腹侧海马体对边缘下皮质的输入对于应激大鼠中消退的治疗样效应是必要的。
Ventral Hippocampal Input to Infralimbic Cortex Is Necessary for the Therapeutic-Like Effects of Extinction in Stressed Rats.
机构信息
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
South Texas Veterans Health Care System, San Antonio, TX.
出版信息
Int J Neuropsychopharmacol. 2023 Aug 29;26(8):529-536. doi: 10.1093/ijnp/pyad043.
BACKGROUND
Posttraumatic stress disorder is characterized by deficits in cognitive flexibility related to dysfunction of the medial prefrontal cortex (mPFC). Exposure therapy can effectively reverse these deficits. Fear extinction in rodents bears similarity to exposure therapy. Extinction reverses chronic stress-induced deficits in cognitive flexibility on the attentional set-shifting test (AST), an mPFC-mediated process. This therapeutic effect requires activity of pyramidal neurons and brain derived neurotrophic factor (BDNF) signaling in infralimbic cortex (IL). However, the circuit mechanisms governing BDNF-mediated plasticity initiated by extinction in IL are unknown. The ventral hippocampus (vHipp) plays a role in regulating IL activity during extinction, and plasticity in vHipp is necessary for extinction memory consolidation. Therefore, we investigated the role of vHipp input to IL in the effects of extinction in reversing stress-induced cognitive deficits.
METHODS
vHipp input to IL was silenced using a Gi-Designer Receptors Exclusively Activated by Designer Drugs (DREADD) via local infusion of clozapine-N-oxide (CNO) into IL before extinction. A day later, rats were tested on AST. In a separate experiment, we tested whether vHipp input to the IL induces BDNF signaling to exert therapeutic effects. We activated the vHipp using a Gq-DREADD, and injected an anti-BDNF neutralizing antibody into IL. Rats were tested on the AST 24 hours later.
RESULTS
Silencing the vHipp input to IL prevented the beneficial effects of extinction in reversing stress-induced cognitive deficits. Activating vHipp input to IL in the absence of extinction was sufficient to reverse stress-induced deficits in set-shifting. The beneficial effects were blocked by local infusion of a neutralizing anti-BDNF antibody into IL.
CONCLUSIONS
vHipp-driven BDNF signaling in IL is critical for extinction to counteract the deleterious cognitive effects of chronic stress.
背景
创伤后应激障碍的特征是与内侧前额叶皮层（mPFC）功能障碍相关的认知灵活性缺陷。暴露疗法可以有效地逆转这些缺陷。啮齿动物的恐惧消退与暴露疗法相似。消退会逆转注意力转换测试（AST）上慢性应激引起的认知灵活性缺陷，这是一个 mPFC 介导的过程。这种治疗效果需要在扣带皮层（IL）中激活锥体神经元和脑源性神经营养因子（BDNF）信号。然而，尚不清楚由 IL 中的消退引发的 BDNF 介导的可塑性的回路机制。腹侧海马（vHipp）在调节消退期间 IL 的活动中起作用，并且 vHipp 的可塑性对于消退记忆的巩固是必要的。因此，我们研究了 vHipp 对 IL 的输入在消退逆转应激引起的认知缺陷中的作用。
方法
通过在消退前将氯氮平-N-氧化物（CNO）局部输注到 IL 中，使用 Gi 设计的受体专门由 Designer Drugs（DREADD）激活，从而沉默 vHipp 对 IL 的输入。一天后，大鼠进行 AST 测试。在另一个实验中，我们测试了 vHipp 对 IL 的输入是否诱导 BDNF 信号以发挥治疗作用。我们使用 Gq-DREADD 激活 vHipp，并将抗 BDNF 中和抗体注入 IL。24 小时后，大鼠进行 AST 测试。
结果
沉默 vHipp 对 IL 的输入阻止了消退在逆转应激引起的认知缺陷中的有益作用。在没有消退的情况下激活 IL 中的 vHipp 输入足以逆转应激引起的转换缺陷。将中和抗 BDNF 抗体局部注入 IL 会阻断这些有益作用。
结论
IL 中的 vHipp 驱动的 BDNF 信号对于消退抵消慢性应激的有害认知影响至关重要。
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