Enhancement of mediodorsal thalamus rescues aberrant belief dynamics in a mouse model with schizophrenia-associated mutation.
| العنوان: | Enhancement of mediodorsal thalamus rescues aberrant belief dynamics in a mouse model with schizophrenia-associated mutation. |
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| المؤلفون: | Zhou T; Yang Tan Collection and McGovern Institute for Brain Research, Massachusetts Institute of Technology.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology., Ho YY; Yang Tan Collection and McGovern Institute for Brain Research, Massachusetts Institute of Technology.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology., Lee RX; Yang Tan Collection and McGovern Institute for Brain Research, Massachusetts Institute of Technology.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology., Fath AB; Yang Tan Collection and McGovern Institute for Brain Research, Massachusetts Institute of Technology.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology., He K; Yang Tan Collection and McGovern Institute for Brain Research, Massachusetts Institute of Technology.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology., Scott J; Department of Neuroscience, Tufts University School of Medicine., Bajwa N; Department of Neuroscience, Tufts University School of Medicine., Hartley ND; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard., Wilde J; Yang Tan Collection and McGovern Institute for Brain Research, Massachusetts Institute of Technology.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology., Gao X; Yang Tan Collection and McGovern Institute for Brain Research, Massachusetts Institute of Technology.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology., Li C; Yang Tan Collection and McGovern Institute for Brain Research, Massachusetts Institute of Technology.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology., Hong E; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology., Nassar MR; Department of Neuroscience, Brown University., Wimmer RD; Department of Neuroscience, Tufts University School of Medicine., Singh T; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard., Halassa MM; Department of Neuroscience, Tufts University School of Medicine., Feng G; Yang Tan Collection and McGovern Institute for Brain Research, Massachusetts Institute of Technology.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 14. Date of Electronic Publication: 2024 Feb 14. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Optimizing behavioral strategy requires belief updating based on new evidence, a process that engages higher cognition. In schizophrenia, aberrant belief dynamics may lead to psychosis, but the mechanisms underlying this process are unknown, in part, due to lack of appropriate animal models and behavior readouts. Here, we address this challenge by taking two synergistic approaches. First, we generate a mouse model bearing patient-derived point mutation in Grin2a ( Grin2a Y700X+/- ), a gene that confers high-risk for schizophrenia and recently identified by large-scale exome sequencing. Second, we develop a computationally trackable foraging task, in which mice form and update belief-driven strategies in a dynamic environment. We found that Grin2a Y700X+/- mice perform less optimally than their wild-type (WT) littermates, showing unstable behavioral states and a slower belief update rate. Using functional ultrasound imaging, we identified the mediodorsal (MD) thalamus as hypofunctional in Grin2a Y700X+/- mice, and in vivo task recordings showed that MD neurons encoded dynamic values and behavioral states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopied Grin2a Y700X+/- mice, and enhancing MD activity rescued task deficits in Grin2a Y700X+/- mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction, and a potential target for future therapeutics. |
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| معلومات مُعتمدة: | R01 MH134466 United States MH NIMH NIH HHS |
| تواريخ الأحداث: | Date Created: 20240123 Latest Revision: 20240228 |
| رمز التحديث: | 20240228 |
| مُعرف محوري في PubMed: | PMC10802391 |
| DOI: | 10.1101/2024.01.08.574745 |
| PMID: | 38260581 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2024.01.08.574745 |
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