Tronson Natalie C, Schrick Christina, Guzman Yomayra F, Huh Kyu Hwan, Srivastava Deepak P, Penzes Peter, Guedea Anita L, Gao Can, Radulovic Jelena
Department of Psychiatry and Behavioral Sciences, The Asher Center for the Study, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
J Neurosci. 2009 Mar 18;29(11):3387-94. doi: 10.1523/JNEUROSCI.5619-08.2009.
Learning processes mediating conditioning and extinction of contextual fear require activation of several key signaling pathways in the hippocampus. Principal hippocampal CA1 neurons respond to fear conditioning by a coordinated activation of multiple protein kinases and immediate early genes, such as cFos, enabling rapid and lasting consolidation of contextual fear memory. The extracellular signal-regulated kinase (Erk) additionally acts as a central mediator of fear extinction. It is not known however, whether these molecular events take place in overlapping or nonoverlapping neuronal populations. By using mouse models of conditioning and extinction of fear, we set out to determine the time course of cFos and Erk activity, their cellular overlap, and regulation by afferent cholinergic input from the medial septum. Analyses of cFos(+) and pErk(+) cells by immunofluorescence revealed predominant nuclear activation of either protein during conditioning and extinction of fear, respectively. Transgenic cFos-LacZ mice were further used to label in vivo Fos(+) hippocampal cells during conditioning followed by pErk immunostaining after extinction. The results showed that these signaling molecules were activated in segregated populations of hippocampal principal neurons. Furthermore, immunotoxin-induced lesions of medial septal neurons, providing cholinergic input into the hippocampus, selectively abolished Erk activation and extinction of fear without affecting cFos responses and conditioning. These results demonstrate that extinction mechanisms based on Erk signaling involve a specific population of CA1 principal neurons distinctively regulated by afferent cholinergic input from the medial septum.
介导情境恐惧条件反射和消退的学习过程需要激活海马体中的几种关键信号通路。海马体主要的CA1神经元通过多种蛋白激酶和即刻早期基因（如cFos）的协同激活来对恐惧条件反射做出反应，从而实现情境恐惧记忆的快速和持久巩固。细胞外信号调节激酶（Erk）还充当恐惧消退的核心介质。然而，尚不清楚这些分子事件是发生在重叠还是不重叠的神经元群体中。通过使用恐惧条件反射和消退的小鼠模型，我们着手确定cFos和Erk活性的时间进程、它们在细胞层面的重叠情况，以及来自内侧隔区的传入胆碱能输入对其的调节作用。通过免疫荧光分析cFos(+)和pErk(+)细胞发现，在恐惧条件反射和消退过程中，这两种蛋白分别主要在细胞核中被激活。进一步使用转基因cFos-LacZ小鼠在条件反射过程中对体内Fos(+)海马细胞进行标记，然后在消退后进行pErk免疫染色。结果表明，这些信号分子在海马体主要神经元的不同群体中被激活。此外，内侧隔区神经元的免疫毒素诱导损伤（向海马体提供胆碱能输入）选择性地消除了Erk激活和恐惧消退，而不影响cFos反应和条件反射。这些结果表明，基于Erk信号的消退机制涉及一个特定的CA1主要神经元群体，该群体受到来自内侧隔区的传入胆碱能输入的独特调节。
