Alcohol intoxication at early ages is a risk factor for the development of addictive behavior. To uncover neuronal molecular correlates of acute ethanol intoxication, we used stable-isotope–labeled mice combined with quantitative mass spectrometry to screen more than 2,000 hippocampal proteins, of which 72 changed synaptic abundance up to twofold after ethanol exposure. Among those were mitochondrial proteins and proteins important for neuronal morphology, including MAP6 and ankyrin-G. Based on these candidate proteins, we found acute and lasting molecular, cellular, and behavioral changes following a single intoxication in alcohol-naïve mice. Immunofluorescence analysis revealed a shortening of axon initial segments. Longitudinal two-photon in vivo imaging showed increased synaptic dynamics and mitochondrial trafficking in axons. Knockdown of mitochondrial trafficking in dopaminergic neurons abolished conditioned alcohol preference inDrosophilaflies. This study introduces mitochondrial trafficking as a process implicated in reward learning and highlights the potential of high-resolution proteomics to identify cellular mechanisms relevant for addictive behavior.

Background: Parkinson’s disease (PD) is commonly accompanied with anxiety disorder, however, the mechanisms underlying PD-mediated anxiety remain elusive. The lateral habenula (LHb) is a critical brain region that influences the activity of the monoaminergic system in the midbrain and consequently modulates anxiety. Most neurons in the LHb express AMPA receptors (AMPARs). The PD model for the pharmacological intervention of AMPA receptors was established by the unilateral lesion of the substantia nigra pars compacta (SNc) with 6-hydroxydopamine (6-OHDA).Methods: The AMPAR agonist (S)-AMPA and antagonist NBQX were microinjected into the LHb, respectively, to examine whether anxiety-like behaviors were altered in sham-operated and SNc-lesion rats, measured with the paradigms of the open-field test (OPT) and elevated plus maze (EPM). Furthermore, dopamine (DA) and 5-hydroxytryptamine (5-HT) levels in the basolateral amygdala (BLA) were measured using in vivo microdialysis immediately following the injections of (S)-AMPA and NBQX into the LHb.Results: Activation of LHb AMPA receptors by (S)-AMPA produced anxiolytic-like behaviors and enhanced the extracellular DA and 5-HT in the BLA. Conversely, NBQX induced anxiety-like effects and suppressed the extracellular DA and 5-HT in the BLA. In addition, the minimal doses inducing the effects in the SNc-lesion rats were lower than those in sham-operated rats.Conclusion: These findings suggest that the effects of AMPA receptors in the LHb on anxiety-like behaviors likely involve the extracellular levels of DA and 5-HT in the BLA. The present results may improve our understanding of the neuropathology and/or treatment of PD.

Background. Recent studies have shown that Ras‐like without CAAX2 (RIT2) polymorphism is a susceptible factor for Parkinson’s disease (PD) and autism spectrum disorder (ASD). SNP rs12456492 and rs16976358 show the emerging evidence of increased risk of PD and ASD, respectively. A meta‐analysis examining the relationship between rs12456492 and PD was reported, but the association between rs16976358 and ASD has not been investigated. Methods. We searched literature from the databases PubMed, Embase, Google Scholar, ScienceDirect, EBSCOhost, OVID, Web of Science, and Wiley up to February 2021. Three studies including 1160 ASD cases and 1367 controls were eventually enrolled in the meta‐analysis based on strict inclusion and exclusion criteria. Results. All genetics models indicate a significant association between rs16976358 polymorphism and ASD susceptibility (C vs. T: p = 0.001; CC vs. TT: p = 0.001; CT vs. TT: p = 0.009; CC+CT vs. TT: p = 0.001; CC vs. CT+TT: p = 0.001; TT+CC vs. CT: p = 0.013). The results of sensitivity analysis and publication bias of Begg’s and Egger’s tests were stable in the models of allele (C vs. T), codominant (CC vs. TT), dominant (CC+CT vs. TT), and recessive (CC vs. CT+TT). Conclusions. Our meta‐analysis exhibits that the allele C, CC, and CT genotyping of rs16976358 suggest the risk for ASD, but additional studies using a large sample size and ethnically diverse populations need to be included in the future.