Endocannabinoid signaling mediates oxytocin-driven social reward.

Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions.

Administration of CoQ10 analogue ameliorates dysfunction of the mitochondrial respiratory chain in a mouse model of Angelman syndrome.

Genetic defects in the UBE3A gene, which encodes for the imprinted E6-AP ubiquitin E3 ligase (UBE3A), is responsible for the occurrence of Angelman syndrome (AS), a neurodegenerative disorder which arises in 1 out of every 12,000-20,000 births. Classical symptoms of AS include delayed development, impaired speech, and epileptic seizures with characteristic electroencephalography (EEG) readings. We have previously reported impaired mitochondrial structure and reduced complex III in the hippocampus and cerebellum in the Ube3a(m-/p+) mice. CoQ10 supplementation restores the electron flow to the mitochondrial respiratory chain (MRC) to ultimately increase mitochondrial antioxidant capacity. A number of recent studies with CoQ10 analogues seem promising in providing therapeutic benefit to patients with a variety of disorders. CoQ10 therapy has been reported to be safe and relatively well-tolerated at doses as high as 3000mg/day in patients with disorders of CoQ10 biosynthesis and MRC disorders. Herein, we report administration of idebenone, a potent CoQ10 analogue, to the Ube3a(m-/p+) mouse model corrects motor coordination and anxiety levels, and also improves the expression of complexes III and IV in hippocampus CA1 and CA2 neurons and cerebellum in these Ube3a(m-/p+) mice. However, treatment with idebenone illustrated no beneficial effects in the reduction of oxidative stress. To our knowledge, this is the first study to suggest an improvement in mitochondrial respiratory chain dysfunction via bioenergetics modulation with a CoQ10 analogue. These findings may further elucidate possible cellular and molecular mechanism(s) and ultimately a clinical therapeutic approach/benefit for patients with Angelman syndrome.

Combinatorial approaches for treating neuropsychiatric social impairment.

Social behaviour is an essential component of human life and deficits in social function are seen across multiple psychiatric conditions with high morbidity. However, there are currently no FDA-approved treatments for social dysfunction. Since social cognition and behaviour rely on multiple signalling processes acting in concert across various neural networks, treatments aimed at social function may inherently require a combinatorial approach. Here, we describe the social neurobiology of the oxytocin and endocannabinoid signalling systems as well as translational evidence for their use in treating symptoms in the social domain. We leverage this systems neurobiology to propose a network-based framework that involves pharmacology, psychotherapy, non-invasive brain stimulation and social skills training to combinatorially target trans-diagnostic social impairment. Lastly, we discuss the combined use of oxytocin and endocannabinoids within our proposed framework as an illustrative strategy to treat specific aspects of social function. Using this framework provides a roadmap for actionable treatment strategies for neuropsychiatric social impairment. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.

Unveiling the Pathogenesis of Psychiatric Disorders Using Network Models.

Psychiatric disorders are complex brain disorders with a high degree of genetic heterogeneity, affecting millions of people worldwide. Despite advances in psychiatric genetics, the underlying pathogenic mechanisms of psychiatric disorders are still largely elusive, which impedes the development of novel rational therapies. There has been accumulating evidence suggesting that the genetics of complex disorders can be viewed through an omnigenic lens, which involves contextualizing genes in highly interconnected networks. Thus, applying network-based multi-omics integration methods could cast new light on the pathophysiology of psychiatric disorders. In this review, we first provide an overview of the recent advances in psychiatric genetics and highlight gaps in translating molecular associations into mechanistic insights. We then present an overview of network methodologies and review previous applications of network methods in the study of psychiatric disorders. Lastly, we describe the potential of such methodologies within a multi-tissue, multi-omics approach, and summarize the future directions in adopting diverse network approaches.

Cortical Representations of Conspecific Sex Shape Social Behavior.

A central question related to virtually all social decisions is how animals integrate sex-specific cues from conspecifics. Using microendoscopic calcium imaging in mice, we find that sex information is represented in the dorsal medial prefrontal cortex (dmPFC) across excitatory and inhibitory neurons. These cells form a distributed code that differentiates the sex of conspecifics and is strengthened with social experience. While males and females both represent sex in the dmPFC, male mice show stronger encoding of female cues, and the relative strength of these sex representations predicts sex preference behavior. Using activity-dependent optogenetic manipulations of natively active ensembles, we further show that these specific representations modulate preference behavior toward males and females. Together, these results define a functional role for native representations of sex in shaping social behavior and reveal a neural mechanism underlying male- versus female-directed sociality.

Benzisothiazolinone Derivatives as Potent Allosteric Monoacylglycerol Lipase Inhibitors That Functionally Mimic Sulfenylation of Regulatory Cysteines.

We describe a set of benzisothiazolinone (BTZ) derivatives that are potent inhibitors of monoacylglycerol lipase (MGL), the primary degrading enzyme for the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Structure-activity relationship studies evaluated various substitutions on the nitrogen atom and the benzene ring of the BTZ nucleus. Optimized derivatives with nanomolar potency allowed us to investigate the mechanism of MGL inhibition. Site-directed mutagenesis and mass spectrometry experiments showed that BTZs interact in a covalent reversible manner with regulatory cysteines, Cys201 and Cys208, causing a reversible sulfenylation known to modulate MGL activity. Metadynamics simulations revealed that BTZ adducts favor a closed conformation of MGL that occludes substrate recruitment. The BTZ derivative 13 protected neuronal cells from oxidative stimuli and increased 2-AG levels in the mouse brain. The results identify Cys201 and Cys208 as key regulators of MGL function and point to the BTZ scaffold as a useful starting point for the discovery of allosteric MGL inhibitors.

[Application of panoramic film in predicting orthodontic treatment time for impacted maxillary canine].

PURPOSE: To evaluate the influence of pretreatment radiographic features (angle, distance, and location) on the duration of active orthodontic traction. METHODS: Sixty maxillary unilateral impacted canines were selected to analyze the panoramic features(angle, line spacing, and location) in pre-treatment patients， the results were evaluated using SPSS19.0 software package for multivariate regression analysis. RESULTS: Pretreatment radiographic variables (angle, line spacing, and location) were significantly associated with the duration of orthodontic traction. The sex and site of impaction did not significantly affect the duration of traction. CONCLUSIONS: Impacted canine angle, distance and position can predict the orthodontic traction time.

Endocannabinoid Signaling in the Control of Social Behavior.

Many mammalian species, including humans, exhibit social behavior and form complex social groups. Mechanistic studies in animal models have revealed important roles for the endocannabinoid signaling system, comprising G protein-coupled cannabinoid receptors and their endogenous lipid-derived agonists, in the control of neural processes that underpin social anxiety and social reward, two key aspects of social behavior. An emergent insight from these studies is that endocannabinoid signaling in specific circuits of the brain is context dependent and selectively recruited. These insights open new vistas on the neural basis of social behavior and social impairment.

Extensibility effect of poly(3-hexylthiophene) on the glucose sensing performance of mixed poly(3-hexylthiophene)/octadecylamine/glucose oxidase Langmuir-Blodgett films.

Poly(3-hexylthiophene) (P3HT) is utilized as a material to enhance the glucose sensing performance of glucose oxidase (GOx) Langmuir-Blodgett (LB) films. To enhance the extensibility and homogeneity of the P3HT in the LB films, octadecylamine (ODA) is introduced. The characteristics of the mixed P3HT/ODA Langmuir monolayers are investigated first and then, utilized as template layers to adsorb GOx from the subphase, preparing P3HT/ODA/GOx Langmuir-Blodgett films for glucose sensing. The results show that P3HT molecules tend to aggregate at the air/liquid interface and, furthermore, the P3HT monolayer has a weak ability to adsorb GOx from the subphase. By using mixed P3HT/ODA monolayer, the presence of ODA not only inhibits the aggregation of P3HT, but also increases the adsorption ability of the monolayer to GOx. The extensibility of P3HT and the homogeneity of the P3HT/ODA monolayers are closely related to the concentration of P3HT/ODA stock solutions. On the glucose sensing experiments, the performance of the P3HT/ODA/GOx LB film is greatly improved due to the presence of P3HT and, furthermore, the sensibility increases with increasing extensibility of P3HT molecules. The best sensitivity achieved for the P3HT/ODA/GOx film is 5.4µAmM-1cm-2 which is over two times the value obtained by the ODA/GOx film (2.3µAmM-1cm-2).

A role for the endocannabinoid 2-arachidonoyl-sn-glycerol for social and high-fat food reward in male mice.

RATIONALE: The endocannabinoid system is an important modulator of brain reward signaling. Investigations have focused on cannabinoid (CB1) receptors, because dissection of specific contributions of individual endocannabinoids has been limited by the available toolset. While we recently described an important role for the endocannabinoid anandamide in the regulation of social reward, it remains to be determined whether the other major endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), serves a similar or different function. OBJECTIVES: To study the role of 2-AG in natural reward, we used a transgenic mouse model (MGL-Tg mice) in which forebrain 2-AG levels are selectively reduced. We complemented behavioral analysis with measurements of brain 2-AG levels. METHODS: We tested male MGL-Tg mice in conditioned place preference (CPP) tasks for high-fat food, social contact, and cocaine. We measured 2-AG content in the brain regions of interest by liquid chromatography/mass spectrometry. RESULTS: Male MGL-Tg mice are impaired in developing CPP for high-fat food and social interaction, but do develop CPP for cocaine. Furthermore, compared to isolated mice, levels of 2-AG in socially stimulated wild-type mice are higher in the nucleus accumbens and ventral hippocampus (183 and 140 % of controls, respectively), but unchanged in the medial prefrontal cortex. CONCLUSIONS: The results suggest that reducing 2-AG-mediated endocannabinoid signaling impairs social and high-fat food reward in male mice, and that social stimulation mobilizes 2-AG in key brain regions implicated in the control of motivated behavior. The time course of this response differentiates 2-AG from anandamide, whose role in mediating social reward was previously documented.

Enhancement of Anandamide-Mediated Endocannabinoid Signaling Corrects Autism-Related Social Impairment.

Introduction: We recently uncovered a signaling mechanism by which the endocannabinoid anandamide mediates the action of oxytocin, a neuropeptide that is crucial for social behavior, to control social reward. Oxytocin signaling has been implicated in autism spectrum disorder (ASD), and social reward is a key aspect of social functioning that is thought to be disrupted in ASD. Therefore, as a proof of principle for the core component of ASD-social impairment-we tested an endocannabinoid-enhancing compound on two widely studied mouse models of ASD, the BTBR and fmr1-/- (model of Fragile X Syndrome). Methods: We used the established three-chambered social approach test. We specifically increased the activity of anandamide by administering the compound URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH), the hydrolytic enzyme for anandamide. Results: Remarkably, we found that FAAH blockade completely reversed the social impairment in both mouse models. CB1 receptor blockade prevented the prosocial action of FAAH inhibition in BTBR mice. These results were likely independent of effects on anxiety, as FAAH inhibition did not alter the performance of BTBR mice in the elevated plus maze. Conclusions: The results suggest that increasing anandamide activity at CB1 receptors improves ASD-related social impairment and identify FAAH as a novel therapeutic target for ASD.

Peroxide-Dependent MGL Sulfenylation Regulates 2-AG-Mediated Endocannabinoid Signaling in Brain Neurons.

The second messenger hydrogen peroxide transduces changes in the cellular redox state by reversibly oxidizing protein cysteine residues to sulfenic acid. This signaling event regulates many cellular processes but has never been shown to occur in the brain. Here, we report that hydrogen peroxide heightens endocannabinoid signaling in brain neurons through sulfenylation of cysteines C201 and C208 in monoacylglycerol lipase (MGL), a serine hydrolase that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) in nerve terminals. The results suggest that MGL sulfenylation may provide a presynaptic control point for 2-AG-mediated endocannabinoid signaling.