Laricchiuta Daniela, Sciamanna Giuseppe, Gimenez Juliette, Termine Andrea, Fabrizio Carlo, Caioli Silvia, Balsamo Francesca, Panuccio Anna, De Bardi Marco, Saba Luana, Passarello Noemi, Cutuli Debora, Mattioni Anna, Zona Cristina, Orlando Valerio, Petrosini Laura
Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
Department of Systems Medicine, Tor Vergata University of Rome, 00133 Rome, Italy.
Int J Mol Sci. 2021 Jan 15;22(2):810. doi: 10.3390/ijms22020810.
Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.
恐惧消退需要杏仁核与内侧前额叶皮质（mPFC）内的神经活动协调一致。任何行为都有一个会因环境经历而改变的转录组特征，并且特定基因参与恐惧消退过程中的功能可塑性和突触连接。在此，我们研究了对前边缘区（PrL）锥体神经元进行光遗传学操控以及杏仁核基因表达的影响，以分析与适应性和适应不良性恐惧消退相关的特定转录途径。为此，对转基因小鼠进行（或不进行）恐惧条件化训练，在消退阶段，对可光激活的PrL锥体神经元给予光遗传学（或假）刺激。在行为测试结束时，评估PrL锥体神经元的电生理（神经细胞兴奋性和兴奋性突触后电流）和形态学（树突棘生成）相关性。此外，对杏仁核锥体神经元进行转录组细胞特异性RNA分析（差异基因表达谱分析和功能富集分析）。我们的结果表明，在恐惧条件化小鼠中，PrL锥体神经元的光遗传学激活会导致恐惧消退缺陷，表现为PrL锥体神经元的细胞兴奋性、兴奋性神经传递和树突棘生成增加，并且与杏仁核锥体神经元转录组的强烈改变有关。了解恐惧消退的电生理、形态学和转录组结构可能有助于理解与恐惧相关的障碍。
