Kuhn Brittany N, Cannella Nazzareno, Crow Ayteria D, Lunerti Veronica, Gupta Arkobrato, Walterhouse Stephen J, Allen Carter, Chalhoub Reda M, Dereschewitz Eric, Roberts Analyse T, Cockerham Mackenzie, Beeson Angela, Nall Rusty W, Palmer Abraham A, Hardiman Gary, Solberg Woods Leah C, Chung Dongjun, Ciccocioppo Roberto, Kalivas Peter W
bioRxiv. 2024 Aug 4:2024.02.22.581440. doi: 10.1101/2024.02.22.581440.
The behavioral and diagnostic heterogeneity within human opioid use disorder (OUD) diagnosis is not readily captured in current animal models, limiting translational relevance of the mechanistic research that is conducted in experimental animals. We hypothesize that a non-linear clustering of OUD-like behavioral traits will capture population heterogeneity and yield subpopulations of OUD vulnerable rats with distinct behavioral and neurocircuit profiles.
Over 900 male and female heterogeneous stock rats, a line capturing genetic and behavioral heterogeneity present in humans, were assessed for several measures of heroin use and rewarded and non-rewarded seeking behaviors. Using a non-linear stochastic block model clustering analysis, rats were assigned to OUD vulnerable, intermediate and resilient clusters. Additional behavioral tests and circuit analyses using c-fos protein activation were conducted on the vulnerable and resilient subpopulations.
OUD vulnerable rats exhibited greater heroin taking and seeking behaviors relative to those in the intermediate and resilient clusters. Akin to human OUD diagnosis, further vulnerable rat sub-clustering revealed subpopulations with different combinations of behavioral traits, including sex differences. Lastly, heroin cue-induced neuronal patterns of circuit activation differed between resilient and vulnerable phenotypes. Behavioral sex differences were recapitulated in patterns of circuitry activation, including males preferentially engaging extended amygdala stress circuitry, and females cortico-striatal drug cue-seeking circuitry.
Using a non-linear clustering approach in rats, we captured behavioral diagnostic heterogeneity reflective of human OUD diagnosis. OUD vulnerability and resiliency were associated with distinct neuronal activation patterns, posing this approach as a translational tool in assessing neurobiological mechanisms underpinning OUD.
目前的动物模型难以体现人类阿片类物质使用障碍（OUD）诊断中的行为和诊断异质性，这限制了在实验动物中进行的机制研究的转化相关性。我们假设，类似OUD的行为特征的非线性聚类将捕捉群体异质性，并产生具有不同行为和神经回路特征的OUD易感性大鼠亚群。
对900多只雄性和雌性异质品系大鼠（该品系捕捉了人类中存在的遗传和行为异质性）进行了多项海洛因使用及奖励和非奖励寻求行为的评估。使用非线性随机块模型聚类分析，将大鼠分为OUD易感性、中等和弹性聚类。对易感性和弹性亚群进行了额外的行为测试和使用c-fos蛋白激活的回路分析。
与中等和弹性聚类中的大鼠相比，OUD易感性大鼠表现出更多的海洛因摄取和寻求行为。与人类OUD诊断相似，进一步对易感性大鼠进行亚聚类，发现了具有不同行为特征组合的亚群，包括性别差异。最后，弹性和易感性表型之间，海洛因线索诱导的回路激活神经元模式不同。行为上的性别差异在回路激活模式中得到体现，包括雄性优先激活扩展杏仁核应激回路，而雌性优先激活皮质-纹状体药物线索寻求回路。
通过在大鼠中使用非线性聚类方法，我们捕捉到了反映人类OUD诊断的行为诊断异质性。OUD易感性和弹性与不同的神经元激活模式相关，这使得该方法成为评估OUD潜在神经生物学机制的一种转化工具。
