Oliveira Gabriela V M, Hernandes Paloma M, Santos Fábio H Dos, Soares Victor P M N, Falconi-Sobrinho Luiz Luciano, Coimbra Norberto C, Wotjak Carsten T, Almada Rafael Carvalho
Laboratory of Neurobiology and Neurobiotechnology, Department of Biological Sciences, School of Sciences, Humanities and Languages of the São Paulo State University (Unesp), Assis, São Paulo, 19806-900, Brazil.
Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.
Psychopharmacology (Berl). 2025 Mar;242(3):521-532. doi: 10.1007/s00213-024-06701-x. Epub 2024 Oct 10.
Despite the existing anatomical and physiological evidence pointing to the involvement of orexinergic projections from the lateral hypothalamus (LH) in regulating fear-related responses, little is known regarding the contribution of the orexin system in the prelimbic cortex (PL) on contextual fear.
We investigated the role of orexin-A (Orx) and orexin type 1 receptors (OrxR) in the PL during the expression of contextual conditioned fear in mice.
Neural tract tracing of the LH-PL pathway and OrxR immunoreactivity in the PL of C57BL/6 male mice were performed. In a pharmacological approach, the animals were treated with either the OrxR selective antagonist SB 334,867 (3, 30, and 300 nM/0.1 µL) or Orx (28, 70, and 140 pmol/0.1 µL) in the PL before the test session of contextual fear conditioning.
Neural tract tracing deposits in the LH showed some perikarya, mainly axons and terminal buttons in the PL, suggesting LH-PL reciprocate pathways. Furthermore, we showed a profuse network comprised of OrxR-labeled thin varicose fibers widely distributed in the same field of LH-PL pathways projection. The selective blockade of OrxR with SB 334,867 at 30 and 300 nM in the PL caused a decrease in freezing response, whereas the treatment with Orx at 140 pmol promoted an increase in freezing response.
In summary, these data confirmed an anatomical link between LH and PL, established the presence of OrxR in the PL, and a modulatory role of the orexin system in such structure, possibly mainly via OrxR, during contextual fear conditioning.
尽管现有解剖学和生理学证据表明，下丘脑外侧区（LH）的食欲素能投射参与调节恐惧相关反应，但关于食欲素系统在前边缘皮层（PL）对情境性恐惧的作用知之甚少。
我们研究了食欲素A（Orx）和1型食欲素受体（OrxR）在小鼠情境性条件性恐惧表达过程中在PL中的作用。
对C57BL/6雄性小鼠的LH-PL通路进行神经束追踪，并检测PL中的OrxR免疫反应性。在药理学方法中，在情境性恐惧条件测试前，给动物在PL中注射OrxR选择性拮抗剂SB 334,867（3、30和300 nM/0.1 μL）或Orx（28、70和140 pmol/0.1 μL）。
LH中的神经束追踪沉积物显示一些胞体，主要是PL中的轴突和终扣，提示LH-PL存在往返通路。此外，我们发现一个由OrxR标记的细曲张纤维组成的丰富网络，广泛分布在LH-PL通路投射的同一区域。在PL中用30和300 nM的SB 334,867选择性阻断OrxR导致僵住反应减少，而用140 pmol的Orx处理则促进僵住反应增加。
总之，这些数据证实了LH和PL之间的解剖学联系，确定了PL中存在OrxR，以及在情境性恐惧条件反射过程中，食欲素系统在该结构中可能主要通过OrxR发挥调节作用。
