Clathrin, a cytosolic protein composed of heavy and light chain subunits, assembles into a vesicle coat, controlling receptor-mediated endocytosis. To establish clathrin light chain (CLC) function in vivo, we engineered mice lacking CLCa, the major CLC isoform in B lymphocytes, generating animals with CLC-deficient B cells. In CLCa-null mice, the germinal centers have fewer B cells, and they are enriched for IgA-producing cells. This enhanced switch to IgA production in the absence of CLCa was attributable to increased transforming growth factor β receptor 2 (TGFβR2) signaling resulting from defective endocytosis. Internalization of C-X-C chemokine receptor 4 (CXCR4), but not CXCR5, was affected in CLCa-null B cells, and CLC depletion from cell lines affected endocytosis of the δ-opioid receptor, but not the β2-adrenergic receptor, defining a role for CLCs in the uptake of a subset of signaling receptors. This instance of clathrin subunit deletion in vertebrates demonstrates that CLCs contribute to clathrin’s role in vivo by influencing cargo selectivity, a function previously assigned exclusively to adaptor molecules.

Perceived loneliness was identified to have a unique role in relation to the negative affective processing in LLD at the functional brain connectional and network levels. The findings increas our understanding of LLD and provide initial evidence of the neurobiological mechanisms of loneliness in LLD. Loneliness might be a potential intervention target in depressive patients.

Differences in GABAergic function are critical to autistic visual sensory neurobiology and can be modulated by targeting GABA B .

Loneliness is prevalent in adolescents. Although it can be a normative experience, children and adolescents who experience loneliness are often at risk for anxiety, depression, and suicide. Research efforts have been made to identify the neurobiological basis of such distressful feelings in our social brain. In adolescents, the social brain is still undergoing significant development, which may contribute to their increased and differential sensitivity to the social environment. Many behavioral studies have shown the significance of attachment security and social skills in adolescents' interactions with the social world. In this review, we propose a developmental social neuroscience model that extends from the social neuroscience model of loneliness. In particular, we argue that the social brain and social skills are both important for the development of adolescents' perceived loneliness and that adolescents' familial attachment sets the baseline for neurobiological development. By reviewing the related behavioral and neuroimaging literature, we propose a developmental social neuroscience model to explain the heightened perception of loneliness in adolescents using social skills and attachment style as neurobiological moderators. We encourage future researchers to investigate adolescents' perceived social connectedness from the developmental neuroscience perspective.

Chronic loneliness predicts mood disturbances and onset of major depressive disorder. However, little research has examined the neural correlates of individual difference in susceptibility to perceiving loneliness. In addition, the role of cerebellum, which is heavily implicated in social, cognitive and affective processes, in loneliness is unclear. We studied 99 healthy individuals divided into susceptible, concordant and robust groups depending on whether the participant’s loneliness level was greater, comparable or less than her/his objective social isolation level. The cerebellar gray matter structure, functional activity and connectivity patterns during performing an emotion stroop task were examined. We found greater posterior and medial cerebellar volume in the susceptible group than the other groups. In addition, the posterior and medial cerebellar activities when processing positive versus neutral words exhibited significant interactive effects of both loneliness and social network, and susceptibility to isolation. Loneliness and social network also had positive effects on the right posterior cerebellar functional connectivity with the visual and premotor cortices. Our findings provide novel evidence on the intricate role of the cerebellum in loneliness and susceptibility to isolation, suggesting that socio-cognitive processes of the cerebellum in the hedonic domain may be a key mechanism underlying loneliness proneness.Electronic supplementary materialThe online version of this article (10.1007/s00429-019-01965-y) contains supplementary material, which is available to authorized users.

BackgroundValidating the high-risk (HR) and ultra-high-risk (UHR) stages of bipolar disorder (BP) may help enable early intervention strategies.MethodsWe followed up with 44 offspring of parents with BP, subdividing into the HR and UHR categories. The offspring were aged 8–28 years and were free of any current DSM-IV diagnoses. Our multilevel, integrative approach encompassed gray matter (GM) volumes, brain network connectivity, neuropsychological performance, and clinical outcomes.FindingsCompared with the healthy controls (HCs) (n = 33), the HR offspring (n = 26) showed GM volume reductions in the right orbitofrontal cortex. Compared with the HR offspring, the UHR offspring (n = 18) exhibited increased GM volumes in four regions. Both the HR and UHR offspring displayed abnormalities in the inferior occipital cortex regarding the measures of degree and centrality, reflecting the connections and roles of the region, respectively. In the UHR versus the HR offspring, the UHR offspring exhibited upwards-shifted small world topologies that reflect high clustering and efficiency in the brain networks. Compared with the HCs, the UHR offspring had significantly lower assortativity, which was suggestive of vulnerability. Finally, processing speed, visual–spatial, and general function were impaired in the UHR offspring but not in the HR offspring.InterpretationThe abnormalities observed in the HR offspring appear to be inherited, whereas those associated with the UHR offspring represent stage-specific changes predisposing them to developing the disorder.

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Background: Alterations in the serotonergic control of brain pathways responsible for facial emotion processing in people with autism spectrum disorder (ASD) may be a target for intervention. However, the molecular underpinnings of autistic-neurotypical serotonergic differences are challenging to access in vivo. Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) has helped define molecular-enriched functional magnetic resonance imaging (fMRI) brain networks based on a priori information about the spatial distribution of neurochemical systems from available PET templates. Methods: We used REACT to estimate the dominant fMRI signal related to the serotonin (5-HT) transporter (SERT) distribution during processing of aversive facial emotion in adults with and without ASD. We first predicted a group difference in baseline (placebo) functioning of this system. We next used a single 20 mg oral dose of citalopram, a serotonin reuptake inhibitor, to test the hypothesis that network activity in people with and without ASD would respond differently to inhibition of SERT. To confirm the specificity of our findings, we also repeated the analysis with 5-HT1A, 5-HT1B, 5-HT2A and 5-HT4 receptor maps. Results: Using REACT with the SERT map, we found a baseline group difference in the SERT-enriched response to faces in the ventromedial prefrontal cortex. A single oral dose of citalopram ‘shifted’ the response in the ASD group towards the neurotypical baseline but did not alter response in the control group. Similar differences in SERT-enriched response were observed after controlling for other 5-HT maps. Conclusions: Our findings suggest that the SERT-enriched functional network is dynamically different in ASD during processing of socially relevant stimuli. Whether this acute neurobiological response to citalopram in ASD translates to a clinical target will be an important next step.