Emory University Neuroscience Graduate Program, Atlanta, GA, USA.
Division of Behavioral Neuroscience and Psychiatric Disorders, Yerkes National Primate Research Center, Atlanta, GA, USA.
Neuropsychopharmacology. 2021 Aug;46(9):1658-1668. doi: 10.1038/s41386-021-01006-5. Epub 2021 Apr 16.
Fear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI → RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI → RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI → RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI → RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI → RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.
恐惧泛化和消退学习缺陷是创伤后应激障碍（PTSD）的两个重要方面。大多数对这些方面的神经生物学基础的理解都来自于对皮质和边缘脑区的研究。虽然丘脑和下丘脑区域被认为可以调节恐惧，但尚未探索中脑-丘脑通路抑制恐惧泛化和挽救消退记忆缺陷的潜力。我们首先使用膜片钳电生理学研究了下丘脑未定带和丘脑束旁核（RE）之间的功能连接。体外光遗传刺激 GABA 能 ZI→RE 细胞末梢在 RE 中诱导抑制性突触后电流（IPSCs）。然后，我们结合高强度辨别性听觉恐惧条件反射和细胞类型特异性和投射特异性光遗传学在小鼠中评估 GABA 能 ZI→RE 细胞投射在调节恐惧泛化和消退记忆中的功能作用。此外，我们还使用类似的方法来测试 GABA 能 ZI→RE 细胞的一小部分（A13 多巴胺能细胞群）是否可以调节恐惧泛化和消退记忆的可能性。光遗传刺激 GABA 能 ZI→RE 细胞末梢可减轻恐惧泛化并增强消退记忆。相比之下，光遗传刺激多巴胺能 ZI→RE 细胞末梢对恐惧泛化没有影响，但以多巴胺受体 D1 依赖的方式增强了消退记忆。我们的发现为 ZI 定位细胞的神经解剖学和神经化学提供了新的认识，这些细胞通过增加学习关联的准确性和消退来促进适应性恐惧。这样，这些数据揭示了新的神经解剖学基质，这些基质可能成为治疗 PTSD 的治疗靶点。
