Gasalla Patricia, Manahan-Vaughan Denise, Dwyer Dominic Michael, Hall Jeremy, Méndez-Couz Marta
Neuroscience & Mental Health Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK; School of Psychology, Cardiff University, Tower Building, 70 Park Place, Cardiff, CF10 3AT, UK.
Dept. Neurophysiology, Medical Faculty, Ruhr-University Bochum, Universitätsstraße 150, Building MA 4/158, 44780, Bochum, Germany.
Neuropharmacology. 2023 Apr 1;227:109444. doi: 10.1016/j.neuropharm.2023.109444. Epub 2023 Jan 29.
Recent studies have revealed impairments in Cacna1c ± heterozygous animals (a gene that encodes the Cav 1.2 L-type voltage-gated calcium channels and is implicated in risk for multiple neuropsychiatric disorders) in aversive forms of learning, such as latent inhibition, reversal learning or context discrimination. However, the role of Cav 1.2 L-type voltage-gated calcium channels in extinction of appetitive associations remains under-investigated. Here, we used an appetitive Pavlovian conditioning task and evaluated extinction learning (EL) with a change of context from that of training and test (ABA) and without such a change (AAA) in Cacna1c ± male rats versus their wild-type (WT) littermates. In addition, we used fluorescence in situ hybridization of somatic immediate early genes (IEGs) Arc and Homer1a expression to scrutinize associated changes in the medial prefrontal cortex and the amygdala. Cacna1c ± animals successfully adapt their responses by engaging in appetitive EL and renewal. However, the regional IEG expression profile changed. For the EL occurring in the same context, Cacna1c ± animals presented higher IEG expression in the infralimbic cortex and the central amygdala than controls. The prelimbic region presented a larger neural ensemble in Cacna1c ± than WT animals, co-labelled for the time window of EL in the original context and prolonged exposure to the unrewarded context. With a context change, the Cacna1c ± infralimbic region displayed higher IEG expression during renewal than controls. Taken together, our findings provide novel evidence of distinct brain activation patterns occurring in Cacna1c ± rats after appetitive extinction and renewal despite preserved behavioral responses. This article is part of the Special Issue on "L-type calcium channel mechanisms in neuropsychiatric disorders".
最近的研究表明，Cacna1c ± 杂合动物（一种编码Cav 1.2 L型电压门控钙通道的基因，与多种神经精神疾病的风险有关）在厌恶性学习形式中存在缺陷，如潜在抑制、逆向学习或情境辨别。然而，Cav 1.2 L型电压门控钙通道在消退性条件反射中的作用仍未得到充分研究。在这里，我们使用了一个经典的巴甫洛夫式条件反射任务，在Cacna1c ± 雄性大鼠及其野生型（WT）同窝仔鼠中，通过改变训练和测试的情境（ABA）以及不改变情境（AAA）来评估消退学习（EL）。此外，我们使用了体细胞即刻早期基因（IEGs）Arc和Homer1a表达的荧光原位杂交技术，来仔细检查内侧前额叶皮质和杏仁核的相关变化。Cacna1c ± 动物通过参与消退性条件反射和恢复，成功地调整了它们的反应。然而，区域IEG表达谱发生了变化。对于在相同情境下发生的消退性条件反射，Cacna1c ± 动物在边缘下皮质和中央杏仁核中的IEG表达高于对照组。在Cacna1c ± 动物中，边缘前区在原始情境下的消退性条件反射时间窗口以及长时间暴露于无奖励情境下，共标记的神经集合比WT动物更大。随着情境的改变，Cacna1c ± 边缘下区域在恢复过程中显示出比对照组更高的IEG表达。综上所述，我们的研究结果提供了新的证据，表明尽管行为反应得以保留，但在消退性条件反射和恢复后，Cacna1c ± 大鼠中出现了不同的脑激活模式。本文是“神经精神疾病中的L型钙通道机制”特刊的一部分。
