Mármol Contreras Yorkiris, Dvorak Nolan M, Tapia Cynthia M, Zaman Roxana, Annareddy Jyothika, Balikosa Yves, Gupta Nikita S, Rader Alex P, Vasquez Tileena E S, Koshy Shyny, Li Dingge, Balaji Varun K, Laezza Fernanda, Green Thomas A
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Dr., Medical Research Bldg 7.102c, Galveston, TX, 77555, USA.
Center for Addiction Sciences and Therapeutics, The University of Texas Medical Branch, Galveston, TX, USA.
Psychopharmacology (Berl). 2025 Jul 2. doi: 10.1007/s00213-025-06838-3.
In previous work, a convergent transcriptomic approach strongly suggested a role for retinoic acid (RA) in controlling the emotion- and reward-related functions of the nucleus accumbens shell (NAcSh).
Here, we causally assess the role of NAcSh RA in controlling anxiety-, emotion-, and reward-related behavior in rats and explore cellular mechanisms that may underlie this phenotype.
Rats underwent bilateral knockdown of the retinoic acid synthesis enzyme Aldh1a1 in the NAcSh. Anxiety-related behavior was assessed using open-field exploration, elevated plus maze, and sucrose neophobia tests. Emotion-related behavior was assessed via sucrose preference, post-isolation social contact, and forced swim tests. Animals were subsequently allowed to self-administer fentanyl to assess reward- and frustration-related behavior. In parallel, electrophysiological testing of medium spiny neurons (MSNs) in the NAcSh was used to explore the role of RA in NAcSh cellular function.
We observed an anxiety-vulnerable, depression-resilient phenotype in knockdown animals compared to controls. During operant tasks, knockdown animals took fewer fentanyl infusions during FR5 maintenance and showed decreased demand intensity in behavioral economics sessions. Finally, electrophysiological assessment of NAcSh MSNs revealed attenuated excitability following Aldh1a1 knockdown. Altogether, our findings reveal a key role for NAcSh RA signaling in determining emotional resilience and drug-taking, likely via decreased MSN excitability.
Our results posit the RA synthesis enzyme Aldh1a1 as a promising therapeutic target for depression-, frustration-, and addiction-associated disorders. This is the first report linking RA to frustrative nonreward, the NAcSh to operant frustration, and RA to fentanyl drug-taking behavior.
在之前的研究中，一种整合的转录组学方法有力地表明，视黄酸（RA）在控制伏隔核壳（NAcSh）的情绪和奖赏相关功能中发挥作用。
在此，我们通过因果关系评估NAcSh中RA在控制大鼠焦虑、情绪和奖赏相关行为中的作用，并探索可能构成这种表型基础的细胞机制。
对大鼠进行双侧NAcSh视黄酸合成酶Aldh1a1基因敲低。使用旷场探索、高架十字迷宫和蔗糖新物恐惧症测试评估焦虑相关行为。通过蔗糖偏好、隔离后社交接触和强迫游泳测试评估情绪相关行为。随后让动物自行注射芬太尼，以评估奖赏和挫折相关行为。同时，对NAcSh中的中等棘状神经元（MSNs）进行电生理测试，以探索RA在NAcSh细胞功能中的作用。
与对照组相比，我们在基因敲低动物中观察到一种焦虑易感性、抑郁抗性的表型。在操作性任务中，基因敲低动物在FR5维持期间接受的芬太尼注射较少，并且在行为经济学实验中表现出需求强度降低。最后，对NAcSh MSNs的电生理评估显示，Aldh1a1基因敲低后兴奋性减弱。总之，我们的研究结果揭示了NAcSh RA信号通路在决定情绪恢复力和药物摄取方面的关键作用，可能是通过降低MSN兴奋性实现的。
我们的结果表明视黄酸合成酶Aldh1a1是治疗与抑郁、挫折和成瘾相关疾病的一个有前景的治疗靶点。这是第一份将RA与挫折性无奖赏、NAcSh与操作性挫折以及RA与芬太尼药物摄取行为联系起来的报告。
