders.

Risk Assessment for Heroin Use and Craving Score Using Polygenic Risk Score

Addiction is characterized by drug-craving, compulsive drug-taking, and relapse, and results from the interaction between multiple genetic and environmental factors. Reward pathways play an important role in mediating drug-seeking and drug-taking behaviors, and relapse. The objective of this study was to identify heroin addicts who carry specific genetic variants in their dopaminergic reward systems. A total of 326 heroin-dependent patients undergoing methadone maintenance therapy (MMT) were recruited from the Addiction Center of the China Medical University Hospital. A heroin-use and craving questionnaire was used to evaluate the urge for heroin, the daily or weekly frequency of heroin usage, daily life disturbance, anxiety, and the ability to overcome heroin use. A general linear regression model was used to assess the associations of genetic polymorphisms in one’s dopaminergic reward system with heroin-use and craving scores. Results: The most significant results were obtained for rs2240158 in GRIN3B (p = 0.021), rs3983721 in GRIN3A (p = 0.00326), rs2129575 in TPH2 (p = 0.033), rs6583954 in CYP2C19 (p = 0.033), and rs174699 in COMT (p = 0.036). These were all associated with heroin-using and craving scores with and without adjustments for age, sex, and body mass index. We combined five variants, and the ensuing dose-response effect indicated that heroin-craving scores increased with the numbers of risk alleles (p for trend = 0.0008). These findings will likely help us to understand the genetic mechanism of craving, which will help in predicting the risk of relapse in clinical practice and the potential for therapies to target craving in heroin addiction.

The role of mGlu4 receptors within the nucleus accumbens in acquisition and expression of morphine-induced conditioned place preference in male rats

Background Several studies have shown that glutamate neurotransmission in the nucleus accumbens (NAc) is required for the development of morphine-induced conditional place preference (CPP). In addition, metabotropic glutamate receptors (mGluRs) in NAc play important roles in the reward pathways. However, the precise role of mGluR4 in different steps of the morphine-induced CPP is less well known. In the present study the effect of bilateral intra-accumbal infusion of VU0155041, as a specific mGluR4 agonist on the acquisition and expression of morphine induced CPP in male Wistar rats was investigated. The animals were bilaterally implanted with guide cannulae above the NAc. In the first step of the study, the VU0155041 was administered at doses of 10, 30 and 50 μg/0.5 μL saline per side into the NAc during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase of morphine-induced CPP. In the second step of the study, the rats bilaterally received VU0155041 at the dose of 50 μg/0.5 μL, 5 min before the post-conditioning test in order to check the effect of VU0155041 on the expression of morphine-induced CPP. Results The results showed that the intra-accumbal injection of VU0155041 inhibits the acquisition of morphine-induced CPP in a dose dependent manner, but had no effect on expression. Conclusions The data indicated that intra-NAc administration of VU0155041 dose dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine. These effects may be related to changes in glutamate activity in the NAC and/or learning dependent mechanism of glutamate neurotransmission in reward pathway(s).

Effect of chronic JUUL aerosol inhalation on inflammatory states of the brain, lung, heart and colon in mice

While health effects of conventional tobacco are well defined, data on vaping devices, including the most popular e-cigarette JUUL, are less established. Prior acute e-cigarette studies demonstrated inflammatory and cardiopulmonary physiology changes while chronic studies demonstrated extra-pulmonary effects, including neurotransmitter alterations in reward pathways. In this study we investigated effects of chronic flavored JUUL aerosol inhalation on inflammatory markers in brain, lung, heart, and colon. JUUL induced upregulation of cytokine and chemokine gene expression and increased HMGB1 and RAGE in the nucleus accumbens. Inflammatory gene expression increased in colon, and cardiopulmonary inflammatory responses to acute lung injury with lipopolysaccharide were exacerbated in the heart. Flavor-dependent changes in several responses were also observed. Our findings raise concerns regarding long-term risks of e-cigarette use as neuroinflammation may contribute to behavioral changes and mood disorders, while gut inflammation has been tied to poor systemic health and cardiac inflammation to development of heart disease.One Sentence SummaryChronic, daily inhalation of pod-based e-cigarette aerosols alters the inflammatory state across multiple organ systems in mice.

Long-term Hippocampal and Amydalar Dendritic Spine Alterations after Adolescence Psychosocial Stress

Stress, in particularly adolescence stress has been shown to result in long-term changes in brain and behavior of humans and rodents as well as predisposing individuals to multiple neuropsychiatric disorders like depression and schizophrenia. Stress-resulting in behavioral changes are often associated with structural changes of the neuronal dendritic spines, especially of the limbic system. Thus, analyzing alterations in structure of the dendritic spines in animals, which were subjected to adolescence stress, might provide useful information on pathogenesis of mental disorders. Herein, we analyzed the length, head width and area of dendritic spines of neurons from the hippocampal CA3, the central amygdala and the basolateral amygdala (BLA) regions in mature C57BL/6 mice, which were subjected to adolescent psychosocial stress. Results showed that stressed animals had longer spines in the hippocampus, larger spines in the BLA and shorter, smaller spines in the central amygdala (CeA). The latter finding is particularly intriguing, as it has been shown that central amygdala is not just the relay center for signals from the BLA in fear response, but is involved in antagonistic and inhibitory function to the BLA and active in appetitive and reward pathways.

The Role of mGluR4 Receptors Within the Nucleus Accumbens in the Acquisition and Expression of Morphine-induced Conditioned Place Preference in Male Rats

Background: Several studies have shown that glutamate neurotransmission in the nucleus accumbens (NAc) is required for the development of morphine-induced conditional place preference (CPP). Also, metabotropic glutamate receptors (mGluRs) into the NAc play important roles in the reward pathways. However, the precise role of mGluR4 in different steps of the morphine-induced CPP is less well known. In the present study we investigated the effect of bilateral intra-accumbal infusion of VU0155041, as a specific mGluR4 agonist on the acquisition and expression of morphine induced CPP in male Wistar rats. Animals were bilaterally implanted with guide cannulae above the NAc. In the first part of the study, the VU0155041 was administered at doses of 10, 30 and 50 μg/0.5 μL saline per side into the NAc during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase of morphine-induced CPP. In the next part of the study, the rats bilaterally received VU0155041 at the dose of 50 μg/0.5 μL, 5 min before the post-conditioning test to check the effect of VU0155041 on the expression of morphine-induced CPP. Results: The results showed that the intra-accumbal injection of VU0155041 inhibits the acquisition of morphine-induced CPP in a dose dependent manner, but had no effect on expression Our data indicated that intra-NAc administration of VU0155041 dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine.These effects may be related to changes in glutamate activity in the NAC and/or learning dependent mechanism of glutamate neurotransmission in reward pathway(s).

Can GLP-1 Be a Target for Reward System Related Disorders? A Qualitative Synthesis and Systematic Review Analysis of Studies on Palatable Food, Drugs of Abuse, and Alcohol

The role of glucagon-like peptide 1 (GLP-1) in insulin-dependent signaling is well-known; GLP-1 enhances glucose-dependent insulin secretion and lowers blood glucose in diabetes. GLP-1 receptors (GLP-1R) are also widely expressed in the brain, and in addition to its role in neuroprotection, it affects reward pathways. This systematic review aimed to analyze the studies on GLP-1 and reward pathways and its currently identified mechanisms.Methods: “Web of Science” and “Pubmed” were searched to identify relevant studies using GLP-1 as the keyword. Among the identified 26,539 studies, 30 clinical, and 71 preclinical studies were included. Data is presented by grouping rodent studies on palatable food intake, drugs of abuse, and studies on humans focusing on GLP-1 and reward systems.Results: GLP-1Rs are located in reward-related areas, and GLP-1, its agonists, and DPP-IV inhibitors are effective in decreasing palatable food intake, along with reducing cocaine, amphetamine, alcohol, and nicotine use in animals. GLP-1 modulates dopamine levels and glutamatergic neurotransmission, which results in observed behavioral changes. In humans, GLP-1 alters palatable food intake and improves activity deficits in the insula, hypothalamus, and orbitofrontal cortex (OFC). GLP-1 reduces food cravings partially by decreasing activity to the anticipation of food in the left insula of obese patients with diabetes and may inhibit overeating by increasing activity to the consumption of food in the right OFC of obese and left insula of obese with diabetes.Conclusion: Current preclinical studies support the view that GLP-1 can be a target for reward system related disorders. More translational research is needed to evaluate its efficacy on human reward system related disorders.