The neural mechanisms coordinating social behavior and attentional control are often disrupted together in individuals with neuropsychiatric disorders such as autism spectrum disorder (ASD); however, how distinct circuits within a shared brain region separately regulate these functions remains unclear. Here, we identified two functionally distinct subpopulations of glutamatergic neurons in the anterior cingulate cortex (ACC) that project to different downstream targets: the zona incerta (ZI) and the limbic sector of the thalamic reticular nucleus (lTRN). These two ACC subpopulations differentially mediate social interaction and attentional allocation. Deficits in both behaviors were observed in Shank3b mutant ASD model mice. Optogenetic activation of the ACC→ZI circuit rescued social impairments, whereas activation of the ACC→lTRN pathway restored attentional performance. Our findings reveal dissociable ACC subpopulations and their downstream circuits for social and attentional behaviors, providing circuit-level insights that may inform future research on modulating related symptoms in patients with psychiatric disorders.

Social memory, the ability to recognize and remember conspecifics, is frequently impaired in psychiatric disorders such as autism, yet the underlying mechanisms remain unclear. We examined the role of sleep spindles across non-rapid eye movement sleep in social memory consolidation, focusing on the sensory thalamic reticular nucleus (sTRN). Here we show that impaired spindles were associated with defective social memory. Through pharmacological/optogenetic manipulations and optical Ca2+ recordings, we demonstrated that parvalbumin-positive neurons in the sTRN (sTRNPvalb) are essential for sleep spindle generation, mediated by the sTRNPvalb-ventroposteromedial (VPM) thalamic nucleus circuit. Increasing the activity of the sTRNPvalb-VPM pathway could rescue impaired spindles and social memory deficits in Neuroligin 2 mutant mice. Moreover, we developed machine learning-based models to predict autism in children based on spindle eigenvalues. These findings underscore the critical role of spindles in social memory, suggesting spindles may serve as candidate diagnostic markers.

Anxiety disorders are prevalent mental health conditions with significant impacts on quality of life. While the melatonin type 2 receptor (MT2) has been implicated in anxiety, its specific role and neural mechanisms remain unclear. This study investigates the deficiency of MT2 induces robust anxiety-like phenotypes in mice, mediated through anterior cingulate cortex (ACC) dysfunction. Global knockout (MT2-KO) and conditional ACC-targeted deletion (MT2-cKO) models consistently demonstrated increased anxiety responses in standardized behavioral batteries, establishing ACC MT2 as a key neuromodulator in emotional regulation. Electrophysiological recordings revealed that MT2 deficiency disrupted excitatory-inhibitory (E/I) balance of ACC pyramidal neurons. Chemogenetic activation of MT2-positive neurons in the ACC restored E/I balance and ameliorated anxiety-like behaviors in chronic immobility stress (CIS) model mice. These findings establish MT2 as a pivotal regulator of ACC neurocircuitry and implicate targeted modulation of ACC MT2 signaling as a potential therapeutic strategy for anxiety disorders.

Social memory has been developed in humans and other animals to recognize familiar conspecifics and is essential for their survival and reproduction. Here, we demonstrated that parvalbumin-positive neurons in the sensory thalamic reticular nucleus (sTRNPvalb) are necessary and sufficient for mice to memorize conspecifics. sTRNPvalb neurons receiving glutamatergic projections from the posterior parietal cortex (PPC) transmit individual information by inhibiting the parafascicular thalamic nucleus (PF). Mice in which the PPCCaMKII→sTRNPvalb→PF circuit was inhibited exhibited a disrupted ability to discriminate familiar conspecifics from novel ones. More strikingly, a subset of sTRNPvalb neurons with high electrophysiological excitability and complex dendritic arborizations is involved in the above corticothalamic pathway and stores social memory. Single-cell RNA sequencing revealed the biochemical basis of these subset cells as a robust activation of protein synthesis. These findings elucidate that sTRNPvalb neurons modulate social memory by coordinating a hitherto unknown corticothalamic circuit and inhibitory memory engram.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders that affects children and even continues into adulthood. Dexmedetomidine (DEX), a short-term sedative, can selectively activate the alpha 2-adrenoceptor. Treatment with alpha 2-adrenergic agonists in patients with ADHD is becoming increasingly common. However, the therapeutic potential of DEX for the treatment of ADHD is unknown. Here, we evaluated the effect of DEX on ADHD-like behavior in spontaneously hypertensive rats (SHRs), a widely used animal model of ADHD. DEX treatment ameliorated hyperactivity and spatial working memory deficits and normalized theta electroencephalogram (EEG) rhythms in SHRs. We also found that DEX treatment altered the gut microbiota composition and promoted the enrichment of beneficial gut bacterial genera associated with antiinflammatory effects in SHRs. The gut pathological scores and permeability and the level of inflammation observed in the gut and brain were remarkably improved after DEX administration. Moreover, transplantation of fecal microbiota from DEX-treated SHRs produced effects that mimicked the therapeutic effects of DEX administration. Therefore, DEX is a promising treatment for ADHD that functions by reshaping the composition of the gut microbiota and reducing inflammation in the gut and brain.

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.

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.