Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous psychiatric disorder that can have three phenotypical presentations: inattentive (I-ADHD), hyperactive-impulsive (HI-ADHD), and combined (C-ADHD). Environmental factors correlated with the gut microbiota community have been implicated in the development of ADHD. However, whether different ADHD symptomatic presentations are associated with distinct microbiota compositions and whether patients could benefit from the correction of aberrant bacterial colonization are still largely unclear. We carried out metagenomic shotgun analysis with 207 human fecal samples to characterize the gut microbial profiles of patients with ADHD grouped according to their phenotypical presentation. Then, we transplanted the candidate low-abundance bacteria identified in patient subgroups into ADHD rats and evaluated ADHD-associated behaviors and neuronal activation in these rats. Patients with C-ADHD had a different gut microbial composition from that of healthy controls (HCs) ( p = .02), but not from that of I-ADHD patients. Eight species became progressively attenuated or enriched when comparing the compositions of HCs to those of I-ADHD and C-ADHD; in particular, the abundance of Bacteroides ovatus was depleted in patients with C-ADHD. In turn, Bacteroides ovatus supplementation ameliorated spatial working memory deficits and reversed θ electroencephalogram rhythm alterations in ADHD rats. In addition, Bacteroides ovatus induced enhanced neuronal activation in the hippocampal CA1 subregion. These findings indicate that gut microbial characteristics that are unique to patients with C-ADHD may be masked when considering a more heterogeneous group of patients. We link the gut microbiota to brain function in an ADHD animal model, suggesting the relevance of testing a potential bacteria-based intervention for some aspects of ADHD.

Little is known about the effects of transcutaneous electrical acupoint stimulation (TEAS) for children with attention-deficit/hyperactivity disorder (ADHD). Here, we carried out a 4 week randomized clinical trial in which patients aged 6–12 years old with an ADHD diagnosis received TEAS or sham TEAS. The primary outcome measure was the investigator-rated Clinical Global Impression-Improvement (CGI-I) score at week 4. Secondary outcomes included changes from baseline to week 4 in the investigator-rated Clinical Global Impression-Severity of Illness (CGI-S) score, the Conners’ Parent/Teacher Rating Scales-Revised: Short Form (CPRS-R: S/CTRS-R: S) score, go/no-go task performance, and functional near-infrared spectroscopy (fNIRS)-based oxygenated hemoglobin level within the prefrontal cortex. At week 4, the CGI-I score indicated improvement in 33.3% of the TEAS group compared with 7.7% of the sham group (P = 0.005). The TEAS group had a greater decrease in the mean CGI-S score (−0.87) than the sham TEAS group (−0.28) (P = 0.003). A greater enhancement in the mean cerebral oxygenated hemoglobin within the prefrontal cortex was found in the TEAS group (0.099 mM mm) compared with the sham TEAS group (0.005 mM mm) (P < 0.001). CPRS-R: S score, CTRS-R: S score, and go/no-go performance exhibited no significant improvement after TEAS treatment. The manipulation-associated adverse events were uncommon in both groups, and events were very mild. Our results show that noninvasive TEAS significantly improved general symptoms and increased prefrontal cortex blood flow within 4 weeks for children with ADHD. Further clinical trials are required to understand the long-term efficacy in a larger clinical sample. This trial was registered on ClinicalTrials.gov (NCT 03917953).

Social isolation during the juvenile stage results in structural and functional impairment of the brain and deviant adult aggression. However, the specific subregions and cell types that underpin this deviant behavior are still largely unknown. Here, we found that adolescent social isolation led to a shortened latency to attack onset and extended the average attack time, accompanied by anxiety-like behavior and deficits in social preference in adult mice. However, when exposed to social isolation during adulthood, the mice did not show these phenotypes. We also found that the structural plasticity of prefrontal pyramidal neurons, including the dendritic complexity and spine ratio, was impaired in mice exposed to adolescent social isolation. The parvalbumin (PV) interneurons in the prefrontal infralimbic cortex (IL) are highly vulnerable to juvenile social isolation and exhibit decreased cell numbers and reduced activation in adulthood. Moreover, chemogenetic inactivation of IL-PV interneurons can mimic juvenile social isolation-induced deviant aggression and social preference. Conversely, artificial activation of IL-PV interneurons significantly attenuated deviant aggression and rescued social preference during adulthood in mice exposed to adolescent social isolation. These findings implicate juvenile social isolation-induced damage to IL-PV interneurons in long-term aggressive behavior in adulthood.

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Background Anxiety is a negative emotion that contributes to craving and relapse during drug withdrawal. SIRT1 has been reported to be critical in both negative emotions and drug addiction. However, it remains incompletely elucidated whether SIRT1 is involved in morphine withdrawal-associated anxiety. Methods We established a mouse model of anxiety-like behaviors induced by morphine withdrawal, and then detected neuronal activity with immunofluorescence and mitochondrial morphology with electron microscopy, mtDNA contents with qPCR, and mitochondrial function with the ATP content detection kit and the Mitochondrial Complex IV Activity Kit in the basolateral amygdala (BLA). The mitochondrial molecules were detected by Western blot. Then, we used virus-mediated down-regulation and overexpression of SIRT1 in BLA to investigate the effect of SIRT1 on anxiety and mitochondrial function. Finally, we examine the effects of pharmacological inhibition of SIRT1 on anxiety and mitochondrial function. Results We found that BLA neuronal activity, mitochondrial function, and mtDNA content were significantly higher in morphine withdrawal mice. Furthermore, the expression levels of mitochondrial molecules were increased in BLA cells. Virus-mediated down-regulation of SIRT1 in BLA prevented anxiety-like behaviors in morphine withdrawal mice, while overexpression of SIRT1 in BLA facilitated anxiety-like behaviors in untreated mice through the SIRT1/PGC-1α pathway. Intra-BLA infusion of selective SIRT1 antagonist EX527 effectively ameliorated anxiety-like behaviors and mitochondrial dysfunction in mice with morphine withdrawal. Conclusion Our results implicate a causal role for SIRT1 in the regulation of anxiety through actions on mitochondrial biogenesis. Inhibitors targeting SIRT1 may have therapeutic potential for the treatment of opioids withdrawal-associated anxiety.