Social learning is the process of acquiring social skills, new information, or associating negative or positive valence to a context through the observation of others and through direct social interaction with others. Neurodevelopmental disorders such as autism spectrum disorder show deficits in social salience and reciprocal affective responses. Social learning implicates the basolateral amygdala (BLA), anterior cingulate cortex (ACC), and anterior insula (AI). The lateral habenula (LHb), a brain area renowned for its role in negative reinforcement learning, has not been yet extensively studied in the domain of social learning. We developed a fear conditioning by proxy paradigm called ‘social transmission of negative valence’ (STNV) and tested prairie voles on the task. Observers experienced negative social conditioning through a proxy cage mate that served as the demonstrator during retrieval of a cued fear memory. Observers went through a social memory recall session 24 h after observation. We measured observers’ freezing time, self-grooming, rearing, and ultrasonic vocalizations emitted as signs of distress. We also quantified immediate early gene translation as a proxy for neural activity using c-Fos immunochemistry 80 min after observing demonstrators going through memory recall. Socially-conditioned observers that were exposed to the fear-conditioned demonstrators displayed increased freezing time, self-grooming, and rearing during social recall sessions compared to control observers. They also displayed higher ultrasonic vocalization frequency compared to controls. Socially-conditioned observers showed increased c-Fos expression in the LHb, BLA, ACC and AI compared to controls. The c-Fos findings are correlational and additional experiments involving chemo- or optogenetic inhibition or excitation of LHb neurons in observers are necessary for causality confirmation. We found that the LHb is co-activated with other key areas during social learning in prairie voles. These findings extend the traditional view of the LHb as an area involved in negative reinforcement learning and position it as a critical area for social affect. This offers a fresh perspective on the neural mechanisms of social affect and opens a new line of inquiry into brain dysfunction of social salience in neurodevelopmental disorders.

Complex motor dysfunction is a common comorbidity of autism spectrum disorder (ASD) and may be attributed to the perturbation of cerebellar function. Purkinje cells (PCs), which serve as the primary output neurons of the cerebellum, are integral to various aspects of cerebellar motor function, such as gait control. However, the specific contribution of PCs to ASD has not been fully characterized. In this study, we utilized adult male homozygous Shank3-knockout (Δ13–16, KO) mice, a well-established autism mouse model, to investigate the relationship between structural and functional deficits in PCs and impaired motor performance. Digital gait analysis was used to examine gait abnormalities. Changes in dendritic arborization and cell body area were measured using sparse labeling technology. In vitro electrophysiology was used to evaluate alterations in PC firing patterns in Shank3-KO mice. Shank3-KO mice displayed autistic-like behaviors (stereotyped grooming behavior and social disorders) and motor impairments. Gait impairment was obvious in Shank3-KO mice and was mainly spatiotemporal and anatomical in nature. The stand duration and swing duration decreased, the body speed and swing speed clearly increased, and the print position parameters changed. PCs, the sole output neurons of the cerebellar cortex, exhibited reduced line density in different lobules and decreased cell body area in Shank3-KO mice, accompanied by cellular hypoactivity. Notably, the optogenetic inhibition of PCs in wild-type (WT) mice induced gait impairments, whereas the excitation of PCs in Shank3-KO mice rescued gait abnormalities. Although cerebellar dysfunction, particularly in PCs, is implicated in gait abnormalities, the contributions of other regions, such as the basal ganglia and cerebral cortex, remain to be fully elucidated. Similarly, within the cerebellar circuitry, other cell types, including granule cells and interneurons, are also likely involved. An important limitation of our study is its restriction to male mice, leaving potential sex-dependent differences unexplored. Future studies are therefore necessary to delineate the roles of these various brain regions and cell types and to examine their interactions in both sexes. In this study, we found that Shank3-KO mice exhibit deficits in motor performance and gait, which are also observed in ASD patients. These motor dysfunctions were strongly linked to cerebellar pathology, and we established that PC dysfunction underlies the disrupted gait patterns in this ASD model.

The awareness of autism spectrum condition (ASC) and the estimated prevalence rate are lower in the context of the Chinese mainland, compared to western countries. The Chinese adaptation of the Autism Diagnostic Observation Schedule – Generic (ADOS-G) has been widely used in the diagnostic process of ASC for many years despite its psychometric properties not having been established in a large clinical sample. Thus, the purpose of this study was to evaluate the metrics of the ADOS-G in a well characterized sample from a renowned child developmental-behavioural centre that provides clinical services to a nationwide reach of people in China. The present study analysed a large retrospective record review of individuals who visited the centre’s outpatient clinic between January of 2018 and August of 2021. Participants in this study were divided into ASC (n = 2330) and non-ASC (n = 473) groups according to their clinical diagnosis. All participants completed the ADOS-G Chinese version, with 1333 administered Module 1, 867 Module 2 and 603 Module 3. Psychometric properties of the ADOS-G Chinese version were evaluated in terms of item characteristics, internal consistency, concurrent validity, and convergent validity. The ADOS-G Chinese version demonstrated different levels of internal consistency reliability for different domains, with low Cronbach alpha values for Communication domains (0.40-0.60), but higher for the Communication and Social Interaction combined domains (above 0.75). Evaluation of validity yielded good sensitivity (> 90%) and positive predictive values (> 0.85), but low specificity (0.15-0.60) and negative predictive values (around 0.60). Agreement between ADOS-G diagnosis and clinician’s diagnosis was fair (Cohen’s kappa ranging from 0.20 to 0.35 for different modules), but low between the ADOS-G and ADI-R (< 0.15). Almost all items of the ADOS-G differentiated between ASC and non-ASC. Sample sizes were unevenly distributed between ADOS-G Modules 1 to 3, with Module 1 having the largest sample and none for Module 4. Retest reliability could not be assessed with the retrospective chart data. This study is the first to examine the ADOS-G Chinese adapted version in a large clinical sample in the Chinese mainland. The ADOS-G contributes valuable information to support the clinical diagnosis of ASC, though additional research into its psychometric properties and cultural adaptation in the Chinese mainland context may be necessary. This study highlights the importance of cultural validation and the considerations required when interpreting ADOS results in non-Western settings.

Epilepsy is a common comorbidity in individuals with autism spectrum disorders (ASDs). Many patients with epilepsy as well as ASD experience disruptions in their sleep-wake cycle and daily fluctuations in symptom severity. Chronic exposure to light at nighttime can disrupt sleep and circadian rhythms. Contactin associated protein-like 2 knockout (Cntnap2 KO) mice, a model of ASD and epilepsy, exhibit sleep and circadian disturbances and abnormal events in the electroencephalogram (EEG). Here, we investigated how chronic dim light at night (DLaN) exposure affects sleep architecture, EEG power spectra, and abnormal EEG events in Cntnap2 KO and wildtype (WT) mice. Male and female Cntnap2 KO and WT mice were exposed to DLaN (5 lx) for 6 weeks. EEG recordings were collected and analyzed to assess sleep architecture, spectral power, and abnormal EEG events. A two-way repeated-measures analysis of variance (ANOVA) was used to evaluate the effects of DLaN across time and EEG frequencies, followed by Bonferroni-corrected post hoc tests where appropriate. DLaN exposure delayed wake onset and disrupted sleep patterns in a sex-dependent manner, with females being more affected. DLaN significantly increased slow-wave activity (SWA, 0.5–4 Hz) in both WT and KO mice, consistent with increased sleep pressure. Notably, DLaN markedly elevated the frequency of abnormal hypersynchronized EEG events in Cntnap2 KO mice and even induced such events in WT mice. Spectral analysis of abnormal EEG events revealed elevated theta power, suggesting hippocampal involvement. Chronic DLaN exposure disrupts sleep architecture in a sex-dependent fashion and increases the occurrence of abnormal EEG events in Cntnap2 KO mice. These findings highlight the potential risks of nighttime light exposure for individuals with ASD and epilepsy, underscoring the importance of managing light environments to improve sleep quality and neurological health.

Camouflaging autistic traits is suggested to increase stress and the risk of autistic burnout. However, the relationship with psychological and biological markers of stress and the influence of familial factors on this relationship remain unclear. In a neurodiverse twin sample (N = 315; 69 diagnosed with autism), we examined associations between camouflaging behaviors (operationalized as the discrepancy between the Autism Diagnostic Observation Schedule 2nd edition [ADOS-2] and the Autism Quotient [AQ]), rated stress-related symptoms, and biological long-term stress measured via hair cortisol concentration (HCC). Associations were analyzed across the full sample, accounting for age, sex, and HCC confounders, as well as within-twin pairs, implicitly adjusting for genetic and environmental confounding. Across individuals, camouflaging was associated with increased HCC, particularly in autistic and adult subsamples, while associations with stress-related symptoms were only evident in adults. Within-pair analyses revealed no associations in the full sample, suggesting familial confounding. Interestingly, in adjusted within-pair models in autistic and adult twin-pairs, camouflaging was linked to lower HCC. Only the adult participants provided self-reports of autistic traits (AQ) and stress-related symptoms, while parent-reports were used for the younger participants. This difference in reporting sources may have reduced the accuracy of data for the younger subgroups in our sample. The findings indicate that camouflaging is associated with increased biological long-term stress at the population level but that familial factors may influence this relationship. Future research is needed to explore these complex dynamics and their implications for mental health and adaptive functioning in autistic individuals.

BackgroundFragile X syndrome (FXS) is the most common inherited intellectual disability, caused by the loss of fragile X mental retardation protein (FMRP), which regulates neuronal signaling and plasticity. FXS patients and Fmr1 knockout (KO) mice exhibit sensory hypersensitivity, hyperarousal, and hippocampus-dependent learning deficits. Dysregulated metabotropic glutamate receptor (mGluR) and muscarinic acetylcholine receptor (mAChR) signaling, along with reduced kainate receptor (KAR) function, have been implicated in FXS pathophysiology. Activation of these signaling pathways induce gamma-frequency network oscillations hippocampal slices in vitro. However, their specific contribution to aberrant gamma oscillations in FXS remains unclear.MethodsWe recorded local field potential (LFP) gamma oscillations in vitro in hippocampal CA3 from wild-type (WT) and Fmr1 KO mice. Oscillations were induced pharmacologically using carbachol (CCh), the group I mGluR agonist dihydroxyphenylglycine (DHPG), or kainate (KA). In addition, we quantified synaptic protein expression of mAChR M1, mGluR1, mGluR5, GluK1, and GluK2-receptors involved in gamma oscillation generation under these conditions.ResultsFmr1 KO slices exhibited increased integrated gamma power (20–80 Hz) in response to DHPG and CCh, suggesting higher network synchronization through mGluR and mAChR pathways. In contrast, KA-induced oscillations showed reduced synchrony and gamma peak power, indicating disrupted network coordination. Aberrant spiking activity during both CCh- and KA-induced oscillations further supports impaired temporal coordination in Fmr1 KO mice. These physiological changes were only partially reflected by altered expression of the corresponding receptor proteins.LimitationsIn the current study, we found aberrant gamma oscillation power in in vitro hippocampal slices of Fmr1 KO mice. It remains to be determined whether these oscillatory changes extend to pharmacologically induced gamma oscillations in cortical slice preparations in vitro.ConclusionsOur findings demonstrate that hippocampal gamma oscillations are differentially affected by distinct neuromodulatory pathways in Fmr1 KO mice. Enhanced responsiveness to cholinergic and mGluR activation and reduced coherence of KA-induced rhythms suggest that multiple dysregulated mechanisms contribute to gamma oscillopathies in FXS.Supplementary informationThe online version contains supplementary material available at 10.1186/s13229-025-00687-9.

BackgroundAutism spectrum disorder (ASD) is marked by disruptions in low-level sensory processing and higher-order sociocognitive functions, suggesting a complex interplay between different brain regions across the cortical hierarchy. However, the developmental trajectory of this hierarchical organization in ASD remains underexplored. Herein, we investigated the maturational abnormalities in the cortical hierarchy among individuals with ASD.MethodsResting-state functional magnetic resonance imaging data from three large-scale datasets were analyzed: Autism Brain Imaging Data Exchange I and II and Lifespan Human Connectome Project Development (aged 5–22 years). The principal functional connectivity gradient representing cortical hierarchy was estimated using diffusion map embedding. By applying normative modeling with the generalized additive model for location, scale, and shape (GAMLSS), we captured the nonlinear trajectories of the developing functional gradient, as well as the individual-level deviations in ASD from typical development based on centile scores measured as deviations from the normative curves. A whole-brain summary metric, the functional hierarchy score, was derived to measure the extent of abnormal maturation in individuals with ASD. Finally, through a series of mediation analyses, we examined the potential role of network-level connectomic disruptions between the diagnoses and deviations in the cortical hierarchy.ResultsThe maturation of cortical hierarchy in individuals with ASD followed a non-linear trajectory, showing delayed maturation during childhood compared to that of typically developing individuals, followed by an accelerated “catch-up” phase during adolescence and a subsequent decline in young adulthood. The nature of these deviations varied across networks, with sensory and attention networks displaying the most pronounced abnormalities in childhood, while higher-order networks, particularly the default mode network (DMN), remaining impaired from childhood to adolescence. Mediation analyses revealed that the persistent reduction in DMN segregation throughout development was a key contributor to the atypical development of cortical hierarchy in ASD.LimitationsThe uneven distribution of samples across age groups, particularly in the later stages of development, limited our ability to fully capture developmental trajectories among older individuals.ConclusionsThese findings highlight the importance of understanding the developmental trajectories of cortical organization in ASD, collectively suggesting that early interventions aimed at promoting the normative development of higher-order networks may be critical for improving outcomes in individuals with ASD.

We and others have demonstrated the resting-state (RS) peak alpha frequency (PAF) as a potential clinical marker for young children with autism spectrum disorder (ASD), with previous studies observing a higher PAF in school-age children with ASD versus typically developing (TD) children, as well as an association between the RS PAF and measures of processing speed in TD but not ASD. The brain mechanisms associated with these findings are unknown. A few studies have found that in children more mature optic radiation white matter is associated with a higher PAF. Other studies have reported white matter and neural activity associations in TD but not ASD. The present study hypothesized that group differences in the RS PAF are due, in part, to group differences in optic radiation white matter and PAF associations. The maturation of the RS PAF (measured using magnetoencephalography(MEG)), optic radiation white matter (measured using diffusion tensor imaging(DTI)), and associations with processing speed were assessed in a longitudinal cohort of TD and ASD children. Time 1 MEG and DTI measures were obtained at 6–8 years old (59TD and 56ASD) with follow-up brain measures collected ~ 1.5 and ~ 3 years later. The parietal-occipital PAF increased with age in both groups by 0.13 Hz/year, with a main effect of group showing the expected higher PAF in ASD than TD (an average of 0.26 Hz across the 3 time points). Across age, the RS PAF predicted processing speed in TD but not ASD. Finally, more mature optic radiation white matter measures (FA, RD, MD, AD) were associated with a higher PAF in both groups. Present findings provide additional evidence supporting the use of the RS PAF as a brain marker in children with ASD 6–10 years old, and replicate findings of an association between the RS PAF and processing speed in TD but not ASD. The hypothesis that the RS PAF group differences (with ASD leading TD by about 2 years) would be explained by group differences in optic radiation white matter was not supported, with brain structure-function associations indicating that more mature optic radiation white matter is associated with a higher RS PAF in both groups.