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<p>Belief updating is thought to be impaired in schizophrenia, leading to delusions. The neural substrates underlying belief updating are unknown, in part due to a lack of appropriate animal models and behavior readouts. We generated mice bearing a schizophrenia-associated point mutation in <i>Grin2a</i> (<i>Grin2a</i><sup><i>Y700X+/</i>−</sup>) and developed a computationally trackable foraging task to assess belief-driven decision strategies in mice. <i>Grin2a</i><sup><i>Y700X+/</i>−</sup> mice performed less optimally than their wild-type (WT) littermates, due to unstable cognitive states related to noisy representation of dynamic task values. We identified the mediodorsal (MD) thalamus as being hypofunctional in <i>Grin2a</i><sup><i>Y700X+/</i>−</sup> mice and showed that MD neurons encode dynamic task values and cognitive states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopied <i>Grin2a</i><sup><i>Y700X+/</i>−</sup> mice and enhancing MD activity rescued task deficits in <i>Grin2a</i><sup><i>Y700X+/</i>−</sup> mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction and a potential target for future therapeutics.</p>

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Reduced mediodorsal thalamus activity underlies aberrant belief dynamics in a genetic mouse model of schizophrenia

  • 期刊论文

  • 发表日期：

    2026年3月18日

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  • Tingting Zhou,
  • Yi-Yun Ho,
  • Nolan D. Hartley,
  • Ray X. Lee,
  • Amanda B. Fath,
  • Kathleen He,
  • Xun Yuan,
  • Sam Merrow,
  • Jonathan Scott,
  • Navdeep Bajwa,
  • Jonathan Wilde,
  • Xian Gao,
  • Cui Li,
  • Evan Hong,
  • Zhanyan Fu,
  • Matthew R. Nassar,
  • Ralf D. Wimmer,
  • Tarjinder Singh,
  • Michael M. Halassa,
  • Guoping Feng

摘要

Belief updating is thought to be impaired in schizophrenia, leading to delusions. The neural substrates underlying belief updating are unknown, in part due to a lack of appropriate animal models and behavior readouts. We generated mice bearing a schizophrenia-associated point mutation in Grin2a (Grin2aY700X+/−) and developed a computationally trackable foraging task to assess belief-driven decision strategies in mice. Grin2aY700X+/− mice performed less optimally than their wild-type (WT) littermates, due to unstable cognitive states related to noisy representation of dynamic task values. We identified the mediodorsal (MD) thalamus as being hypofunctional in Grin2aY700X+/− mice and showed that MD neurons encode dynamic task values and cognitive states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopied Grin2aY700X+/− mice and enhancing MD activity rescued task deficits in Grin2aY700X+/− mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction and a potential target for future therapeutics.