早期生活逆境以性别依赖的方式损害了背纹状体突触传递和行为适应性。

IF 2.8 4区 医学 Q2 NEUROSCIENCES
Frontiers in Synaptic Neuroscience Pub Date : 2023-04-05 eCollection Date: 2023-01-01 DOI:10.3389/fnsyn.2023.1128640
Gregory de Carvalho, Sheraz Khoja, Mulatwa T Haile, Lulu Y Chen
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引用次数: 1

摘要

早期生活逆境(ELA)是美国的一大健康负担,62%的成年人报告至少有一次不良童年经历。在大脑发育的关键阶段,这些经历会干扰介导感觉线索处理和行为调节的神经回路的发育。最近的研究报道,ELA损害了背外侧纹状体(DLS)神经元的树突棘的成熟,但不损害背内侧纹状体(DMS)神经元的成熟。DMS和DLS是两个不同的皮质纹状体回路的一部分,这两个回路通过调节和整合动作选择与这些动作的奖励值,与行为灵活性广泛相关。到目前为止,还没有研究调查ELA对行为灵活性方面的多方面影响,这些方面需要在不同的动作选择策略或高阶认知过程之间交替,以及皮质纹状体回路中潜在的突触传递。为了解决这一问题,我们采用全细胞膜片钳电生理学来评估ELA对DMS和DLS突触传递的影响。我们还研究了工具学习范式中ELA对更新行动控制以应对结果贬值的能力的影响,以及水T迷宫范式中行动-结果偶然性的逆转。在回路水平上,ELA降低了雄性小鼠的皮质纹状体谷氨酸传递,但没有降低雌性小鼠的传递。有趣的是,在DMS中,雄性ELA小鼠的谷氨酸传递减少,而雌性ELA小鼠则增加。ELA损害了在促进雄性小鼠目标定向的背景下更新动作控制以应对奖励贬值的能力,并导致逆转学习缺陷。总的来说,我们的研究结果证明了ELA对行为灵活性和潜在的皮质纹状体谷氨酸传递的性别和区域依赖性影响。通过在ELA和行为灵活性背后的回路机制之间建立联系,我们的研究结果将开始确定新的分子机制,这些机制可以代表早期经历创伤事件的个体治疗行为灵活性的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Early life adversity impaired dorsal striatal synaptic transmission and behavioral adaptability to appropriate action selection in a sex-dependent manner.

Early life adversity impaired dorsal striatal synaptic transmission and behavioral adaptability to appropriate action selection in a sex-dependent manner.

Early life adversity impaired dorsal striatal synaptic transmission and behavioral adaptability to appropriate action selection in a sex-dependent manner.

Early life adversity impaired dorsal striatal synaptic transmission and behavioral adaptability to appropriate action selection in a sex-dependent manner.

Early life adversity (ELA) is a major health burden in the United States, with 62% of adults reporting at least one adverse childhood experience. These experiences during critical stages of brain development can perturb the development of neural circuits that mediate sensory cue processing and behavioral regulation. Recent studies have reported that ELA impaired the maturation of dendritic spines on neurons in the dorsolateral striatum (DLS) but not in the dorsomedial striatum (DMS). The DMS and DLS are part of two distinct corticostriatal circuits that have been extensively implicated in behavioral flexibility by regulating and integrating action selection with the reward value of those actions. To date, no studies have investigated the multifaceted effects of ELA on aspects of behavioral flexibility that require alternating between different action selection strategies or higher-order cognitive processes, and the underlying synaptic transmission in corticostriatal circuitries. To address this, we employed whole-cell patch-clamp electrophysiology to assess the effects of ELA on synaptic transmission in the DMS and DLS. We also investigated the effects of ELA on the ability to update action control in response to outcome devaluation in an instrumental learning paradigm and reversal of action-outcome contingency in a water T-maze paradigm. At the circuit level, ELA decreased corticostriatal glutamate transmission in male but not in female mice. Interestingly, in DMS, glutamate transmission is decreased in male ELA mice, but increased in female ELA mice. ELA impaired the ability to update action control in response to reward devaluation in a context that promotes goal-directedness in male mice and induced deficits in reversal learning. Overall, our findings demonstrate the sex- and region-dependent effects of ELA on behavioral flexibility and underlying corticostriatal glutamate transmission. By establishing a link between ELA and circuit mechanisms underlying behavioral flexibility, our findings will begin to identify novel molecular mechanisms that can represent strategies for treating behavioral inflexibility in individuals who experienced early life traumatic incidents.

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来源期刊
CiteScore
7.10
自引率
2.70%
发文量
74
审稿时长
14 weeks
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