Departamento de Medicina, Facultad de Ciencias de La Salud, Universitat Jaume I, Castellón, Spain.
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Department of Biochemistry and Pharmacology, The University of Melbourne, Victoria, Australia.
Biochem Pharmacol. 2024 Jul;225:116264. doi: 10.1016/j.bcp.2024.116264. Epub 2024 May 4.
The retrosplenial cortex (RSC) plays a central role in processing contextual fear conditioning. In addition to corticocortical and thalamocortical projections, the RSC receives subcortical inputs, including a substantial projection from the nucleus incertus in the pontine tegmentum. This GABAergic projection contains the neuropeptide, relaxin-3 (RLN3), which inhibits target neurons via its Gi/o-protein-coupled receptor, RXFP3. To assess this peptidergic system role in contextual fear conditioning, we bilaterally injected the RSC of adult rats with an adeno-associated-virus (AAV), expressing the chimeric RXFP3 agonist R3/I5 or a control AAV, and subjected them to contextual fear conditioning. The R3/I5 injected rats did not display any major differences to control-injected and naïve rats but displayed a significantly delayed extinction. Subsequently, we employed acute bilateral injections of the specific RXFP3 agonist peptide, RXFP3-Analogue 2 (A2), into RSC. While the administration of A2 before each extinction trial had no impact on the extinction process, treatment with A2 before each acquisition trial resulted in delayed extinction. In related anatomical studies, we detected an enrichment of RLN3-immunoreactive nerve fibers in deep layers of the RSC, and a higher level of co-localization of RXFP3 mRNA with vesicular GABA transporter (vGAT) mRNA than with vesicular glutamate transporter-1 (vGLUT1) mRNA across the RSC, consistent with an effect of RLN3/RXFP3 signalling on the intrinsic, inhibitory circuits within the RSC. These findings suggest that contextual conditioning processes in the RSC involve, in part, RLN3 afferent modulation of local inhibitory neurons that provides a stronger memory acquisition which, in turn, retards the extinction process.
后隔核（RSC）在处理情境性恐惧条件反射中起着核心作用。除了皮质内和丘脑皮质投射外，RSC 还接收皮质下输入，包括来自桥脑被盖腹侧的未定核的大量投射。这个 GABA 能投射包含神经肽松弛素 3（RLN3），它通过其 Gi/o 蛋白偶联受体 RXFP3 抑制靶神经元。为了评估这种肽能系统在情境性恐惧条件反射中的作用，我们用表达嵌合 RXFP3 激动剂 R3/I5 或对照 AAV 的腺相关病毒（AAV）双侧注射成年大鼠的 RSC，并对它们进行情境性恐惧条件反射。R3/I5 注射的大鼠与对照注射和未处理的大鼠没有明显的差异，但表现出明显的延迟消退。随后，我们采用特异性 RXFP3 激动肽 RXFP3-Analogue 2（A2）的急性双侧注射来研究 RSC。虽然在每次消退试验前给予 A2 对消退过程没有影响，但在每次获得试验前给予 A2 处理会导致延迟消退。在相关的解剖学研究中，我们在 RSC 的深层中检测到 RLN3 免疫反应性神经纤维的富集，并且 RXFP3 mRNA 与囊泡 GABA 转运体（vGAT）mRNA 的共定位水平高于与囊泡谷氨酸转运体-1（vGLUT1）mRNA，这与 RLN3/RXFP3 信号对 RSC 内固有抑制性回路的影响一致。这些发现表明，RSC 中的情境性条件反射过程部分涉及 RLN3 传入对局部抑制性神经元的调制，从而提供更强的记忆获取，进而延迟消退过程。
