Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.
The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
Transl Psychiatry. 2021 Oct 30;11(1):556. doi: 10.1038/s41398-021-01662-7.
Between adolescence and adulthood, the brain critically undergoes maturation and refinement of synaptic and neural circuits that shape cognitive processing. Adolescence also represents a vulnerable period for the onset of symptoms in neurodevelopmental psychiatric disorders. Despite the wide use of rodent models to unravel neurobiological mechanisms underlying neurodevelopmental disorders, there is a surprising paucity of rigorous studies focusing on normal cognitive-developmental trajectories in such models. Here, we sought to behaviorally capture maturational changes in cognitive trajectories during adolescence and into adulthood in male and female mice using distinct behavioral paradigms. C57 BL/6J mice (4.5, 6, and 12 weeks of age) were assessed on three behavioral paradigms: drug-induced locomotor hyperactivity, prepulse inhibition, and a novel validated version of a visuospatial paired-associate learning touchscreen task. We show that the normal maturational trajectories of behavioral performance on these paradigms are dissociable. Responses in drug-induced locomotor hyperactivity and prepulse inhibition both displayed a 'U-shaped' developmental trajectory; lower during mid-adolescence relative to early adolescence and adulthood. In contrast, visuospatial learning and memory, memory retention, and response times indicative of motivational processing progressively improved with age. Our study offers a framework to investigate how insults at different developmental stages might perturb normal trajectories in cognitive development. We provide a brain maturational approach to understand resilience factors of brain plasticity in the face of adversity and to examine pharmacological and non-pharmacological interventions directed at ameliorating or rescuing perturbed trajectories in neurodevelopmental and neuropsychiatric disorders.
在青春期到成年期之间，大脑经历了突触和神经网络的关键成熟和细化，这些过程塑造了认知处理。青春期也是神经发育性精神障碍症状出现的脆弱时期。尽管啮齿动物模型被广泛用于揭示神经发育性疾病的神经生物学机制，但令人惊讶的是，很少有严格的研究关注此类模型中正常的认知发展轨迹。在这里，我们试图使用不同的行为范式，在雄性和雌性小鼠中捕捉青春期和成年期认知轨迹的成熟变化。使用 C57BL/6J 小鼠（4.5、6 和 12 周龄）进行了三种行为范式的评估：药物诱导的运动过度活跃、前脉冲抑制和一种新颖的、经过验证的视觉空间配对联想学习触摸屏任务。我们表明，这些范式上的行为表现的正常成熟轨迹是可分离的。药物诱导的运动过度活跃和前脉冲抑制的反应都表现出“U 形”发育轨迹；与青春期早期和成年期相比，青春期中期较低。相比之下，视觉空间学习和记忆、记忆保留以及反应时间指示的动机处理随着年龄的增长而逐渐提高。我们的研究提供了一个框架，可以研究不同发育阶段的干扰如何扰乱认知发展的正常轨迹。我们提供了一种大脑成熟的方法来理解大脑可塑性的适应因素，以应对逆境，并研究针对改善或挽救神经发育和神经精神障碍中失调轨迹的药理学和非药理学干预措施。
