The cortex, the topmost layer of our brain, is organized into functional regions that enable high-level cognitive functions such as language and future planning. How these areas emerge during gestation is still largely unknown. The thalamus, the brain’s sensory relay system, grows in parallel with the cortex in early embryonic development. We hypothesize that adult thalamic neurons help guide stem cells to regional identities. To test this, we grew cortical and thalamic organoids, 3D stem cell models of the human brain. Through immunostaining and single-nuclei RNA-sequencing of fused thalamic-cortical organoids, we found evidence that thalamic neurons are necessary for cortical neurogenesis. Additionally, experiments knocking out NRXN1, a synaptic protein, altered cortical fate decisions. This suggests that the communication between adult thalamic neurons and cortical progenitors may be synaptic.

Over half of children with autism spectrum disorder (ASD) are estimated to have sensory over-responsivity (SOR), which is defined as extreme reactions to aversive stimulation. SOR is associated with hyperactive sensory cortical responses during stimulation. Cognitive reappraisal, an emotion regulation strategy, may help autistic children cope with SOR. Reappraisal in non-autistic populations is linked to prefrontal cortical downregulation of the amygdala and activation in language-related regions. Given the wide range of language abilities seen in ASD, we investigated if a) reappraisal reduced sensory cortical responses to aversive sensory stimulation for ASD participants, and b) verbal IQ (VIQ) correlated with prefrontal cortical engagement during reappraisal. During an fMRI scan, 41 participants with ASD (aged 9-17 years, VIQ range: 74-160) were rubbed with mildly aversive stimuli and were prompted to either feel the stimuli normally or reappraise them by thinking about them objectively. Participants showed decreased activation in sensory regions during reappraisal compared to the feel condition, and VIQ was positively correlated with activity in language and affective processing regions. Results indicate that reappraisal can reduce neural sensory responses for ASD youth, but those with higher VIQ may more effectively engage in the language and cognitive processing aspects of reappraisal. Interventions improving language skills may indirectly enhance regulatory skills for autistic youth.

Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive neuronal loss driven by Huntingtin gene (HTT) mutation and accumulation of mutant Huntingtin protein (mHTT). Previous study has shown deletion of DNA mismatch repair gene Msh3 can greatly ameliorate disease phenotypes in Q140, a knockin mouse model of HD (Wang et al., Cell 2025). Recent proteomics data suggest Q140 mice have broad cytosolic and nuclear proteopathy, and some of the top dysregulated proteins include Trp53bp1 (53BP1) in the DNA repair pathway and Dnajb6, a chaperone that suppresses protein aggregation and toxicity. In this study, immunohistochemistry assays were performed in WT, Q140, and Q140 mice with Msh3 knockout at 6 and 12 months to assess the expression of 53BP1 and Dnajb6. Quantification analysis was performed through region of interest (ROI) analysis of ten nuclear regions that were identified through DAPI-positive staining. Mean fluorescent intensity values of the target protein through quantification of protein expression for each ROI were averaged together in each sample. Preliminary data revealed that 53BP1 levels were upregulated in Q140 mice and normalized by Msh3KO. More interestingly, Dnajb6 intranuclear distribution and expression alter in Q140 mice in a progressive manner, which are also reversed by Msh3 deletion. These findings suggest that Msh3 regulates the key pathways involved in HD proteostasis and could provide new potential therapeutic targets for HD.