Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and the vacuolar protein sorting-associated protein 4A (VPS4A) gene in humans, and the causal role of Vps4 for hyperactivity was validated in Drosophila. Our data provide a neurobehavioral model explaining the heterogeneity of rewardrelated behaviors and generate a hypothesis accounting for their enduring nature.uccessful behavioral adaptation requires effective reward processing that determines whether a desired goal is approached and maintained. Reward processing can be separated into behavioral anticipation or reward expectancy as a consequence of learning and behavioral and subjective responses to rewarding outcomes (1). In humans, dysfunctional reward processing (in particular, dysfunctional reward anticipation) has been implicated in various externalizing disorders, including attention-deficit hyperactivity disorder (ADHD) (2) and addiction (3). Brain regions involved in reward anticipation include the ventral tegmental area, the medial forebrain bundle, and the nucleus accumbens/ventral striatum (VS; including the ventral caudate-putamen) as well as the ventromedial and insular cortices (4). More recently, observations have been reported to link reward processing in humans with cortical activation (5), including the primary somatosensory (6), primary visual (V1) (7), and auditory (8) cortices. Dopamine is the principal neurotransmitter regulating reward processing, particularly through the mesocorticolimbic pathway (9), the neuronal projection from the ventral tegmental area to the VS and prefrontal cortex. A general feature of striatal information processing is the control by rewardrelated dopamine signals of direct and indirect cortical inputs from different neurotransmitter systems, including noradrenaline, glutamate, and GABA as well as acetylcholine, endogenous opioids, and cannabinoids (10). As a consequence, striatal dopaminergic activity integrates cortical and subcortical inputs with reward response. In addition to direct and indirect regulation by heteroceptors, dopamine release is regulated by presynaptic autoreceptors of the D2 family, in particular D2 dopamine receptors (DRD2) that Author contributions: T.J., S.D., C.P.M., J.F., A.R., H.F., and G.S. designed research; T.J., C.M., S.D., D.A.G., C.T., B.R., F.N., T.B., G.J.B., A.L.W.B., U.B...
SUMMARYUbiquitously expressed genes have been implicated in a variety of specific behaviors, including responses to ethanol. However, the mechanisms that confer this behavioral specificity have remained elusive. Previously, we showed that the ubiquitously expressed small GTPase Arf6 is required for normal ethanol-induced sedation in adult Drosophila. Here, we show that this behavioral response also requires Efa6, one of (at least) three Drosophila Arf6 guanine exchange factors. Ethanol-naïve Arf6 and Efa6 mutants were sensitive to ethanol-induced sedation and lacked rapid tolerance upon re-exposure to ethanol, when compared to wild-type flies. In contrast to wild type-flies, both Arf6 and Efa6 mutants preferred alcohol-containing food without prior ethanol experience. An analysis of the human ortholog of Arf6 and orthologs of Efa6 (PSD1-4) revealed that the minor G-allele of SNP rs13265422 in PSD3, as well as a haplotype containing rs13265422, were associated with increased frequency of drinking and binge drinking episodes in adolescents. The same haplotype was also associated with increased alcohol dependence in an independent European cohort. Unlike the ubiquitously expressed human Arf6 GTPase, PSD3 localization is restricted to the brain, particularly the prefrontal cortex (PFC). Functional magnetic resonance imaging (fMRI) revealed that the same PSD3 haplotype was also associated with a differential fMRI signal in the PFC during a Go/No-Go task, which engages PFC-mediated executive control. Our translational analysis therefore suggests that PSD3 confers regional specificity to ubiquitous Arf6 in the PFC to modulate human alcohol-drinking behaviors.
Alcohol use disorders (AUDs) affect people at great individual and societal cost. Individuals at risk for AUDs are sensitive to alcohol's rewarding effects and/or resistant to its aversive and sedating effects. The molecular basis for these traits is poorly understood. Here, we show that p70 S6 kinase (S6k), acting downstream of the insulin receptor (InR) and the small GTPase Arf6, is a key mediator of ethanolinduced sedation in Drosophila. S6k signaling in the adult nervous system determines flies' sensitivity to sedation. Furthermore, S6k activity, measured via levels of phosphorylation (P-S6k), is a molecular marker for sedation and overall neuronal activity: P-S6k levels are decreased when neurons are silenced, as well as after acute ethanol sedation. Conversely, P-S6k levels rebound upon recovery from sedation and are increased when neuronal activity is enhanced. Reducing neural activity increases sensitivity to ethanol-induced sedation, whereas neuronal activation decreases ethanol sensitivity. These data suggest that ethanol has acute silencing effects on adult neuronal activity, which suppresses InR/Arf6/S6k signaling and results in behavioral sedation. In addition, we show that activity of InR/Arf6/S6k signaling determines flies' behavioral sensitivity to ethanol-induced sedation, highlighting this pathway in acute responses to ethanol.
Norepinephrine exerts powerful influences on the metabolic, neuroprotective and immunoregulatory functions of astrocytes. Until recently, all effects of norepinephrine were believed to be mediated by receptors localized exclusively to the plasma membrane. However, recent studies in cardiomyocytes have identified adrenergic receptors localized to intracellular membranes, including Golgi and inner nuclear membranes, and have shown that norepinephrine can access these receptors via transporter-mediated uptake. We recently identified a high-capacity norepinephrine transporter, organic cation transporter 3 (OCT3), densely localized to outer nuclear membranes in astrocytes, suggesting that adrenergic signaling may also occur at the inner nuclear membrane in these cells. Here, we used immunofluorescence and western blot to show that β 1 -adrenergic receptors are localized to astrocyte inner nuclear membranes; that key adrenergic signaling partners are present in astrocyte nuclei; and that OCT3 and other catecholamine transporters are localized to astrocyte plasma and nuclear membranes. To test the functionality of nuclear membrane β 1 -adrenergic receptors, we monitored real-time protein kinase A (PKA) activity in astrocyte nuclei using a fluorescent biosensor. Treatment of astrocytes with norepinephrine induced rapid increases in PKA activity in the nuclear compartment.
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