Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Rudolf Magnus Institute of Neuroscience, Sorbonnelaan 16, 3584 CA Utrecht, Netherlands.
Neuroscience. 2011 Jan 26;173:82-92. doi: 10.1016/j.neuroscience.2010.11.026. Epub 2010 Nov 18.
Increased central corticotropin-releasing factor (CRF) signaling has been associated with various psychiatric symptoms, including anxiety, depression and psychosis. CRF signaling in both the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) has been implicated in anxiety-like behavior. In addition, repeated activation of CRF receptors within the BLA induces a chronic anxious state. Here we studied the effects of local repeated CRF infusion in the BLA and mPFC on different forms of anxiety, as assessed during light-enhanced startle (LES, general anxiety) and acquisition of fear-potentiated startle (FPS, cue-conditioned fear). In addition, as CRF has been implicated in sensorimotor gating, prepulse inhibition (PPI) was assessed to determine if local CRF infusion within the BLA or mPFC would interfere with the processing of sensory information. To this end, canulas were placed bilaterally in either the BLA or mPFC of Wistar rats. After recovery, animals were infused with h/rCRF (200 ng/side) or vehicle for five consecutive days. Long term effects of local CRF infusion on LES and acquisition of FPS were measured 4 and 10 days post-treatment, respectively. In addition, the acute (day 1), sub-chronic (day 5) and long-term (7 days post treatment) effects on PPI were measured in the same animals. A clear regional differentiation was found on the long lasting effect of CRF on anxiety-like behavior: infusion into the BLA only enhanced acquisition of FPS, whereas infusion into the mPFC only enhanced LES. Sub-chronic CRF infusion into the BLA, but not the mPFC, disrupted PPI. This disturbed PPI was normalized 7 days post-treatment. Together, the current study shows that local repeated CRF receptor activation in the BLA and mPFC is differentially involved in anxiety- and fear-related behavior. In addition, the BLA may be involved in CRF-induced sensorimotor gating deficits. The absence of a long-term effect on these PPI deficits suggests that lasting activation of CRF receptors is a prerequisite for CRF-mediated effects on sensorimotor gating. The long-term effects of repeated CRF infusion on LES and acquisition of FPS on the other hand, show that in case of anxiety-related processes repeated CRF infusion may have lasting effects.
中枢促肾上腺皮质释放因子（CRF）信号的增加与各种精神症状有关，包括焦虑、抑郁和精神病。外侧杏仁核（BLA）和内侧前额叶皮层（mPFC）中的 CRF 信号都与焦虑样行为有关。此外，BLA 内 CRF 受体的反复激活会导致慢性焦虑状态。在这里，我们研究了局部重复 CRF 输注到 BLA 和 mPFC 对不同形式的焦虑的影响，通过光增强性惊跳反应（LES，一般焦虑）和获得恐惧增强性惊跳反应（FPS，线索条件性恐惧）来评估。此外，由于 CRF 与感觉运动门控有关，因此评估了预脉冲抑制（PPI），以确定 BLA 或 mPFC 内的局部 CRF 输注是否会干扰感觉信息的处理。为此，将导管双侧放置在 Wistar 大鼠的 BLA 或 mPFC 中。恢复后，动物连续 5 天用 h/rCRF（200ng/侧）或载体输注。分别在治疗后 4 天和 10 天测量局部 CRF 输注对 LES 和 FPS 获得的长期影响。此外，在同一动物中测量了急性（第 1 天）、亚慢性（第 5 天）和长期（治疗后 7 天）对 PPI 的影响。在长期影响方面，我们发现 CRF 对焦虑样行为的影响存在明显的区域分化：BLA 内输注仅增强了 FPS 的获得，而 mPFC 内输注仅增强了 LES。BLA 内的亚慢性 CRF 输注，但不是 mPFC 内的输注，破坏了 PPI。这种受损的 PPI 在治疗后 7 天得到了纠正。总之，本研究表明，BLA 和 mPFC 中的局部重复 CRF 受体激活在焦虑和恐惧相关行为中具有不同的作用。此外，BLA 可能参与了 CRF 诱导的感觉运动门控缺陷。治疗后 7 天，这些 PPI 缺陷没有长期影响，这表明 CRF 受体的持续激活是 CRF 介导的感觉运动门控作用的前提。另一方面，重复 CRF 输注对 LES 和 FPS 获得的长期影响表明，在焦虑相关过程中，重复 CRF 输注可能会产生持久的影响。
