Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Ponce, Puerto Rico.
J Neurosci. 2010 Sep 15;30(37):12379-86. doi: 10.1523/JNEUROSCI.1295-10.2010.
Growing evidence indicates that the activity of infralimbic prefrontal cortex (IL) is critical for inhibiting inappropriate fear responses following extinction learning. Recently, we showed that fear conditioning and extinction alter the intrinsic excitability and bursting of IL pyramidal neurons in brain slices. IL neurons from Sprague Dawley rats expressing high fear had lower intrinsic excitability and bursting than those from rats expressing low fear, suggesting that regulating the intrinsic excitability and bursting of IL neurons would modulate fear expression. To test this, we combined patch-clamp electrophysiology, auditory fear conditioning, and IL infusions of M-type K(+) channel modulators. Patch-clamp recordings from IL neurons showed that the M-type K(+) channel blocker, XE-991, increased the number of spikes evoked by a depolarizing pulse and reduced the first interspike interval indicating enhanced bursting. To test whether pharmacological enhancement of IL excitability and bursting reduces fear expression and facilitates extinction, fear-conditioned rats were infused with XE-991 into IL before extinction training. XE-infused rats showed reduced freezing and facilitated extinction compared to vehicle-infused rats. The following day, recall of extinction memory was enhanced. Reducing IL excitability and bursting with the M-type K(+) channel agonist, flupirtine, had the opposite effect. Flupirtine reduced IL spike count and bursting in brain slices. Fear-conditioned rats infused with flupirtine into IL before extinction showed significantly higher levels of freezing, indicating that stimulation of M-channels enhanced fear expression. Our findings suggest that the intrinsic excitability and bursting of IL neurons regulate fear expression even before extinction.
越来越多的证据表明，扣带回下前皮质（IL）的活动对于抑制消退学习后不适当的恐惧反应至关重要。最近，我们发现，恐惧条件反射和消退会改变脑片中 IL 锥体神经元的内在兴奋性和爆发。表达高恐惧的 Sprague Dawley 大鼠的 IL 神经元的内在兴奋性和爆发性低于表达低恐惧的大鼠，这表明调节 IL 神经元的内在兴奋性和爆发性可以调节恐惧表达。为了验证这一点，我们结合了膜片钳电生理学、听觉恐惧条件反射和 IL 中 M 型 K(+)通道调节剂的输注。IL 神经元的膜片钳记录显示，M 型 K(+)通道阻断剂 XE-991 增加了去极化脉冲引起的尖峰数量，并减少了第一个尖峰间隔，表明爆发性增强。为了测试 IL 兴奋性和爆发性的药理学增强是否降低恐惧表达并促进消退，在消退训练前将 XE-991 输注到 IL 中，对恐惧条件反射的大鼠进行输注。与载体输注的大鼠相比，XE 输注的大鼠表现出更少的冻结和更易消退。第二天，增强了对消退记忆的回忆。用 M 型 K(+)通道激动剂 flupirtine 降低 IL 兴奋性和爆发性产生了相反的效果。Flupirtine 减少了脑片中的 IL 尖峰计数和爆发。在消退前将 flupirtine 输注到 IL 中的恐惧条件反射大鼠表现出明显更高水平的冻结，这表明 M 型通道的刺激增强了恐惧表达。我们的发现表明，IL 神经元的内在兴奋性和爆发性甚至在消退之前就调节着恐惧的表达。
