Department of Biology and Biotechnology Charles Darwin, University of Rome La Sapienza, Rome, Italy.
Laboratory of Computational Embodied Neuroscience, Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy.
Brain Struct Funct. 2018 Apr;223(3):1071-1089. doi: 10.1007/s00429-017-1533-9. Epub 2017 Oct 28.
Extinction of Pavlovian conditioning is a complex process that involves brain regions such as the medial prefrontal cortex (mPFC), the amygdala and the locus coeruleus. In particular, noradrenaline (NA) coming from the locus coeruleus has been recently shown to play a different role in two subregions of the mPFC, the prelimbic (PL) and the infralimbic (IL) regions. How these regions interact in conditioning and subsequent extinction is an open issue. We studied these processes using two approaches: computational modelling and NA manipulation in a conditioned place preference paradigm (CPP) in mice. In the computational model, NA in PL and IL causes inputs arriving to these regions to be amplified, thus allowing them to modulate learning processes in amygdala. The model reproduces results from studies involving depletion of NA from PL, IL, or both in CPP. In addition, we simulated new experiments of NA manipulations in mPFC, making predictions on the possible results. We searched the parameters of the model and tested the robustness of the predictions by performing a sensitivity analysis. We also present an empirical experiment where, in accord with the model, a double depletion of NA from both PL and IL in CPP with amphetamine impairs extinction. Overall the proposed model, supported by anatomical, physiological, and behavioural data, explains the differential role of NA in PL and IL and opens up the possibility to understand extinction mechanisms more in depth and hence to aid the development of treatments for disorders such as addiction.
巴甫洛夫条件反射的消退是一个复杂的过程，涉及到内侧前额叶皮层（mPFC）、杏仁核和蓝斑等脑区。特别是，来自蓝斑的去甲肾上腺素（NA）最近被证明在 mPFC 的两个亚区——前扣带回皮层（PL）和下边缘皮层（IL）中发挥不同的作用。这些区域在条件反射和随后的消退中是如何相互作用的，这是一个悬而未决的问题。我们使用两种方法研究了这些过程：计算建模和在条件性位置偏好范式（CPP）中对 NA 的操纵在小鼠中。在计算模型中，PL 和 IL 中的 NA 导致到达这些区域的输入被放大，从而使它们能够调节杏仁核中的学习过程。该模型再现了涉及 CPP 中 PL、IL 或两者的 NA 耗竭研究的结果。此外，我们模拟了 mPFC 中 NA 操纵的新实验，对可能的结果进行了预测。我们搜索了模型的参数，并通过进行敏感性分析来测试预测的稳健性。我们还提出了一个经验实验，根据模型，在 CPP 中用安非他命同时耗尽 PL 和 IL 中的 NA 会损害消退。总的来说，该模型得到了解剖学、生理学和行为学数据的支持，解释了 NA 在 PL 和 IL 中的差异作用，并为更深入地理解消退机制提供了可能性，从而有助于开发治疗成瘾等疾病的方法。
