The orbitofrontal cortex (OFC) is central to cognitive and social functions, yet its presynaptic partners remain incompletely defined. In female mice, the OFC modulates infant-directed caregiving behaviors in an experience-dependent manner. Here, we identify the submedius thalamus (SMT) as a major presynaptic partner of the OFC. Trans-synaptic tracing revealed intensive inputs from both the SMT and mediodorsal thalamus (MD) to OFC layer 5 excitatory neurons. We generated a Tnnt1-Cre mouse line that enables selective targeting of these higher-order thalamic nuclei. Axonal tracing demonstrated complementary projection patterns of the SMT and MD across prefrontal regions. Microendoscopic Ca2+ imaging demonstrated pup retrieval-related activity in both SMT and MD, with SMT exhibiting learning-related plasticity. Projection-specific chemogenetic silencing demonstrated that SMT modulates OFC activity during pup retrieval, although its behavioral relevance appeared limited. Collectively, our study provides a presynaptic map of OFC layer 5 neurons and a proof of concept for selective manipulation of the SMT as a previously understudied thalamic input to the OFC.
Gen-Ichi Tasaka, Mitsue Hagihara, Haruna Kobayashi, Miho Kihara, Takaya Abe, Kazunari Miyamichi (2026) Submedius thalamic inputs shape the presynaptic architecture of layer 5 orbitofrontal cortex in mice., iScience, Volume 29, Number 2, pp. 114828
Published in 2026 Feb 20 (Electronic publication in Jan. 29, 2026, midnight )
(Abstract) The orbitofrontal cortex (OFC) is central to cognitive and social functions, yet its presynaptic partners remain incompletely defined. In female mice, the OFC modulates infant-directed caregiving behaviors in an experience-dependent manner. Here, we identify the submedius thalamus (SMT) as a major presynaptic partner of the OFC. Trans-synaptic tracing revealed intensive inputs from both the SMT and mediodorsal thalamus (MD) to OFC layer 5 excitatory neurons. We generated a Tnnt1-Cre mouse line that enables selective targeting of these higher-order thalamic nuclei. Axonal tracing demonstrated complementary projection patterns of the SMT and MD across prefrontal regions. Microendoscopic Ca(2+) imaging demonstrated pup retrieval-related activity in both SMT and MD, with SMT exhibiting learning-related plasticity. Projection-specific chemogenetic silencing demonstrated that SMT modulates OFC activity during pup retrieval, although its behavioral relevance appeared limited. Collectively, our study provides a presynaptic map of OFC layer 5 neurons and a proof of concept for selective manipulation of the SMT as a previously understudied thalamic input to the OFC.