Timic Stamenic Tamara, Joksimovic Srdjan M, Fine-Raquet Brier, Tadic Vasilije P, Tesic Vesna, Jevtovic-Todorovic Vesna, Todorovic Slobodan M
Department of Anesthesiology, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA.
Neuroscience and Pharmacology Graduate Program, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA.
Int J Mol Sci. 2025 Apr 9;26(8):3543. doi: 10.3390/ijms26083543.
The potential contribution of the ion channels that control the excitability of the midline and intralaminar nuclei of the thalamus to the modulation of behaviors has not been well studied. In this study, we used both global genetic deletion (knock-out, KO) and thalamus-specific molecular knock-down (KD) approaches to investigate the role of thalamic Ca3.1 T-type calcium channels (T-channels) in fear learning and fear responses. Previously, we have shown that the dominant subtype of T-channels in the central medial nucleus of the thalamus (CMT) is the Ca3.1 isoform and that CMT neurons from Ca3.1 KO animals have decreased burst firing. By specifically knocking down Ca3.1 T-channels in the CMT using the shRNA approach, we also reduced burst firing without affecting the tonic firing mode of the transfected neurons. We report that global Ca3.1 KO animals showed stronger freezing behaviors during both the conditioning and testing phases of contextual fear conditioning, while CMT-specific Ca3.1 KD mice only had stronger fear responses during testing. In contrast, the cue-mediated fear responses were similar between Ca3.1 KO and Ca3.1 KD mice and the controls. Our findings validate thalamic Ca3.1 T-channels as a potential new target for the development or treatment of different psychiatric diseases, such as post-traumatic stress disorder, schizophrenia, anxiety, and substance abuse disorders.
控制丘脑中线和板内核兴奋性的离子通道对行为调节的潜在贡献尚未得到充分研究。在本研究中，我们使用了全局基因敲除（knock-out，KO）和丘脑特异性分子敲低（KD）方法，来研究丘脑Ca3.1 T型钙通道（T通道）在恐惧学习和恐惧反应中的作用。此前，我们已经表明，丘脑中央内侧核（CMT）中T通道的主要亚型是Ca3.1亚型，并且来自Ca3.1基因敲除动物的CMT神经元的爆发式放电减少。通过使用shRNA方法特异性敲低CMT中的Ca3.1 T通道，我们也减少了爆发式放电，而不影响转染神经元的紧张性放电模式。我们报告，全局Ca3.1基因敲除动物在情境恐惧条件反射的条件化和测试阶段均表现出更强的僵立行为，而CMT特异性Ca3.1敲低小鼠仅在测试期间有更强的恐惧反应。相比之下，Ca3.1基因敲除小鼠和Ca3.1敲低小鼠与对照组之间的线索介导的恐惧反应相似。我们的研究结果证实丘脑Ca3.1 T通道是开发或治疗不同精神疾病（如创伤后应激障碍、精神分裂症、焦虑症和物质使用障碍）的潜在新靶点。
