Flandreau Elizabeth, Risbrough Victoria, Lu Ailing, Ableitner Martin, Geyer Mark A, Holsboer Florian, Deussing Jan M
Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA.
Veterans Administration Center of Excellence for Stress and Mental Health, 3350 La Jolla Village Drive San Diego, CA 92161, USA.
Psychoneuroendocrinology. 2015 Mar;53:16-28. doi: 10.1016/j.psyneuen.2014.12.005. Epub 2014 Dec 11.
The corticotropin-releasing factor (CRF) family of peptides and receptors coordinates the mammalian endocrine, autonomic, and behavioral responses to stress. Excessive CRF production has been implicated in the etiology of stress-sensitive psychiatric disorders such as posttraumatic stress disorder (PTSD), which is associated with alterations in startle plasticity. The CRF family of peptides and receptors mediate acute startle response changes during stress, and chronic CRF activation can induce startle abnormalities. To determine what neural circuits modulate startle in response to chronic CRF activation, transgenic mice overexpressing CRF throughout the central nervous system (CNS; CRF-COE(CNS)) or restricted to inhibitory GABAergic neurons (CRF-COE(GABA)) were compared across multiple domains of startle plasticity. CRF overexpression throughout the CNS increased startle magnitude and reduced ability to inhibit startle (decreased habituation and decreased prepulse inhibition (PPI)), similar to previous reports of exogenous effects of CRF. Conversely, CRF overexpression confined to inhibitory neurons decreased startle magnitude but had no effect on inhibitory measures. Acute CRF receptor 1 (CRF1) antagonist treatment attenuated only the effects on startle induced by CNS-specific CRF overexpression. Specific deletion of CRF1 receptors from forebrain principal neurons failed to alter the effects of exogenous CRF or stress on startle, suggesting that these CRF1 expressing neurons are not required for CRF-induced changes in startle behaviors. These data indicate that the effects of CRF activation on startle behavior utilize an extensive neural circuit that includes both forebrain and non-forebrain regions. Furthermore, these findings suggest that the neural source of increased CRF release determines the startle phenotype elicited. It is conceivable that this may explain why disorders characterized by increased CRF in cerebrospinal fluid (e.g. PTSD and major depressive disorder) have distinct symptom profiles in terms of startle reactivity.
促肾上腺皮质激素释放因子（CRF）肽家族和受体协调哺乳动物对压力的内分泌、自主神经和行为反应。CRF产生过多与创伤后应激障碍（PTSD）等压力敏感性精神障碍的病因有关，PTSD与惊吓可塑性改变有关。CRF肽家族和受体介导应激期间急性惊吓反应的变化，慢性CRF激活可诱发惊吓异常。为了确定哪些神经回路在慢性CRF激活时调节惊吓反应，对在整个中枢神经系统（CNS；CRF-COE（CNS））或限于抑制性GABA能神经元（CRF-COE（GABA））中过表达CRF的转基因小鼠在惊吓可塑性的多个领域进行了比较。与先前关于CRF外源性作用的报道相似，整个中枢神经系统中CRF的过表达增加了惊吓幅度并降低了抑制惊吓的能力（习惯化降低和前脉冲抑制（PPI）降低）。相反，仅限于抑制性神经元的CRF过表达降低了惊吓幅度，但对抑制性指标没有影响。急性CRF受体1（CRF1）拮抗剂治疗仅减弱了中枢神经系统特异性CRF过表达对惊吓的影响。从前脑主要神经元中特异性删除CRF1受体未能改变外源性CRF或应激对惊吓的影响，这表明CRF诱导的惊吓行为变化不需要这些表达CRF1的神经元。这些数据表明，CRF激活对惊吓行为的影响利用了一个广泛的神经回路，该回路包括前脑和非前脑区域。此外，这些发现表明，CRF释放增加的神经来源决定了所引发的惊吓表型。可以想象，这可能解释了为什么以脑脊液中CRF增加为特征的疾病（如PTSD和重度抑郁症）在惊吓反应性方面具有不同的症状特征。
