Oprl1, also known as opioid receptor-like 1, encodes the nociceptin/orphanin FQ (N/OFQ) receptor (NOP). The N/OFQ system is an important regulator of hippocampal function, and thus Oprl1 is involved in cognitive-related biological processes [1]. It is also associated with the regulation of autophagy as ligands targeting OPRL1 can affect autophagy flux [4]. Additionally, it has connections with the body's stress-response and alcohol-related behaviors through its methylation-mediated effects [2].

In a mouse model combining maternal Western diet, prenatal environmental stress, and post-weaning Western diet (AME-WD model), an adverse maternal environment (AME) and AME-WD significantly increased the total hippocampal expression of Oprl1 and variant V4 in male offspring, concurrent with an increased accumulation of active histone marks in the promoter. This suggests that an AME and AME-WD can alter hippocampal Oprl1 expression in offspring through an epigenetic mechanism in a variant-specific and sex-specific manner, potentially contributing to cognitive impairment in adult males [1]. In mice with dysregulated fear, there was altered expression of Oprl1 within the amygdala, and systemic and central amygdala infusion of an NOP-R agonist impaired fear memory consolidation. In humans, a SNP within OPRL1 is associated with childhood trauma, PTSD symptoms, physiological startle measures of fear discrimination, and amygdala-insula functional connectivity, indicating Oprl1's association with amygdala function, fear processing, and PTSD symptoms [3].

In conclusion, Oprl1 plays crucial roles in cognitive function, fear processing, and is associated with stress-related and alcohol-related behaviors. Mouse models have been instrumental in revealing its role in cognitive impairment and PTSD-related processes, highlighting its potential as a target for understanding and treating related diseases.

References:

1. Ke, Xingrao, Huang, Yingliu, Fu, Qi, Sampath, Venkatesh, Lane, Robert H. 2022. Adverse maternal environment alters Oprl1 variant expression in mouse hippocampus. In Anatomical record (Hoboken, N.J. : 2007), 306, 162-175. doi:10.1002/ar.25056. https://pubmed.ncbi.nlm.nih.gov/35983908/

2. Ruggeri, Barbara, Macare, Christine, Stopponi, Serena, Ciccocioppo, Roberto, Schumann, Gunter. 2017. Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents. In Journal of child psychology and psychiatry, and allied disciplines, 59, 650-658. doi:10.1111/jcpp.12843. https://pubmed.ncbi.nlm.nih.gov/29197086/

3. Andero, Raül, Brothers, Shaun P, Jovanovic, Tanja, Wahlestedt, Claes, Ressler, Kerry J. . Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. In Science translational medicine, 5, 188ra73. doi:10.1126/scitranslmed.3005656. https://pubmed.ncbi.nlm.nih.gov/23740899/

4. Sanz-Martinez, Pablo, Tascher, Georg, Cano-Franco, Sara, Homan, Evert J, Stolz, Alexandra. 2024. GPCR Function in Autophagy Control: A Systematic Approach of Chemical Intervention. In Journal of molecular biology, 436, 168643. doi:10.1016/j.jmb.2024.168643. https://pubmed.ncbi.nlm.nih.gov/38848865/