Using loss- and gain-of-function approaches to target amygdala-projecting serotonergic neurons in the dorsal raphe nucleus that enhance anxiety-related and conditioned fear behaviors.
Using loss- and gain-of-function approaches to target amygdala-projecting serotonergic neurons in the dorsal raphe nucleus that enhance anxiety-related and conditioned fear behaviors.
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DOI：
10.1177/0269881119900981
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发表时间：
2020-04
影响因子：
4.1
通讯作者：
Johnson, Philip L.
中科院分区：
文献类型：
--
作者：
Bernabe, Cristian S.;Caliman, Izabela F.;Truitt, William A.;Molosh, Andrei, I;Lowry, Christopher A.;Hay-Schmidt, Anders;Shekhar, Anantha;Johnson, Philip L.
起源于中缝背核(DR)的中枢5-羟色胺能系统在焦虑症和创伤后应激障碍等创伤相关障碍中起重要作用。尽管选择性5-羟色胺再摄取抑制剂是治疗这些疾病的一线药物，但它们不是快速起作用的，而且一开始往往会增加焦虑和增强恐惧反应，所需的临床效果在开始治疗后2-3周出现。虽然许多研究已经调查了5-羟色胺(5-HT)在杏仁核等亲恐惧脑区的作用，但这些研究中的大多数都使用了非选择性的药理学方法或知之甚少的损害技术，这限制了它们的解释。在这里，我们研究了杏仁核投射的5-羟色胺神经元在DR中在先天焦虑和条件性恐惧行为中的作用。为实现这一目标，我们利用(1)选择性5-羟色胺损毁与抗5-羟色胺转运蛋白(SERT)结合的5-羟色胺损毁杏仁核和(2)光遗传兴奋杏仁核投射的DR细胞体，结合逆行转运犬CRE重组酶注射到杏仁核和CRE依赖通道视紫红质注射到DR，而皂苷治疗损害了DR局部的5-HT纤维和神经元，并减少了条件性恐惧行为，LED激活杏仁核投射的DR神经元增强了焦虑样行为和条件性恐惧反应。总而言之，这些研究支持这样的假设，即DR中投射杏仁核的5-羟色胺神经元代表着焦虑和恐惧网络。这项工作得到了K01 AG044466对PLJ，R01 MH52619和MH52619对AS，1R01MH106568-01A1对Wat的支持。
Central serotonergic system originating from the dorsal raphe nucleus (DR) plays a critical role in anxiety disorders and trauma-related disorders such as posttraumatic stress disorder. Even though selective serotonin reuptake inhibitors are the first line of pharmacological treatment to these conditions, they are not fast-acting and tend to increase anxiety and enhance fear responses initially, with the desired clinical effects arising 2-3 weeks following initiation treatment. Although many studies have investigated the role of serotonin (5-HT) within pro-fear brain regions such as the amygdala, the majority of these studies have utilized non-selective pharmacological approaches or poorly understood lesioning techniques which limit their interpretation. Here we investigated the role of amygdala-projecting 5-HT neurons in the DR in innate anxiety and conditioned fear behaviors. To achieve this goal, we utilized (1) selective 5-HT lesioning with saporin toxin conjugated to anti-serotonin transporter (SERT) injected into the amygdala and (2) optogenetic excitation of amygdala-projecting DR cell bodies with a combination of a retrogradely transported canine adenovirus-expressing Cre-recombinase injected into the amygdala and a Cre-dependent-channelrhodopsin injected into the DR. While saporin treatment lesioned both local 5-HT fibers and neurons in the DR and reduced conditioned fear behavior, LED activation of amygdala-projecting DR neurons enhanced anxiety-like behavior and conditioned fear response. Collectively, these studies support the hypothesis that amygdala-projecting 5-HT neurons in the DR represent an anxiety and fear-on network. This work was supported with K01 AG044466 to PLJ, R01 MH52619 and MH52619 to AS, and 1R01MH106568-01A1 to WAT.
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影响因子：
9.2
作者：
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