Isoxazole-9 reduces enhanced fear responses and retrieval in ethanol-dependent male rats,Journal of Neuroscience Research

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Isoxazole-9 reduces enhanced fear responses and retrieval in ethanol-dependent male rats
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2021-09-08 , DOI: 10.1002/jnr.24932
Miranda C Staples ₁ , Melissa A Herman ₂ , Jonathan W Lockner ₃ , Yosef Avchalumov ₁ , Khush M Kharidia ₁ , Kim D Janda ₃ , Marisa Roberto ₄ , Chitra D Mandyam _{1,

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Affiliation

Plasticity in the dentate gyrus (DG) is strongly influenced by ethanol, and ethanol experience alters long-term memory consolidation dependent on the DG. However, it is unclear if DG plasticity plays a role in dysregulation of long-term memory consolidation during abstinence from chronic ethanol experience. Outbred male Wistar rats experienced 7 weeks of chronic intermittent ethanol vapor exposure (CIE). Seventy-two hours after CIE cessation, CIE and age-matched ethanol-naïve Air controls experienced auditory trace fear conditioning (TFC). Rats were tested for cue-mediated retrieval in the fear context either twenty-four hours (24 hr), ten days (10 days), or twenty-one days (21 days) later. CIE rats showed enhanced freezing behavior during TFC acquisition compared to Air rats. Air rats showed significant fear retrieval, and this behavior did not differ at the three time points. In CIE rats, fear retrieval increased over time during abstinence, indicating an incubation in fear responses. Enhanced retrieval at 21 days was associated with reduced structural and functional plasticity of ventral granule cell neurons (GCNs) and reduced expression of synaptic proteins important for neuronal plasticity. Systemic treatment with the drug Isoxazole-9 (Isx-9; small molecule that stimulates DG plasticity) during the last week and a half of CIE blocked altered acquisition and retrieval of fear memories in CIE rats during abstinence. Concurrently, Isx-9 modulated the structural and functional plasticity of ventral GCNs and the expression of synaptic proteins in the ventral DG. These findings identify that abstinence-induced disruption of fear memory consolidation occurs via altered plasticity within the ventral DG, and that Isx-9 prevented these effects.

中文翻译：

Isoxazole-9 可降低乙醇依赖性雄性大鼠增强的恐惧反应和恢复

齿状回 (DG) 的可塑性受乙醇的强烈影响，乙醇经验会改变依赖于 DG 的长期记忆巩固。然而，尚不清楚 DG 可塑性是否在长期酒精戒断期间的长期记忆巩固失调中起作用。远交系雄性 Wistar 大鼠经历了 7 周的慢性间歇性乙醇蒸气暴露 (CIE)。CIE 停止后 72 小时，CIE 和年龄匹配的未接触乙醇的 Air 控制经历了听觉痕迹恐惧条件反射 (TFC)。在二十四小时（24 小时）、十天（10 天）或二十一天（21 天）后的恐惧环境中测试大鼠的线索介导检索。与 Air 大鼠相比，CIE 大鼠在 TFC 采集期间表现出增强的冻结行为。空气鼠表现出显着的恐惧恢复，并且这种行为在三个时间点没有差异。在 CIE 大鼠中，恐惧提取在禁欲期间随着时间的推移而增加，表明恐惧反应在潜伏期。21 天时恢复增强与腹侧颗粒细胞神经元 (GCN) 的结构和功能可塑性降低以及对神经元可塑性重要的突触蛋白表达降低有关。在过去一周半的 CIE 期间，使用药物 Isoxazole-9（Isx-9；刺激 DG 可塑性的小分子）进行全身治疗，阻止了 CIE 大鼠在禁欲期间改变了恐惧记忆的获取和检索。同时，Isx-9 调节腹侧 GCN 的结构和功能可塑性以及腹侧 DG 中突触蛋白的表达。

更新日期：2021-09-08

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